Oxytocin, GABA, and dopamine interplay in autism.

Oxytocin plays an important role in brain development and is associated with various neurotransmitter systems in the brain. Abnormalities in the production, secretion, and distribution of oxytocin in the brain, at least during some stages of the development, are critical for the pathogenesis of neuropsychiatric diseases, particularly in the autism spectrum disorder. The etiology of autism includes changes in local sensory and dopaminergic areas of the brain, which are also supplied by the hypothalamic sources of oxytocin. It is very important to understand their mutual relationship. In this review, the relationship of oxytocin with several components of the dopaminergic system, gamma-aminobutyric acid (GABA) inhibitory neurotransmission and their alterations in the autism spectrum disorder is discussed. Special attention has been paid to the results describing a reduced expression of inhibitory GABAergic markers in the brain in the context of dopaminergic areas in various models of autism. It is presumed that the altered GABAergic neurotransmission, due to the absence or dysfunction of oxytocin at certain developmental stages, disinhibits the dopaminergic signaling and contributes to the autism symptoms.

Meta-analyses of partial correlations are biased: Detection and solutions.

We demonstrate that all meta-analyses of partial correlations are biased, and yet hundreds of meta-analyses of partial correlation coefficients (PCCs) are conducted each year widely across economics, business, education, psychology, and medical research. To address these biases, we offer a new weighted average, UWLS+3 . UWLS+3 is the unrestricted weighted least squares weighted average that makes an adjustment to the degrees of freedom that are used to calculate partial correlations and, by doing so, renders trivial any remaining meta-analysis bias. Our simulations also reveal that these meta-analysis biases are small-sample biases (n < 200), and a simple correction factor of (n - 2)/(n - 1) greatly reduces these small-sample biases along with Fisher's z. In many applications where primary studies typically have hundreds or more observations, partial correlations can be meta-analyzed in standard ways with only negligible bias. However, in other fields in the social and the medical sciences that are dominated by small samples, these meta-analysis biases are easily avoidable by our proposed methods.

Unveiling triglyceride levels in preterm neonates: a study to guide targeted monitoring.

BACKGROUND: Mixed lipid emulsion (MLE), most commonly soybean, medium chain triglycerides, olive, and fish oils (SMOF), has replaced soybean-based lipid emulsions in many neonatal intensive care units. Only a few studies report the triglyceride (TG) trajectory in neonates receiving MLE. We designed a study to compare TG levels in neonates receiving MLE stratified by gestational age (GA), birth weight (BW), and growth restriction status. METHODS: We included neonates born at <32 weeks GA or with BW <1500 gm. SMOF is started on admission, and plasma TG levels are measured 24 hours after 2 gm/kg/day and 24 hours after 3 gm/kg/day. TG levels were compared across groups defined by GA (<28 weeks vs. 328 weeks), BW (<1000 gm vs. 31000 gm), and small for GA (SGA) vs. appropriate plus large for GA groups using the Wilcoxon rank sum test. RESULTS: From 2018 to 2021, 427 infants met the inclusion criteria. TG levels were significantly higher in neonates with GA <28 weeks, BW <1000 grams, and SGA with a notable broad distribution of TG levels. Logistic regression analysis confirmed SGA and BW as significant independent predictors of hypertriglyceridemia after SMOF at 2 gm/kg/day and 3 gm/kg/day, respectively. CONCLUSIONS: The study emphasizes the importance of TG monitoring for neonates with GA <28 weeks, BW <1000 grams, and SGA. Conversely, it is advisable to individualize TG monitoring for infants with GA>28 weeks, BW>1000 grams, and non-SGA status. Prospective studies with larger sample sizes are warranted to validate our findings.

SNAPPE-II and MDAS scores as predictors for surgical intervention in very low birth weight neonates with necrotizing enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) is the most common life-threatening gastrointestinal emergency in preterm and term neonates, with the majority of cases affecting neonates classified as very low birth weight (VLBW, bw <1500 g). Scores for neonatal acute physiology-perinatal extension-II (SNAPPE-II) and metabolic derangement acuity score (MDAS) have been developed and utilized to assess neonatal morbidity and mortality including the subset of VLBW neonates. Serial SNAPPE-II and MDAS scores have been reported in neonates with necrotizing enterocolitis to assist in surgical management, yielding mixed results. OBJECTIVE: To determine the relationship between clinical and/or laboratory deterioration using SNAPPE-II and MDAS scores measured at the time of NEC diagnosis and surgical management of NEC. METHODS: We retrospectively evaluated preterm neonates ≥23 weeks gestational age who developed pneumatosis intestinalis on radiographic imaging coupled with clinical signs of NEC. SNAPPE-II and MDAS scores were calculated within twelve hours of birth and within twelve hours of initial finding of pneumatosis intestinalis. Baseline characteristics and clinical variables between those who did and did not require surgical intervention were compared. Logistic regression and receiver - operator characteristics (ROC) curve analyses were also performed, and areas under the curve (AUC) computed, to assess the performance of SNAPPE-II and MDAS scoring systems to differentiate neonates with NEC in the two groups. RESULTS: Sixty-four neonates were evaluated in our study of which 20 required surgical management of NEC. While the baseline SNAPPE-II and MDAS scores did not differ between the surgical management and medical management only groups, when rescored within 12 h of NEC diagnosis, the surgical management group had significantly higher SNAPPE -II (38 (18.5-69) vs. 19 (10-34.5), p = .04) and MDAS (2.5 (1-3) vs. 1 (0-2), p = .0004) scores. The AUCs for MDAS 0.77 (95% CI 0.65-0.89 and 0.71 (95% CI 0.57-0.85) for SNAPPE-II, indicating an acceptable level of diagnostic ability of both scoring systems to differentiate between those who did and did not need surgical management. CONCLUSION: SNAPPE II and MDAS scores performed within 12 h of NEC diagnosis may be useful in predicting which preterm VLBW neonates will require surgical intervention.

Discharge of Medically Complex Infants and Developmental Follow-up.

At the time of discharge from the NICU, many infants have ongoing complex medical issues that will require coordinated, multispecialty follow-up. Discharge planning and transfer of care for infants with medical complexity require a multidisciplinary team effort that begins early during the NICU hospitalization. It is critical that the primary care physician is involved in this process because he or she will serve as the chief communicator and coordinator of care after discharge. Although some infants with medical complexity may be followed in specialized multidisciplinary NICU follow-up clinics, these are not universally available. The responsibility then falls to the primary care physician to coordinate with different subspecialties based on the infant's needs. Many infants with medical complexity are technology-dependent at the time of discharge and may require home oxygen, ventilators, monitors, or tube feeding. Prematurity, critical illness, and prolonged NICU hospitalization that lead to medical complexity also increase the risk of neurodevelopmental delay or impairment. As such, these infants will not only require routine developmental surveillance and screening by the primary care physician but also should be followed longitudinally by a neurodevelopmental specialist, either a developmental-behavioral pediatrician or a neonatologist with experience in neurodevelopmental assessment.

The role of selected postsynaptic scaffolding proteins at glutamatergic synapses in autism-related animal models.

Pathological changes in synapse formation, plasticity, and development are caused by altered trafficking and assembly of postsynaptic scaffolding proteins at sites of glutamatergic and gamma-aminobutyric acid (GABA)ergic synapses, suggesting their involvement in the etiology of neurodevelopmental disorders, including autism. Several autism-related mouse models have been developed in recent years for studying molecular, cellular, and behavioural defects in order to understand the etiology of autism and test the potential treatment strategies. In this review, we explain the role of alterations in selected postsynaptic scaffolding proteins in relevant transgene autism-like mouse models. We also provide a summary of selected animal models by paying special attention to interactions between guanylate kinases or membrane-associated guanylate kinases (MAGUKs), as well as other synapse protein components which form functional synaptic networks. The study of early developmental stages of autism-relevant animal models can help us understand the origin and development of diverse autistic symptomatology.

Respiratory outcomes after neonatal prone versus supine positioning following scheduled cesarean delivery: a randomized trial.

BACKGROUND: Prone positioning is a common practice after vaginal birth promoting skin to skin contact and has been associated with improved oxygenation in mechanically ventilated neonates in the recent analysis. Neonates of women not in labor delivered via C-section are at increased risk of respiratory distress; it is unclear whether vigorous neonates without a need of resuscitation would benefit from prone positioning immediately after birth. OBJECTIVE: To determine whether prone positioning of vigorous term neonates for the first 5 min after scheduled cesarean delivery will decrease the incidence of respiratory distress and therapeutic interventions, characterized by the frequency and duration of respiratory support (RS). DESIGN/METHODS: In a single center, randomized parallel clinical trial, vigorous term neonates delivered via scheduled cesarean delivery were positioned prone or supine and their heart rate, oxygen saturation and signs of respiratory distress were recorded at 1-min intervals for the first 5 min. Infants not reaching target oxygen saturations suggested by the neonatal resuscitation guidelines received RS via Neopuff in supine position; respiratory support was discontinued once oxygen saturation targets were met and infant was free of respiratory symptoms. Primary outcomes measured were frequency and duration of RS, secondary outcomes were admission to the NICU for respiratory distress, length of stay, heart rate and oxygen saturation during the initial 5 min of life. RESULTS: Two hundred twenty-five neonates in prone and 231 in supine position completed the study out of 500 randomized subjects. Frequency of RS (31 versus 30%, p = .93), mean RS duration (4.08 versus 4.39 min; p = .71), frequency of admission to the NICU (5% in both groups; p = .95) and mean length of stay (0.14 versus 0.28 days; p = .42) were similar between the prone and supine groups. The supine cohort had higher initial oxygen saturation (p = .02) as well as heart rate (p = .004). CONCLUSIONS: Prone or supine positioning of term neonates after scheduled cesarean delivery resulted in comparable respiratory outcomes including the need for resuscitation in the first minutes of life.

Factors related to passing the safety fast test among neonates with hypoglycaemia in the neonatal intensive care unit.

AIM: To investigate the success rates and predictors of safety fast test among neonates admitted to the neonatal intensive care unit for hypoglycaemia. METHODS: A retrospective review of neonates transferred from the newborn nursery unit to the neonatal intensive care unit for intravenous dextrose therapy for hypoglycaemia from January 2016 to June 2019. Neonatal clinical and demographic variables were abstracted from the medical records. A successful safety fast test was defined by blood glucose >60 mg/dL (3.3 mmol/L) at 3, 4, 5 and 6 h after a feed. RESULTS: Of the 76 neonates who had a safety fast test, 80% passed on their first attempt. Neonates who passed the safety fast test were less likely to be premature/small for gestational age (54.1% vs. 92.9%, P = 0.03), required less maximum glucose infusion rate (median 6 vs. 7 mg/kg/min; P = 0.04), and were younger at fasting challenge (median 5 vs. 9 days; P = 0.02), required lower overall intravenous glucose load (median 12 vs. 24 g/kg; P = 0.006). CONCLUSION: Safety fast test may be a useful tool evaluating discharge readiness of neonates with persistent hypoglycaemia.

Hepcidin Status at 2 Months in Infants Fed Breast Milk Compared with Formula.

INTRODUCTION: The basis for the superior absorption of iron from breast milk compared with infant formulas is unclear. The hormone hepcidin downregulates dietary iron absorption. Hepcidin production increases with increased body iron status (reflected in serum ferritin levels). We hypothesized that serum hepcidin levels are suppressed relative to iron status in infants fed breast milk compared with formula. METHODS: Subjects were healthy infants presenting for routine 2-month clinic visit and strictly fed either breast milk or standard infant formula. Urinary hepcidin and ferritin levels (reflective of serum levels) were analyzed and compared across the breast milk- and formula-fed groups. The relationship between urinary hepcidin and ferritin levels within each group was analyzed by linear regression. RESULTS: Twenty-four subjects were enrolled in each group. The median urinary hepcidin level in the group fed breast milk was lower than in formula (130 vs. 359 ng hepcidin/mg creatinine, p < 0.05). However, the median ferritin levels were similar (2.1 vs. 1.9 ng/mL). Within each group, urinary hepcidin correlated with urinary ferritin (r = 0.5, p < 0.05 for each group); however, the slope of the regression line was lower in the group fed breast milk compared with formula (p < 0.005). CONCLUSION: Despite similar urinary ferritin levels, urinary hepcidin levels are lower at 2 months in infants fed breast milk compared with infants fed formula. Hepcidin levels correlate with iron status in each group; however, this relationship is relatively dampened in infants fed breast milk. We speculate that relatively lower infant hepcidin contributes to the superior efficiency of iron absorption from breast milk.

Cell proliferation and anti-oxidant effects of oxytocin and oxytocin receptors: role of extracellular signal-regulating kinase in astrocyte-like cells.

OBJECTIVES: Oxytocin (OXT) participates in various physiological functions ranging from reproduction to social and non-social behaviors. Recent studies indicate that OXT affects cell growth and metabolism. Here we characterized the growth stimulating and antioxidant actions of OXT and of OXT receptors (OXTR) in a glial cell-line (U-87MG). METHODS: We developed an OXTR-knockdown cell-line (U-87MG KD) to establish the receptor specificity of OXT's actions, and the impact of lacking OXTR on growth and survival in glial cells. The role Extracellular-Signal Regulated Kinases (ERK1/2) on glial cell protection against consequences of oxidative stress, and cell proliferation was investigated. RESULTS: In U-87MG cells, OXT stimulated cell proliferation and increased ERK1/2 phosphorylation. The specific ERK1/2 inhibitor, PD098059, produced marked inhibition of cell proliferation, and antagonized the stimulating effect of OXT on ERK1/2 phosphorylation and on cell proliferation. Slower growth rates and lower levels of phosphorylated ERK1/2 were observed in OXTR-knockdown cells and in U-87MG cells treated with an OXTR antagonist (L-371,257). In addition to increasing cell proliferation, OXT significantly blunted the rise in reactive oxygen species induced by H2O2, and antagonized the reductions in cell viability induced by H2O2 and camptothecin. The cell protective and antioxidant actions of OXT in U-87MG cells were not observed in the OXTR-knockdown cells. CONCLUSION: OXT stimulates the growth of astrocyte-like cells acting on OXTR via ERK1/2 phosphorylation. The protection against apoptosis and the antioxidant capacity of OXT may contribute to the observed increase in cell proliferation. Oxytocin and OXTR appear to be fundamental for cell growth and viability of glial cells.

The effect of hemodynamically significant patent ductus arteriosus on acute kidney injury and systemic hypertension in extremely low gestational age newborns.

Background: Acute kidney injury (AKI) in preterm neonates is becoming an increasingly recognized morbidity in the neonatal intensive care unit neonatal intensive care unit (NICU), yet its epidemiology, delineation and relation to numerous toxic exposures and common morbidities such as systemic hypertension is just evolving. With a frequency of the patent ductus arteriosus (PDA) as high as 70% in preterm infants born before 28-week gestation, the role of the hemodynamically significant PDA (hs-PDA) remains unclear. Objective: To determine if AKI and systemic hypertension is more common in extremely low gestational age newborns (ELGAN) with hs PDA compared to ELGAN with no or non-hs PDA using modified AKIN and Neonatal Risk, Injury, Failure, Loss of Kidney Function, and End-stage (N-RIFLE) scoring systems. Methods: This was a retrospective cohort study of infants ≤28 weeks gestational age born between 2010 and 2016 who had echocardiographic PDA evaluation completed for hemodynamical significance as well as serial serum creatinine and urine output measurement documented, needed for the two AKI scoring systems: modified AKIN (based on serial serum creatinine) and N-RIFLE (using urine output data). Blood pressure measurements and therapy were evaluated during the hospitalization and on the day of NICU discharge. Baseline characteristics and outcome variables were compared between the hs-PDA and no or non-hs PDA using unpaired t-tests for continuous variables and chi square tests for categorical data. Results: One hundred fifty-one infants were eligible of which 110 had hs-PDA. Infants with hs-PDA were smaller (777 versus 867 g, p = .026), less mature (25.8 versus 26.4 weeks, p = .023) and had greater exposure to nephrotoxic drugs (14 versus 9.4 days, p = .001). Other clinical and demographic variables were similar between the two groups. The overall incidence of AKI was not different between the hs-PDA and no PDA or non-hs PDA groups when evaluated by the acute kidney injury network (AKIN) or N-RIFLE staging; however, preterm newborns with hs-PDA demonstrated a trend towards increased risk of AKI injury (12.7 versus 0.02%, p = .06). The N-RIFLE and AKIN scoring systems demonstrated very poor degree of agreement (kappa = 0.00853) in our study. There was no difference in the rates of hypertension during the hospitalization as well as on the day of NICU discharge. Conclusion: Preterm neonates with hs-PDA had similar rates of AKI and hypertension as neonates with no or non-hs PDA.

Molecular Mechanisms of Oxytocin Signaling at the Synaptic Connection.

Aberrant regulation of oxytocin signaling is associated with the etiology of neurodevelopmental disorders. Synaptic dysfunctions in neurodevelopmental disorders are becoming increasingly known, and their pathogenic mechanisms could be a target of potential therapeutic intervention. Therefore, it is important to pay attention to the role of oxytocin and its receptor in synapse structure, function, and neuron connectivity. An early alteration in oxytocin signaling may disturb neuronal maturation and may have short-term and long-term pathological consequences. At the molecular level, neurodevelopmental disorders include alterations in cytoskeletal rearrangement and neuritogenesis resulting in a diversity of synaptopathies. The presence of oxytocin receptors in the presynaptic and postsynaptic membranes and the direct effects of oxytocin on neuronal excitability by regulating the activity of ion channels in the cell membrane implicate that alterations in oxytocin signaling could be involved in synaptopathies. The ability of oxytocin to modulate neurogenesis, synaptic plasticity, and certain parameters of cytoskeletal arrangement is discussed in the present review.

Intracerebroventricular oxytocin administration in rats enhances object recognition and increases expression of neurotrophins, microtubule-associated protein 2, and synapsin I.

Brain oxytocin regulates a variety of social and affiliative behaviors and affects also learning and memory. However, mechanisms of its action at the level of neuronal circuits are not fully understood. The present study tests the hypothesis that molecular factors required for memory formation and synaptic plasticity, including brain-derived neurotrophic factor, neural growth factor, nestin, microtubule-associated protein 2 (MAP2), and synapsin I, are enhanced by central administration of oxytocin. We also investigated whether oxytocin enhances object recognition and acts as anxiolytic agent. Therefore, male Wistar rats were infused continuously with oxytocin (20 ng/µl) via an osmotic minipump into the lateral cerebral ventricle for 7 days; controls were infused with vehicle. The object recognition test, open field test, and elevated plus maze test were performed on the sixth, seventh, and eighth days from starting the infusion. No significant effects of oxytocin on anxious-like behavior were observed. The object recognition test showed that oxytocin-treated rats significantly preferred unknown objects. Oxytocin treatment significantly increased gene expression and protein levels of neurotrophins, MAP2, and synapsin I in the hippocampus. No changes were observed in nestin expression. Our results provide the first direct evidence implicating oxytocin as a regulator of brain plasticity at the level of changes of neuronal growth factors, cytoskeletal proteins, and behavior. The data support assumption that oxytocin is important for short-term hippocampus-dependent memory.

Neonatal manipulation of oxytocin prevents lipopolysaccharide-induced decrease in gene expression of growth factors in two developmental stages of the female rat.

Oxytocin production and secretion is important for early development of the brain. Long-term consequences of manipulation of oxytocin system might include changes in markers of brain plasticity - cytoskeletal proteins and neurotrophins. The aim of the present study was (1) to determine whether neonatal oxytocin administration affects gene expression of nestin, microtubule-associated protein-2 (MAP-2), brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the brain of two developmental stages of rat and (2) to evaluate whether neonatal oxytocin administration protects against lipopolysaccharide (LPS) induced inflammation. Neonatal oxytocin did not prevent a decrease of body weight in the LPS treated animals. Oxytocin significantly increased gene expression of BDNF in the right hippocampus in 21-day and 2-month old rats of both sexes. Gene expression of NGF and MAP-2 significantly increased in males treated with oxytocin. Both, growth factors and intermediate filament-nestin mRNA levels, were reduced in females exposed to LPS. Oxytocin treatment prevented a decrease in the gene expression of only growth factors. In conclusion, neonatal manipulation of oxytocin has developmental and sex-dependent effect on markers of brain plasticity. These results also indicate, that oxytocin may be protective against inflammation particularly in females.