Neurocognitive sequelae of antenatal corticosteroids in a late preterm rabbit model.

BACKGROUND: Late preterm birth is associated with short-term respiratory and adaptive problems. Although antenatal corticosteroids seem to reduce the respiratory burden, this may come at the cost of adverse neuropsychological outcomes later in life. This impact has not been investigated. OBJECTIVE: Herein, we investigate what the short- and long-term neurodevelopmental effects of a single course of betamethasone in simulated late preterm birth. STUDY DESIGN: Time-mated pregnant does received 0.1 mg/kg betamethasone (n=8) or 1 mL saline intramuscular (n=6) at the postconceptional ages of 28 and 29 days. The antenatal corticosteroid dose and scheme were based on previous studies and were comparable with routine clinical use. Cesarean delivery was done on postconceptional age 30 days (term=31 days), and new-born rabbits were foster-cared for 28 days and were thereafter cared for in group housing. Neonatal lung function testing and short-term neurobehavioral testing was done. Open field, spontaneous alternation, and novel object recognition tests were subsequently performed at 4 and 8 weeks of age. On postnatal day 1 and at 8 weeks, a subgroup was euthanized and transcardially perfuse fixated. Ex vivo high-resolution Magnetic Resonance Imaging was used to calculate the Diffusion Tensor Imaging-derived fractional anisotropy and mean diffusivity. Fixated brains underwent processing and were serial sectioned, and a set of 3 coronal sections underwent anti-NeuN, Ki67, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. RESULTS: Antenatal corticosteroid exposure was associated with improved neonatal lung function, yet resulted in a long-term growth deficit that coincided with a persistent neurobehavioral deficit. We demonstrated lower neonatal motor scores; a persistent anxious behavior in the open field test with more displacements, running, and self-grooming episodes; persistent lower alternation scores in the T-Maze test; and lower discriminatory indexes in the novel object recognition. On neuropathological assessment, antenatal corticosteroid exposure was observed to result in a persistent lower neuron density and fewer Ki67+ cells, particularly in the hippocampus and the corpus callosum. This coincided with lower diffusion tensor imaging-derived fractional anisotropy scores in the same key regions. CONCLUSION: Clinical equivalent antenatal corticosteroid exposure in this late preterm rabbit model resulted in improved neonatal lung function. However, it compromised neonatal and long-term neurocognition.

Neurodevelopmetal effects of maternal blood pressure management with noradrenaline during general anaesthesia for nonobstetric surgery in the pregnant rabbit model.

In pregnant women, anaesthesia-induced hypotension is commonly treated using phenylephrine or noradrenaline, the rationale being to maintain uterine perfusion pressure and thereby uterine blood flow. Evidence for this strategy during general anaesthesia for nonobstetric surgery is absent. To analyse the effects of treating anaesthesia-induced hypotension with noradrenaline on brain development of rabbit foetuses of mothers subjected to general anaesthesia for nonobstetric surgery. We hypothesised that treatment of maternal hypotension would improve foetal outcomes. Randomised controlled laboratory study using 21 pregnant rabbits (does) at 28 days of gestation. Two hours of sevoflurane anaesthesia for a laparotomy without treatment of anaesthesia-induced hypotension (hypotension group) or with maintaining maternal mean arterial pressure above 80% of the awake value using noradrenaline (noradrenaline group). In the control group, does remained untouched. At term, all pups were delivered by caesarean section. One day later, the neurobehaviour of the pups was assessed and brains were harvested. Neuron density in the frontal cortex for the comparison of noradrenaline groups versus hypotension groups was the primary outcome; the neurobehavioural scores and other histological outcomes were secondary outcomes. In the noradrenaline groups and hypotension groups, neuron density in the frontal cortex was similar (1181 ±â€Š162 versus 1189 ±â€Š200 neurons mm-2, P  = 0.870). However, significantly less foetal survival, lower sensory scores in neurobehavioural assessment and less proliferation were observed in the noradrenaline group when compared with the hypotension group. Neuron densities in other regions, total cell densities, biometrics and synaptogenesis were not affected. There were no differences between the control group and hypotension group. During general anaesthesia for nonobstetric surgery in rabbits, treatment of anaesthesia-induced hypotension using noradrenaline did not affect neuron densities but was associated with impaired foetal outcomes according to several secondary outcome parameters. Further studies are needed to investigate any clinical relevance and to determine the target blood pressure in pregnant women during general anaesthesia.KEY POINTSIn pregnant women, anaesthesia-induced hypotension is commonly treated using phenylephrine or noradrenaline, with the rationale to maintain uterine perfusion pressure and thereby uterine blood flow.Evidence for this strategy during general anaesthesia for nonobstetric surgery is absent.We investigated the effects of treating anaesthesia-induced hypotension with noradrenaline on the brain development of rabbit foetuses, of mothers subjected to general anaesthesia for nonobstetric surgery.We hypothesised that treatment of maternal hypotension would improve foetal outcomes.Neuron densities were similar but significantly less foetal survival, impaired neurobehaviour and less proliferation were observed after treatment of anaesthesia-induced hypotension with noradrenaline, compared with untreated hypotension.

Ultrasound-Guided Extraction of Intrauterine Devices With Nonvisible Threads: 254 Consecutive Cases: An Effective, Noninvasive Technique.

Intrauterine devices (IUDs) are among the most efficient and widely used contraceptive methods available. Removal is recommended after a certain time or in some cases when adverse effects are observed. A considerable number of patients have nonvisible guides or "lost threads" on speculum examinations, hindering the extraction. In this article, we report a consecutive series of 254 nonpregnant patients referred to our center after 1 or more failed attempts at IUD removal. We describe a novel ultrasound-guided approach, using a laparoscopic forceps to safely and effectively remove IUDs in nonpregnant patients.

Correlation between Maternal Characteristics during Early Pregnancy, Fetal Growth Rate and Newborn Weight in Healthy Pregnancies.

BACKGROUND: The objective of this study was to evaluate the association between maternal characteristics in early pregnancy and fetal growth (FG) and birth weight (BW). METHODS: A prospective cohort study was performed in unselected pregnant women who attended an ultrasound evaluation at 11-14 weeks of pregnancy. Medical history, biochemical blood tests, biophysical variables and fetal weight at 20-25 and 30-36 weeks as well as the BW were assessed. Bivariate and multivariate linear models were constructed. RESULTS: In all, 543 patients with normal pregnancy and labor were selected. The multiple regression analysis showed a statistically significant association between maternal body mass index (BMI) in early pregnancy and the uterine artery pulsatility index (UtAPI) in the first trimester with BW (p < 0.0008) and with the ratio of fetal growth between the second and third trimesters (p < 0.0001). No correlation was found between these variables and first trimester levels of hemoglobin or glycemia. CONCLUSION: Maternal first trimester BMI and UtAPI correlate with the rate of intrauterine FG and with the BW. This evidence highlights the influence of maternal first trimester variables on fetuses with normal growth and the potential role of these variables in fetal programming.

Novel methodology for detecting and localizing cancer area in histopathological images based on overlapping patches.

Cancer disease is one of the most important pathologies in the world, as it causes the death of millions of people, and the cure of this disease is limited in most cases. Rapid spread is one of the most important features of this disease, so many efforts are focused on its early-stage detection and localization. Medicine has made numerous advances in the recent decades with the help of artificial intelligence (AI), reducing costs and saving time. In this paper, deep learning models (DL) are used to present a novel method for detecting and localizing cancerous zones in WSI images, using tissue patch overlay to improve performance results. A novel overlapping methodology is proposed and discussed, together with different alternatives to evaluate the labels of the patches overlapping in the same zone to improve detection performance. The goal is to strengthen the labeling of different areas of an image with multiple overlapping patch testing. The results show that the proposed method improves the traditional framework and provides a different approach to cancer detection. The proposed method, based on applying 3x3 step 2 average pooling filters on overlapping patch labels, provides a better result with a 12.9% correction percentage for misclassified patches on the HUP dataset and 15.8% on the CINIJ dataset. In addition, a filter is implemented to correct isolated patches that were also misclassified. Finally, a CNN decision threshold study is performed to analyze the impact of the threshold value on the accuracy of the model. The alteration of the threshold decision along with the filter for isolated patches and the proposed method for overlapping patches, corrects about 20% of the patches that are mislabeled in the traditional method. As a whole, the proposed method achieves an accuracy rate of 94.6%. The code is available at https://github.com/sergioortiz26/Cancer_overlapping_filter_WSI_images.

End-tidal concentration of sevoflurane for optimal surgical conditions in pregnant sheep: a pragmatic approach to a retrospective observational study.

The aim of this pragmatic approach to retrospective observational study was to identify the end-tidal concentration of sevoflurane which was associated with optimal surgical conditions (i.e., absence of any movement, coughing and straining) in 127 pregnant sheep. Optimal surgical conditions were observed in 90% of the ewes with an end-tidal concentration of sevoflurane of 2.4 Vol-% [95% CI: 2.2; 2.8] during minimal-mild nociceptive stimuli (placement of arterial catheter, bladder catheter, shaving), with 4.4 Vol-% [95% CI: 4.0; 5.2] during maternal laparotomy and hysterotomy and with 4.4 Vol-% [95% CI: 3.9; 5.8] during subsequent manipulation of the uterus and fetal surgery.

The Effects of Prenatal Pravastatin Treatment in the Rabbit Fetal Growth Restriction Model.

Fetal growth restriction (FGR) remains without an effective prenatal treatment. Evidence from murine FGR models suggests a beneficial effect of prenatal pravastatin. Since the rabbit hemodichorial placenta more closely resembles the human condition, we investigated the effects of prenatal maternal pravastatin administration in the rabbit FGR model. At a gestational age of 25 days (term 31d), pregnant dams underwent partial uteroplacental vessel ligation (UPVL) in one uterine horn to induce FGR, leaving the other horn as a control. Dams were randomized to either receive 5 mg/kg/d pravastatin dissolved in their drinking water or normal drinking water until delivery. At GA 30d, the rabbits were delivered and were divided into four groups: control without pravastatin (C/NoPrav), FGR without pravastatin (FGR/NoPrav), FGR with pravastatin (FGR/Prav), and controls with pravastatin (C/Prav). The newborn rabbits underwent pulmonary functional assessment and neurobehavioral assessment, and they were harvested for alveolar morphometry or neuropathology. The placentas underwent histology examination and RNA expression. Birth weight was lower in the FGR groups (FGR/Prav, FGR/NoPrav), but there was no difference between FGR/Prav and C/NoPrav. No differences were noted in placental zone proportions, but eNOS in FGR/Prav placentas and VEGFR-2 in FGR/Prav and C/Prav were upregulated. There were no differences in pulmonary function assessment and alveolar morphometry. FGR/Prav kittens had increased neurosensory scores, but there were no differences in neuromotor tests, neuron density, apoptosis, and astrogliosis. In conclusion, in the rabbit FGR model, pravastatin upregulated the expression of VEGFR-2 and eNOS in FGR placentas and was associated with higher neurosensory scores, without measurable effects on birthweight, pulmonary function and morphology, and neuron density.

Fetal Growth Restriction Impairs Lung Function and Neurodevelopment in an Early Preterm Rabbit Model.

We previously reported the multi-system sequelae of fetal growth restriction, induced by placental underperfusion, in near-term born rabbits, in the immediate neonatal period and up to pre-adolescence. Herein, we describe the pulmonary and neurodevelopmental consequences of FGR in rabbits born preterm. We hypothesize that FGR has an additional detrimental effect on prematurity in both pulmonary function and neurodevelopment. FGR was induced at gestational day (GD) 25 by placental underperfusion, accomplished by partial uteroplacental vessel ligation in one uterine horn. Rabbits were delivered by cesarean section at GD 29, and placentas were harvested for histology. Neonates underwent neurobehavioral or pulmonary functional assessment at postnatal day 1, followed by brain or lung harvesting, respectively. The neurodevelopmental assessment included neurobehavioral testing and multiregional quantification of cell density and apoptosis in the brain. Lung assessment included functional testing, alveolar morphometry, and airway histology. FGR was associated with higher perinatal mortality, lower birth and placental weight, and a similar brain-to-body weight ratio compared to controls. Placental underperfusion decreased labyrinth and junction zone volumes in FGR placentas. FGR impaired pulmonary function, depicted by higher parenchymal resistance, damping, and elastance. Alveolar morphometry and airway smooth muscle content were comparable between groups. Neurobehavioral tests showed motoric and sensorial impairment in FGR rabbits. In FGR brains, cell density was globally reduced, with higher apoptosis in selected areas. In conclusion, in preterm-born rabbits, placental underperfusion leads to higher mortality, FGR, and impaired lung and brain development in early assessment. This study complements previous findings of placental, pulmonary, and neurodevelopmental impairment in near-term born rabbits in this model.

Long-term pulmonary and neurodevelopmental impairment in a fetal growth restriction rabbit model.

Fetal growth restriction (FGR) remains one of the main obstetrical problems worldwide, with consequences beyond perinatal life. Animal models with developmental and structural similarities to the human are essential to understand FGR long-term consequences and design novel therapeutic strategies aimed at preventing or ameliorating them. Herein, we described the long-term consequences of FGR in pulmonary function, structure, and gene expression, and characterized neurodevelopmental sequelae up to preadolescence in a rabbit model. FGR was induced at gestational day 25 by surgically reducing placental blood supply in one uterine horn, leaving the contralateral horn as internal control. Neonatal rabbits born near term were assigned to foster care in mixed groups until postnatal day (PND) 21. At that time, one group underwent pulmonary biomechanical testing followed by lung morphometry and gene expression analysis. A second group underwent longitudinal neurobehavioral assessment until PND 60 followed by brain harvesting for multiregional oligodendrocyte and microglia quantification. FGR was associated with impaired pulmonary function and lung development at PND 21. FGR rabbits had higher respiratory resistance and altered parenchymal biomechanical properties in the lungs. FGR lungs presented thicker alveolar septal walls and reduced alveolar space. Furthermore, the airway smooth muscle content was increased, and the tunica media of the intra-acinar pulmonary arteries was thicker. In addition, FGR was associated with anxiety-like behavior, impaired memory and attention, and lower oligodendrocyte proportion in the frontal cortex and white matter. In conclusion, we documented and characterized the detrimental pulmonary function and structural changes after FGR, independent of prematurity, and beyond the neonatal period for the first time in the rabbit model, and describe the oligodendrocyte alteration in pre-adolescent rabbit brains. This characterization will allow researchers to develop and test therapies to treat FGR and prevent its sequelae.

Development and validation of a flexible fetoscope for fetoscopic laser coagulation.

PURPOSE: Fetoscopic laser coagulation for twin-to-twin transfusion syndrome is challenging for anterior placenta due to the rigidity of current tools. The capacity to keep entry port forces minimal is critical for this procedure, as is optimal coagulation distance and orientation. This work introduces technological tools to this end. METHODS: A novel fetoscope is presented with a rigid shaft and a flexible steerable segment at the distal end. The steerable segment can bend up to 90[Formula: see text] even when loaded with a laser fiber. An artificial pneumatic muscle makes such acute bending possible while allowing for a low-weight and disposable device. RESULTS: The flexible fetoscope was validated in a custom-made phantom model to measure visual range and coagulation efficacy. The flexible fetoscope shows promising results when compared to a clinical rigid curved fetoscope to reach anterior targets. The new fetoscope was then evaluated in vivo (pregnant ewe) where it successfully coagulated placental vasculature. CONCLUSION: The flexible fetoscope improved the ability to achieve optimal coagulation angle and distance on anteriorly located targets. The fetoscope also showed the potential to lead fetoscopic laser coagulation and other fetal surgical procedures toward safer and more effective interventions.

Duration of fetoscopic spina bifida repair does not affect the central nervous system in fetal lambs.

BACKGROUND: Prenatal spina bifida aperta repair improves neurologic outcomes yet comes with a significant risk of prematurity and uterine scar-related complications. To reduce such complications, different fetoscopic techniques, for example, with varying numbers of ports, are being explored. This has an effect on the duration of the procedure, potentially affecting central nervous system development. Both the condition and anesthesia can affect the central nervous system, particularly the hippocampus, a region crucial for prospective and episodic memory. Previous animal studies have shown the potential influence of anesthesia, premature delivery, and maternal surgery during pregnancy on this area. OBJECTIVE: This study aimed to compare the effects of 2- vs 3-port fetoscopic spina bifida aperta repair in the fetal lamb model using neuron count of the hippocampus as the primary outcome. STUDY DESIGN: Based on the hippocampal neuron count from previous lamb experiments, we calculated that we required 5 animals per group to achieve a statistical power of ≥ 80%. A spina bifida aperta defect was developed in fetal lambs at 75 days of gestation (term: 145 days). At 100 days, fetuses underwent either a 2-port or 3-port fetoscopic repair. At 143 days, all surviving fetuses were delivered by cesarean delivery, anesthetized, and transcardially perfused with a mixture of formaldehyde and gadolinium. Next, they underwent neonatal brain and spine magnetic resonance imaging after which these organs were harvested for histology. Hippocampus, frontal cortex, caudate nucleus, and cerebellum samples were immunostained to identify neurons, astrocytes, microglia, and markers associated with cell proliferation, myelination, and synapses. The degree of hindbrain herniation and the ventricular diameter were measured on magnetic resonance images and volumes of relevant brain and medulla areas were segmented. RESULTS: Both treatment groups included 5 fetuses and 9 unoperated littermates served as normal controls. The durations for both skin-to-skin (341±31 vs 287±40 minutes; P=.04) and fetal surgery (183±30 vs 128±22; P=.01) were longer for the 2-port approach than for the 3-port approach. There was no significant difference in neuron density in the hippocampus, frontal cortex, and cerebellum. In the caudate nucleus, the neuron count was higher in the 2-port group (965±156 vs 767±92 neurons/mm2; P=.04). There were neither differences in proliferation, astrogliosis, synaptophysin, or myelin. The tip of the cerebellar vermis was closer to the foramen magnum in animals undergoing the 2-port approach than in animals undergoing the 3-port approach (-0.72±0.67 vs -2.47±0.91 mm; P=.009). There was no significant difference in the ratio of the hippocampus, caudate nucleus, or cerebellar volume to body weight. For the spine, no difference was noted in spine volume-to-body weight ratio for the lower (L1-L2), middle (L3-L4), and higher (L5-L6) levels. Compared with controls, in repaired animals, the cerebellar vermis tip laid closer to the foramen magnum, parietal ventricles were enlarged, and medulla volumes were reduced. CONCLUSION: In the experimental spina bifida fetal lamb model, a 2-port repair took 40% longer than a 3-port repair. However, there was no indication of any relevant morphologic differences in the fetal brain.

Effects of cumulative duration of repeated anaesthesia exposure on foetal brain development in the ovine model.

OBJECTIVE: Anaesthesia is required in 0.4-1% of pregnant women, and prolonged and repeated exposures to anaesthesia may be required. It is unknown whether these exposures may result in foetal neurotoxicity in humans. As sheep have a gestation comparable to that of humans, the objective of this study was to analyse the neurodevelopmental outcome of ovine foetuses that had been exposed in utero to repeated and prolonged anaesthesia. DESIGN: Randomized controlled preclinical study. SETTING: Anaesthesia for non-obstetric surgery during pregnancy. ANIMALS: Twenty-four healthy pregnant Swifter ewes. INTERVENTIONS: The ewes were randomized to no anaesthesia exposure (control-group), single exposure (at gestational age 68-70 days), or repeated exposure (at gestational age 68-70 days and 96-98 days) to 2.5 h of sevoflurane anaesthesia and maternal laparotomy. All lambs were delivered at approximately term gestation (gestational age: 140-143 days). MEASUREMENTS: The primary outcome was neuron density in the frontal cortex 24 h after birth for the control-group versus the repeated-exposure-group. Key secondary outcome was the time needed to achieve the milestone of standing. Secondary outcomes included other neurobehavioural assessments (e.g., motoric milestones) and histological parameters quantified in multiple brain regions (neuron density, total cell density, proliferation, inflammation, synaptogenesis, astrocytes and myelination). MAIN RESULTS: Neuron density in the frontal cortex did not differ between groups (mean ±â€¯standard deviation: control-group: 403 ±â€¯39, single-exposure group: 436 ±â€¯23 and repeated-exposure-group: 403 ±â€¯40 neurons/mm2, control-group versus repeated-exposure-group: p = 0.986, control-group versus single-exposure-group: p = 0.097). No significant difference was observed for the time needed to achieve the milestone of standing. Only very limited differences were observed for other histological outcome parameters and neurobehavioural assessments. CONCLUSIONS: There is no evidence for foetal neuronal injury or neurobehavioural impairments after a cumulative duration of 5 h repetitive prenatal anaesthesia in sheep.

Fetal evaluation of the modified-myocardial performance index in pregnancies complicated by diabetes.

OBJECTIVE: To evaluate the fetal cardiac function by modified myocardial performance index (Mod-MPI) in pregnant diabetic patients. METHODS: Modified myocardial performance index was measured in fetuses of patients with diabetes (DM) between 30 and 40 weeks of gestation. The isovolumetric contraction time, isovolumetric relaxation time and ejection time were measured. Mod-MPI was calculated as (isovolumetric contraction time + isovolumetric relaxation time)/ejection time. Results were analyzed by using one-way analysis of variance (post hoc Bonferroni correction), Chi-square and Student's test. RESULTS: Modified myocardial performance index values of fetuses from DM mothers were significantly higher than controls (0.43 vs 0.37, P < 0.0001), and it was not different between gestational versus pregestational DM (0.42 vs 0.45, P = 0.18). Mod-MPI was also higher in the presence of polyhydramnios (0.49 vs 0.41, P < 0.0001), insulin use (0.46 vs 0.40, P < 0.05), and large for gestational age fetuses (0.49 vs 0.40, P < 0.0001). There were no significant differences in Mod-MPI between newborns with versus without neonatal complications such as hypoglycemia or polycythemia. CONCLUSIONS: In fetuses of DM mothers, evaluation of the Mod-MPI identifies those with worse maternal disease and large fetal size.

Prenatal interventions for fetal growth restriction in animal models: A systematic review.

Fetal growth restriction (FGR) in human pregnancy is associated with perinatal mortality, short- and long-term morbidities. No prenatal therapy is currently established despite decades of research. We aimed to review interventions in animal models for prenatal FGR treatment, and to seek the next steps for an effective clinical therapy. We registered our protocol and searched MEDLINE, Embase, and The Cochrane Library with no language restrictions, in accordance with the PRISMA guideline. We included all studies that reported the effects of any prenatal intervention in animal models of induced FGR. From 3257 screened studies, 202 describing 237 interventions were included for the final synthesis. Mice and rats were the most used animals (79%) followed by sheep (16%). Antioxidants (23%), followed by vasodilators (18%), nutrients (14%), and immunomodulators (12%) were the most tested therapy. Two-thirds of studies only reported delivery or immediate neonatal outcomes. Adverse effects were rarely reported (11%). Most studies (73%), independent of the intervention, showed a benefit in fetal survival or birthweight. The risk of bias was high, mostly due to the lack of randomization, allocation concealment, and blinding. Future research should aim to describe both short- and long-term outcomes across various organ systems in well-characterized models. Further efforts must be made to reduce selection, performance, and detection bias.

Fetal surgery has no additional effect to general anesthesia on brain development in neonatal rabbits.

BACKGROUND: Fetal surgery is part of modern fetal medicine, and some procedures, such as fetal spina bifida repair, are performed under general anesthesia. Fetuses are operated on in a time window when the developing brain is extremely vulnerable to external, potentially harmful factors. To date, little is known about the effect of fetal surgery on fetal brain development. OBJECTIVE: This study aimed to assess the effect of fetal surgery on the developing fetal brain in the rabbit model. STUDY DESIGN: This was a randomized, sham-controlled study in time-mated pregnant does at 28 days' gestation (term, 31 days), which corresponds to the start of the peak of brain development and end of the second trimester of pregnancy in humans. We included 4 different groups in this experiment: no-surgery, general anesthesia, general anesthesia+hysterotomy, and general anesthesia+fetal surgery. In 11 does, anesthesia was induced using propofol and maintained for 75 minutes with 3.6 vol% (4% is the equivalent of 1 minimum alveolar concentration) sevoflurane. Maternal blood pressure, heart rate, oxygen saturation, temperature, end-tidal CO2 were continuously monitored. For each operated doe, 6 fetuses were part of the experiment. Randomization determined which cornual sac and what opposing third sac were assigned to fetal surgery: hysterotomy, fetal injection (atropine, fentanyl, and cisatracurium), fetal skin incision, and suturing. Only hysterotomy was performed on the opposing cornual and third amniotic sacs of the does. The fetus in these experimental sacs was used as internal unmanipulated control (general anesthesia). All fetuses (n=38) from unmanipulated does (n=4) served as external controls (no-surgery). At term, the does were delivered by cesarean delivery under ketamine-medetomidine sedation and local anesthesia. The pups underwent standardized motoric and sensory neurologic testing on day 1 followed by euthanasia and brain harvesting for histologic assessment of neurons, synapses, proliferation, and glial cells. RESULTS: Maternal vital signs were stable during surgery. Survival was similar in the 4 groups (75%-94%), and brain-to-body weight ratio was comparable; only the no-surgery pups had a higher brain weight. On postnatal day 1, the pups in the 4 groups had a comparable neurobehavioral outcome on both motoric and sensory testing. In the prefrontal cortex, no-surgery pups had significantly higher neuron density than pups who underwent maternal surgery, but there was no difference among pups that underwent general anesthesia, hysterotomy, or fetal surgery. The measurements of proliferation had a similar outcome: a higher proliferation rate in the prefrontal cortex of no-surgery pups. Moreover, synaptic density values were higher in the no-surgery pups, but there was no difference observed among pups who underwent general anesthesia, hysterotomy, and fetal surgery. Lastly, there was no difference in gliosis among the 4 groups. CONCLUSION: In rabbits, fetal surgery through hysterotomy under maternal general anesthesia did not affect brain development, in addition to the effects of general anesthesia per se.

Placental vascular alterations are associated with early neurodevelopmental and pulmonary impairment in the rabbit fetal growth restriction model.

Fetal growth restriction is one of the leading causes of perinatal mortality and morbidity and has consequences that extend well beyond the neonatal period. Current management relies on timely delivery rather than improving placental function. Several prenatal strategies have failed to show benefit in clinical trials after promising results in animal models. Most of these animal models have important developmental and structural differences compared to the human and/or are insufficiently characterized. We aimed to describe placental function and structure in an FGR rabbit model, and to characterize the early brain and lung developmental morbidity using a multimodal approach. FGR was induced in time-mated rabbits at gestational day 25 by partial uteroplacental vessel ligation in one horn. Umbilical artery Doppler was measured before caesarean delivery at gestational day 30, and placentas were harvested for computed microtomography and histology. Neonates underwent neurobehavioral or pulmonary functional assessment the day after delivery, followed by brain or lung harvesting, respectively. Neuropathological assessment included multiregional quantification of neuron density, apoptosis, astrogliosis, cellular proliferation, and oligodendrocyte progenitors. Brain region volumes and diffusion metrics were obtained from ex-vivo brain magnetic resonance imaging. Lung assessment included biomechanical tests and pulmonary histology. Fetal growth restriction was associated with labyrinth alterations in the placenta, driven by fetal capillary reduction, and overall reduced vessels volume. FGR caused altered neurobehavior paralleled by regional neuropathological deficits and reduced fractional anisotropy in the cortex, white matter, and hippocampus. In addition, FGR kittens presented functional alterations in the peripheral lung and structurally underdeveloped alveoli. In conclusion, in a uteroplacental insufficiency FGR rabbit model, placental vascular alterations coincide with neurodevelopmental and pulmonary disruption.

Assessments of Ceanothanes Triterpenes as Cholinesterase Inhibitors: An Investigation of Potential Agents with Novel Inspiration for Drug Treatment of Neurodegenerative Diseases.

The purpose of this study was to determine the inhibitory capacity of ceanothanes triterpenes isolate from Chilean Rhamnaceae on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Seven ceanothanes triterpenes were isolated from aerial parts of plant material by classical phytochemical methods or prepared by the hemisynthetic method. Structures were determined by the spectroscopic method (1H-NMR and 13C NMR) and mass spectrometry (MS). AChE and BChE activity were determined by the Ellmann method for all compounds. All tested compounds exerted a greater affinity to AChE than to BChE, where compound 3 has an IC50 of 0.126 uM for AChE and of >500 uM to BChE. Kinetic studies indicated that its inhibition was competitive and reversible. According to the molecular coupling and displacement studies of the propidium iodide test, the inhibitory effect of compound 3 would be produced by interaction with the peripheral anionic site (PAS) of AChE. The compounds tested (1−7) showed an important inhibitory activity of AChE, binding to PAS. Therefore, inhibitors that bind to PAS would prevent the formation of the AChE-Aß complex, constituting a new alternative in the treatment of Alzheimer's disease (AD).

Daily Intraperitoneal Administration of Rosiglitazone Does Not Improve Lung Function or Alveolarization in Preterm Rabbits Exposed to Hyperoxia.

Thiazolidinediones (TZDs) are potent PPARγ agonists that have been shown to attenuate alveolar simplification after prolonged hyperoxia in term rodent models of bronchopulmonary dysplasia. However, the pulmonary outcomes of postnatal TZDs have not been investigated in preterm animal models. Here, we first investigated the PPARγ selectivity, epithelial permeability, and lung tissue binding of three types of TZDs in vitro (rosiglitazone (RGZ), pioglitazone, and DRF-2546), followed by an in vivo study in preterm rabbits exposed to hyperoxia (95% oxygen) to investigate the pharmacokinetics and the pulmonary outcomes of daily RGZ administration. In addition, blood lipids and a comparative lung proteomics analysis were also performed on Day 7. All TZDs showed high epithelial permeability through Caco-2 monolayers and high plasma and lung tissue binding; however, RGZ showed the highest affinity for PPARγ. The pharmacokinetic profiling of RGZ (1 mg/kg) revealed an equivalent biodistribution after either intratracheal or intraperitoneal administration, with detectable levels in lungs and plasma after 24 h. However, daily RGZ doses of 1 mg/kg did not improve lung function in preterm rabbits exposed to hyperoxia, and daily 10 mg/kg doses were even associated with a significant lung function worsening, which could be partially explained by the upregulation of lung inflammation and lipid metabolism pathways revealed by the proteomic analysis. Notably, daily postnatal RGZ produced an aberrant modulation of serum lipids, particularly in rabbit pups treated with the 10 mg/kg dose. In conclusion, daily postnatal RGZ did not improve lung function and caused dyslipidemia in preterm rabbits exposed to hyperoxia.

Foetal therapies and their influence on preterm birth.

Foetal therapy aims to improve perinatal survival or to prevent severe long-term handicap. Foetal medicine opens a new territory by treating the foetus as a patient. The mother has nothing to gain in terms of health benefits, yet she is inherently also undergoing treatment. In utero foetal interventions can be divided into ultrasound-guided minimally invasive procedures, fetoscopic procedures and open hysterotomy procedures, which carry an inherent risk of ruptured membranes and preterm birth. In this review, we summarise the conditions that may benefit from foetal therapy and review the current therapies on offer, each with their associated risk of ruptured membrane and preterm birth. We also look into some risk limiting and preventative strategies to mitigate these complications.