Evaluating changes in GABAergic and glutamatergic pathways in early life following prenatal stress and postnatal neurosteroid supplementation.

BACKGROUND: A correct balance of activity of the GABA and glutamate systems is vital for optimal neurodevelopment and general CNS function, and the dysregulation of this balance has been implicated in a number of neurological conditions. Maternal exposure to stressors is known to have long lasting, deleterious impacts on neurobehaviour, and similarly, results in dysregulation of inhibitory and excitatory pathways in the offspring. The current study aimed to examine effects on these pathways in a guinea pig model of prenatal stress and to elucidate whether increased neuroprotective support by postnatal neurosteroid supplementation would ameliorate adverse outcomes. METHODS: Prenatal stress was achieved by exposing pregnant guinea pigs dams to a strobe light for 2hrs/day on gestational age (GA) 50, 55, 60 and 65. Dams were allowed to spontaneously deliver (~GA70) and pups were orally administered either allopregnanolone analogue, ganaxolone (5 mg/kg/day in 45% cyclodextrin), the translocator protein (TSPO) agonist, emapunil (XBD173; 0.3 mg/kg/day in 1% tragacanth gum) or vehicle on postnatal days (PND) 1-7. Hippocampal samples were collected at PND30 to measure relative mRNA expression of components involved in the inhibitory GABAergic pathway and exctitatory glutamatergic pathway by real-time PCR. GABAergic interneurons were quantified by assessing immunohistochemical protein expression of markers parvalbumin, calbindin and calretinin. RESULTS: mRNA expression of GABAergic pathway components at one week of age indicated immature expression profiles of the GABAA receptors as well as decreased GABA synthesis and transport suggesting reduced extrasynaptically-mediated tonic inhibition. Expression profiles of the pathways examined evolved between one week and one month of age but an imbalance in inhibitory/excitatory components persisted. The allopregnanolone analogue ganaxolone offered some protection against excitotoxicity in female hippocampus, however neurosteroid supplementation with ganaxolone or emapunil were unable to fully correct the GABAergic/glutamatergic imbalance observed following prenatal stress. CONCLUSION: Prenatal stress leads to programmed lasting effects on the major inhibitory and excitatory pathways in the guinea pig brain that continue evolving between the equivalent of early and late childhood. Neurosteroid therapies particularly improved outcomes in females. Further studies are required to identify additional therapeutic targets that are able to fully restore imbalances in the excitatory and inhibitory systems, which may act to prevent development of childhood behavioural disorders.

Prehabilitation in adult patients undergoing surgery: an umbrella review of systematic reviews.

BACKGROUND: The certainty that prehabilitation improves postoperative outcomes is not clear. The objective of this umbrella review (i.e. systematic review of systematic reviews) was to synthesise and evaluate evidence for prehabilitation in improving health, experience, or cost outcomes. METHODS: We performed an umbrella review of prehabilitation systematic reviews. MEDLINE, Embase, Cochrane, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Joanna Briggs Institute's database, and Web of Science were searched (inception to October 20, 2020). We included all systematic reviews of elective, adult patients undergoing surgery and exposed to a prehabilitation intervention, where health, experience, or cost outcomes were reported. Evidence certainty was assessed using Grading of Recommendations Assessment, Development and Evaluation. Primary syntheses of any prehabilitation were stratified by surgery type. RESULTS: From 1412 titles, 55 systematic reviews were included. For patients with cancer undergoing surgery who participate in any prehabilitation, moderate certainty evidence supports improvements in functional recovery. Low to very low certainty evidence supports reductions in complications (mixed, cardiovascular, and cancer surgery), non-home discharge (orthopaedic surgery), and length of stay (mixed, cardiovascular, and cancer surgery). There was low to very low certainty evidence that exercise prehabilitation reduces the risk of complications, non-home discharge, and length of stay. There was low to very low certainty evidence that nutritional prehabilitation reduces risk of complications, mortality, and length of stay. CONCLUSIONS: Low certainty evidence suggests that prehabilitation may improve postoperative outcomes. Future low risk of bias, randomised trials, synthesised using recommended standards, are required to inform practice. Optimal patient selection, intervention design, and intervention duration must also be determined.

Therapeutic implications of vitamin D and calcium in overweight women with polycystic ovary syndrome.

OBJECTIVE: To assess effects of vitamin D and Calcium (Ca) on hormonal and metabolic milieu of polycystic ovary syndrome (PCOS). DESIGN: Single arm open label trial. METHODS: Twelve overweight and vitamin D deficient women with PCOS underwent a 2 hour oral glucose tolerance testing at baseline and following 3-month supplementation with vitamin D (daily dose of 3533 IU, increased to 8533 IU after the first five participants) and 530 mg elemental Ca daily. MAIN OUTCOME MEASURES: Blood pressure (BP), plasma glucose, insulin, total testosterone (T) androstenedione (A), sex hormone binding globulin, lifestyle parameters were assessed at baseline and following 3-month intervention. Insulin resistance (IR) and area under the curve for glucose and insulin were computed; paired analyses were conducted. RESULTS: Improved serum 25OHD (p < 0.001) and reductions in total T (p = 0.036) and A (p = 0.090) levels were noted following 3-month supplementation, compared to baseline. Significant lowering in BP parameters was seen in participants with baseline BP ≥ 120/80 mmHg (n = 8) and in those with baseline serum 25OHD ≤20 ng/ml (n = 9). Parameters of glucose homeostasis and IR remained unchanged (p > 0.05). CONCLUSIONS: Androgen and BP profiles improved followed three month intervention, suggesting therapeutic implications of vitamin D and Ca in overweight and vitamin D deficient women with PCOS.

The probability of neonatal respiratory distress syndrome as a function of gestational age and lecithin/sphingomyelin ratio.

We sought to define the risk of neonatal respiratory distress syndrome (RDS) as a function of both lecithin/sphingomyelin (L/S) ratio and gestational age. Amniotic fluid L/S ratio data were collected from consecutive women undergoing amniocentesis for fetal lung maturity at Yale-New Haven Hospital from January 1998 to December 2004. Women were included in the study if they delivered a live-born, singleton, nonanomalous infant within 72 hours of amniocentesis. The probability of RDS was modeled using multivariate logistic regression with L/S ratio and gestational age as predictors. A total of 210 mother-neonate pairs (8 RDS, 202 non-RDS) met criteria for analysis. Both gestational age and L/S ratio were independent predictors of RDS. A probability of RDS of 3% or less was noted at an L/S ratio cutoff of > or = 3.4 at 34 weeks, > or = 2.6 at 36 weeks, > or = 1.6 at 38 weeks, and > or = 1.2 at term. Under 34 weeks of gestation, the prevalence of RDS was so high that a probability of 3% or less was not observed by this model. These data describe a means of stratifying the probability of neonatal RDS using both gestational age and the L/S ratio and may aid in clinical decision making concerning the timing of delivery.