Intra-amniotic inflammation in the mid-trimester of pregnancy is a risk factor for neuropsychological disorders in childhood.

OBJECTIVES: Intra-amniotic inflammation is a subclinical condition frequently caused by either microbial invasion of the amniotic cavity or sterile inflammatory stimuli, e.g., alarmins. An accumulating body of evidence supports a role for maternal immune activation in the genesis of fetal neuroinflammation and the occurrence of neurodevelopmental disorders such as cerebral palsy, schizophrenia, and autism. The objective of this study was to determine whether fetal exposure to mid-trimester intra-amniotic inflammation is associated with neurodevelopmental disorders in children eight to 12 years of age. METHODS: This is a retrospective case-control study comprising 20 children with evidence of prenatal exposure to intra-amniotic inflammation in the mid-trimester and 20 controls matched for gestational age at amniocentesis and at delivery. Amniotic fluid samples were tested for concentrations of interleukin-6 and C-X-C motif chemokine ligand 10, for bacteria by culture and molecular microbiologic methods as well as by polymerase chain reaction for eight viruses. Neuropsychological testing of children, performed by two experienced psychologists, assessed cognitive and behavioral domains. Neuropsychological dysfunction was defined as the presence of an abnormal score (<2 standard deviations) on at least two cognitive tasks. RESULTS: Neuropsychological dysfunction was present in 45% (9/20) of children exposed to intra-amniotic inflammation but in only 10% (2/20) of those in the control group (p=0.03). The relative risk (RR) of neuropsychological dysfunction conferred by amniotic fluid inflammation remained significant after adjusting for gestational age at delivery [aRR=4.5 (1.07-16.7)]. Of the 11 children diagnosed with neuropsychological dysfunction, nine were delivered at term and eight of them had mothers with intra-amniotic inflammation. Children exposed to intra-amniotic inflammation were found to have abnormalities in neuropsychological tasks evaluating complex skills, e.g., auditory attention, executive functions, and social skills, whereas the domains of reasoning, language, and memory were not affected in the cases and controls. CONCLUSIONS: Asymptomatic sterile intra-amniotic inflammation in the mid-trimester of pregnancy, followed by a term birth, can still confer to the offspring a substantial risk for neurodevelopmental disorders in childhood. Early recognition and treatment of maternal immune activation in pregnancy may be a strategy for the prevention of subsequent neurodevelopmental disorders in offspring.

Report of Early Childhood Traumatic Injury Observations & Symptoms: Preliminary Validation of an Observational Measure of Postconcussive Symptoms.

OBJECTIVE: To report preliminary empirical data on a novel, developmentally appropriate, observational postconcussive symptoms inventory for infants, toddlers, and preschoolers. SETTING: Emergency departments of 2 tertiary, urban pediatric hospitals. PARTICIPANTS: Ninety-eight children (0-8 years of age; mean age at injury = 33.00, SD = 24.7 months) with mild traumatic brain injury (concussion) divided into younger (0-2 years) and older (3-8 years) age groups. DESIGN: Observational study. MAIN MEASURE: The Report of Early Childhood Traumatic Injury Observations & Symptoms (REACTIONS) documents 17 postconcussive symptoms representing observable manifestations thereof and was completed by parents in the acute (24-48 hours; n = 65), subacute (7-14 days; n = 78), and/or persistent phase (25-35 days; n = 72) post-mild traumatic brain injury. RESULTS: Different patterns of postconcussive symptoms were reported by age group, with behavioral manifestations particularly salient in younger children. More children younger than 2 years had sleep and comfort-seeking symptoms at each of the 3 postinjury time points. CONCLUSION: Postconcussive symptoms may manifest differently after mild traumatic brain injury sustained during early childhood. To fully understand and address their presence and evolution, developmentally sound measures such as the REACTIONS inventory are required.

Operation-related Musculoskeletal Injuries among United States Surgeons: A Gender-stratified National Survey.

Operation-related musculoskeletal injury (ORMI) among surgeons is a well-described phenomenon. Our study aimed to determine the prevalence of self-reported ORMI among surgeons of various subspecialties and preliminarily investigate the role of gender. METHODS: An anonymous survey, querying information pertinent to ORMIs, was distributed online through the American College of Surgeons community membership forum. Nonparametric univariate analysis and a multivariate regression model were conducted. A P value of 0.05 determined significance. RESULTS: A total of 624 male and female surgeons responded to the survey, with 50.8% reporting having an injury related to operating. Among the entire cohort, the prevalence of ORMI was significantly higher among female surgeons than male surgeons (P = 0.01), although there was no significant difference among the genders in ORMI prevalence when stratifying by age group (all P > 0.05). CONCLUSION: Female surgeons are more likely to report an ORMI, although the impact of confounding variables such as age, operative case volume, and surgical subspecialty remain to be fully elucidated.

Levalbuterol lowers the feedback inhibition by dopamine and delays misfolding and aggregation in tyrosine hydroxylase.

Tyrosine hydroxylase (TH) catalyses the (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4)-dependent conversion of L-tyrosine to L-3,4-dihydroxyphenylalanine (L-Dopa), which is the rate-limiting step in the synthesis of dopamine and other catecholamine neurotransmitters and hormones. Dysfunctional mutant TH causes tyrosine hydroxylase deficiency (THD), characterized by symptoms ranging from mild l-Dopa responsive dystonia to severe neuropathy. THD-associated mutations often present misfolding and a propensity to aggregate, characteristics that can also be manifested by dysregulated wild-type TH. TH - and subsequently dopamine - is also reduced in Parkinson's disease (PD) due to the selective death of dopaminergic neurons. Thus, TH is a target for stabilizing small molecular weight compounds that can function as pharmacological chaperones, restoring enzyme folding and function. In this work we carried out a screening of a compound library with 1280 approved drugs and we identified levalbuterol, a beta2-adrenergic agonist that is broadly used in asthma treatment, as an interesting validated binder of human TH. Levalbuterol stabilized TH with reduced affinity compared to dopamine, the end-product and regulatory feedback inhibitor of TH, but without compromising enzymatic activity. Moreover, levalbuterol also delays the formation of TH aggregates and makes the enzyme less sensitive to dopamine, effects that could contribute to ameliorate disorders related to TH, such as THD and PD.

Does the endometrial cavity have a molecular microbial signature?

Recent molecular studies concluded that the endometrium has a resident microbiota dominated by Lactobacillus spp. and is therefore similar to that of the vagina. These findings were largely derived from endometrial samples obtained through a transcervical catheter and thus prone to contamination. Herein, we investigated the molecular microbial profiles of mid-endometrial samples obtained through hysterectomy and compared them with those of the cervix, vagina, rectum, oral cavity, and controls for background DNA contamination. Microbial profiles were examined through 16S rRNA gene qPCR and sequencing. Universal bacterial qPCR of total 16S rDNA revealed a bacterial load exceeding that of background DNA controls in the endometrium of 60% (15/25) of the study subjects. Bacterial profiles of the endometrium differed from those of the oral cavity, rectum, vagina, and background DNA controls, but not of the cervix. The bacterial profiles of the endometrium and cervix were dominated by Acinetobacter, Pseudomonas, Cloacibacterium, and Comamonadaceae. Both 16S rRNA gene sequencing and Lactobacillus species-specific (L. iners & L crispatus) qPCR showed that Lactobacillus was rare in the endometrium. In conclusion, if there is a microbiota in the middle endometrium, it is not dominated by Lactobacillus as was previously concluded, yet further investigation using culture and microscopy is necessary.

Untargeted Metabolomic Analysis of Amniotic Fluid in the Prediction of Preterm Delivery and Bronchopulmonary Dysplasia.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is a serious complication associated with preterm birth. A growing body of evidence suggests a role for prenatal factors in its pathogenesis. Metabolomics allows simultaneous characterization of low molecular weight compounds and may provide a picture of such a complex condition. The aim of this study was to evaluate whether an unbiased metabolomic analysis of amniotic fluid (AF) can be used to investigate the risk of spontaneous preterm delivery (PTD) and BPD development in the offspring. STUDY DESIGN: We conducted an exploratory study on 32 infants born from mothers who had undergone an amniocentesis between 21 and 28 gestational weeks because of spontaneous preterm labor with intact membranes. The AF samples underwent untargeted metabolomic analysis using mass spectrometry combined with ultra-performance liquid chromatography. The data obtained were analyzed using multivariate and univariate statistical data analysis tools. RESULTS: Orthogonally Constrained Projection to Latent Structures-Discriminant Analysis (oCPLS2-DA) excluded effects on data modelling of crucial clinical variables. oCPLS2-DA was able to find unique differences in select metabolites between term (n = 11) and preterm (n = 13) deliveries (negative ionization data set: R2 = 0.47, mean AUC ROC in prediction = 0.65; positive ionization data set: R2 = 0.47, mean AUC ROC in prediction = 0.70), and between PTD followed by the development of BPD (n = 10), and PTD without BPD (n = 11) (negative data set: R2 = 0.48, mean AUC ROC in prediction = 0.73; positive data set: R2 = 0.55, mean AUC ROC in prediction = 0.71). CONCLUSIONS: This study suggests that amniotic fluid metabolic profiling may be promising for identifying spontaneous preterm birth and fetuses at risk for developing BPD. These findings support the hypothesis that some prenatal metabolic dysregulations may play a key role in the pathogenesis of PTD and the development of BPD.