Elevated Endogenous Erythropoietin Concentrations Are Associated with Increased Risk of Brain Damage in Extremely Preterm Neonates

Background

We sought to determine, in very preterm infants, whether elevated perinatal erythropoietin (EPO) concentrations are associated with increased risks of indicators of brain damage, and whether this risk differs by the co-occurrence or absence of intermittent or sustained systemic inflammation (ISSI).

Methods

Protein concentrations were measured in blood collected from 786 infants born before the 28th week of gestation. EPO was measured on postnatal day 14, and 25 inflammation-related proteins were measured weekly during the first 2 postnatal weeks. We defined ISSI as a concentration in the top quartile of each of 25 inflammation-related proteins on two separate days a week apart. Hypererythropoietinemia (hyperEPO) was defined as the highest quartile for gestational age on postnatal day 14. Using logistic regression and multinomial logistic regression models, we compared risks of brain damage among neonates with hyperEPO only, ISSI only, and hyperEPO+ISSI, to those who had neither hyperEPO nor ISSI, adjusting for gestational age.

Results

Newborns with hyperEPO, regardless of ISSI, were more than twice as likely as those without to have very low (< 55) Mental (OR 2.3; 95% CI 1.5-3.5) and/or Psychomotor (OR 2.4; 95% CI 1.6-3.7) Development Indices (MDI, PDI), and microcephaly at age two years (OR 2.4; 95%CI 1.5-3.8). Newborns with both hyperEPO and ISSI had significantly increased risks of ventriculomegaly, hemiparetic cerebral palsy, microcephaly, and MDI and PDI < 55 (ORs ranged from 2.2-6.3), but not hypoechoic lesions or other forms of cerebral palsy, relative to newborns with neither hyperEPO nor ISSI.

Conclusion

hyperEPO, regardless of ISSI, is associated with elevated risks of very low MDI and PDI, and microcephaly, but not with any form of cerebral palsy. Children with both hyperEPO and ISSI are at higher risk than others of very low MDI and PDI, ventriculomegaly, hemiparetic cerebral palsy, and microcephaly.     

Neurodevelopmental Outcomes of Extremely Preterm Infants Randomized to Stress Dose Hydrocortisone

Objective

To compare the effects of stress dose hydrocortisone therapy with placebo on survival without neurodevelopmental impairments in high-risk preterm infants.

Study Design

We recruited 64 extremely low birth weight (birth weight ≤1000g) infants between the ages of 10 and 21 postnatal days who were ventilator-dependent and at high-risk for bronchopulmonary dysplasia. Infants were randomized to a tapering 7-day course of stress dose hydrocortisone or saline placebo. The primary outcome at follow-up was a composite of death, cognitive or language delay, cerebral palsy, severe hearing loss, or bilateral blindness at a corrected age of 18–22 months. Secondary outcomes included continued use of respiratory therapies and somatic growth.

Results

Fifty-seven infants had adequate data for the primary outcome. Of the 28 infants randomized to hydrocortisone, 19 (68%) died or survived with impairment compared with 22 of the 29 infants (76%) assigned to placebo (relative risk: 0.83; 95% CI, 0.61 to 1.14). The rates of death for those in the hydrocortisone and placebo groups were 31% and 41%, respectively (P = 0.42). Randomization to hydrocortisone also did not significantly affect the frequency of supplemental oxygen use, positive airway pressure support, or need for respiratory medications.

Conclusions

In high-risk extremely low birth weight infants, stress dose hydrocortisone therapy after 10 days of age had no statistically significant effect on the incidence of death or neurodevelopmental impairment at 18–22 months. These results may inform the design and conduct of future clinical trials.

Trial Registration

ClinicalTrials.gov NCT00167544     

Early Oxygen-Utilization and Brain Activity in Preterm Infants

The combined monitoring of oxygen supply and delivery using Near-InfraRed spectroscopy (NIRS) and cerebral activity using amplitude-integrated EEG (aEEG) could yield new insights into brain metabolism and detect potentially vulnerable conditions soon after birth. The relationship between NIRS and quantitative aEEG/EEG parameters has not yet been investigated. Our aim was to study the association between oxygen utilization during the first 6 h after birth and simultaneously continuously monitored brain activity measured by aEEG/EEG. Forty-four hemodynamically stable babies with a GA < 28 weeks, with good quality NIRS and aEEG/EEG data available and who did not receive morphine were included in the study. aEEG and NIRS monitoring started at NICU admission. The relation between regional cerebral oxygen saturation (rScO₂) and cerebral fractional tissue oxygen extraction (cFTOE), and quantitative measurements of brain activity such as number of spontaneous activity transients (SAT) per minute (SAT rate), the interval in seconds (i.e. time) between SATs (ISI) and the minimum amplitude of the EEG in μV (min aEEG) were evaluated. rScO₂ was negatively associated with SAT rate (β=-3.45 [CI=-5.76- -1.15], p=0.004) and positively associated with ISI (β=1.45 [CI=0.44-2.45], p=0.006). cFTOE was positively associated with SAT rate (β=0.034 [CI=0.009-0.059], p=0.008) and negatively associated with ISI (β=-0.015 [CI=-0.026- -0.004], p=0.007). Oxygen delivery and utilization, as indicated by rScO₂ and cFTOE, are directly related to functional brain activity, expressed by SAT rate and ISI during the first hours after birth, showing an increase in oxygen extraction in preterm infants with increased early electro-cerebral activity. NIRS monitored oxygenation may be a useful biomarker of brain vulnerability in high-risk infants.     

Executive Function and IQ Predict Mathematical and Attention Problems in Very Preterm Children

Objective of this study was to examine the impact of executive function (EF) on mathematical and attention problems in very preterm (gestational age ≤ 30 weeks) children. Participants were 200 very preterm (mean age 8.2 ± 2.5 years) and 230 term children (mean age 8.3 ± 2.3 years) without severe disabilities, born between 1996 and 2004. EFs assessed included verbal fluency, verbal working memory, visuospatial span, planning, and impulse control. Mathematics was assessed with the Dutch Pupil Monitoring System and parents and teachers rated attention problems using standardized behavior questionnaires. The impact of EF was calculated over and above processing speed indices and IQ. Interactions with group (very preterm versus term birth status) were examined. Analyses were conducted separately for two subsamples: children in preschool and children in primary school. Very preterm children performed poorer on tests for mathematics and had more parent and teacher rated attention problems than term controls (ß_s>.11, P_s<.01). IQ contributed unique variance to mathematics in preschool and in primary school (ß_s>.16, P_s<.007). A significant interaction of group with IQ (ß = −. 24, P = .02) showed that IQ contributed unique variance to attention problems as rated by teachers, but that effects were stronger for very preterm than for term infants. Over and above IQ, EF contributed unique variance to mathematics in primary school (ß = .13, P<.001), to parent rated inattention in preschool and in primary school (ß_s>−.16, P_s<.04), and to teacher rated inattention in primary school (ß = −.19; ß = .19, P_s<.009). In conclusion, impaired EF is, over and above impaired IQ, an important predictor for poor mathematics and attention problems following very preterm birth.     

A Contribution to the Problem of Systematized Delusions in Adolescents

As we know, rigorously systematized delusions of long duration are very rarely seen in children and adolescents. Sander (1) held that "original paranoia" may begin in early childhood. Krafft-Ebing (2) believed that "hereditary primary insanity," as distinguished from its late form, is encountered only in predisposed children— weak-willed, hypochondriac, pathologically quick to take offense — and is manifested in delusions of grandeur and ideas of reference and of special significance. G. E. Sukhareva, (3) describing systematized delusions in schizophrenic adolescents, expresses the opinion that within the framework of schizophrenia, such delusions occur primarily in psychopathic adolescents with schizoid traits: dominating, suspicious and inclined to fantasy. Stable delusions and delusive ideas against the background of a schizophrenic process in adolescents have also been described by certain other authors. (4-8)     

Rat Brain Mast Cells: Contribution to Brain Histamine Levels

Recent studies have shown that mast cells (MCs) are present in rat brain, that they have a predominantly thalamic localization, and that they contain histamine (HA). However, the degree to which these cells contribute to brain HA levels has remained unclear. Our recent studies of the precise distribution of rat brain MCs permitted us to develop a method to determine both the MC numbers and HA content from the same brain. Thalamic MC numbers were highly correlated with both the amount (ng) and the concentration (ng/g) of thalamic HA in both sexes (p less than 0.005). Slopes of these regression lines, suggestive of the HA content of thalamic MCs, were 2.5 and 1.3 pg/cell in males and females, respectively, substantially less than the HA levels in peritoneal MCs. Thalamic MC numbers were not correlated with HA (ng) outside of thalamus, but were significantly (p less than 0.005) correlated with whole brain HA amounts (ng) and levels (ng/g). These results are direct biochemical evidence for a contribution by MCs to brain HA levels, and indicate that thalamic MCs contribute up to 90% of the HA in thalamus, and up to 50% of whole brain HA levels.     

Obstructive Sleep Apnea in Extremely Overweight Adolescents undergoing Bariatric Surgery

Objectives: To determine the prevalence of obstructive sleep apnea (OSA) in extremely overweight adolescents and to examine the effect of significant weight loss on OSA severity. Research Methods and Procedures: We reviewed the anthropometric and polysomnographic data on all extremely overweight adolescents who underwent laparoscopic Roux en Y gastric bypass surgery at Cincinnati Children's Hospital Medical Center from July 2001 to September 2004. Repeat polysomnograms were performed after significant weight loss. Comparisons were made between pre‐ and postoperative polysomnographic data. Results: Nineteen of 34 patients (55%) who underwent bariatric surgery were diagnosed with OSA. Subsequent to surgery, 10 of these patients returned for follow‐up polysomnographic testing. After significant weight loss (mean, 58 kg), OSA severity markedly decreased in all patients (median apnea‐hypopnea index at baseline vs. after weight loss, 9.1 vs. 0.65). Discussion: Our study indicated that OSA was highly prevalent in extremely overweight adolescents meeting eligibility criteria for bariatric surgery. The significant weight loss after gastric bypass was associated with a marked reduction in OSA severity.     

Contribution of Developmental Assets to the Prediction of Thriving Among Adolescents

This article investigated the contribution of developmental assets to the prediction of thriving behaviors among adolescents. The study was based on a sample of 6,000 youth in Grades 6-12 evenly distributed across 6 ethnic groups. Investigated were the effects of gender, grade, and levels of youth assets on 7 thriving indicators: school success, leadership, valuing diversity, physical health, helping others, delay of gratification, and overcoming adversity. Developmental assets are identified that together contribute "over and above demographic variables" between 10% and 43% to the variance of the thriving indicators and between 47% and 54% of the variance in a composite index comprised of the separate thriving indicators. The results substantially reflect the relation of developmental assets and thriving outcomes suggested by the research literature, and provide evidence for the utility of the developmental assets framework.     

胎盘组织学绒毛膜羊膜炎与未足月胎膜早破后早产儿脑损伤关系

目的:研究胎盘组织学绒毛膜羊膜炎与未足月胎膜早破后早产儿出现脑损伤的相关性。方法:选取我院妇产科2017年1月至2019年12月收治的因胎膜早破生产的未足月早产儿80例,根据是否存在绒毛膜羊膜炎分为观察组(绒毛膜羊膜炎)和对照组(无绒毛膜羊膜炎),每组40例,患儿于胎龄40 w时行颅脑核磁共振检查(Magnetic Resonance Examination,MRI),对比两组脑室周围白质软化(periventricular leukomalacia,PVL)阳性率,且采用新生儿20项行为神经评分量表(neonatal behavior neurological assessment,NBNA)评价两组患儿神经行为,然后在纠正胎龄3、6个月时对两组患儿进行智能发育指数(mental developmentalindex,MDI)及心理运动发育指数(psychomotor development index,PDI)测定并对比。结果:观察组PVL阳性率为27.5%,高于对照组的10.0%(P<0.05);观察组纠正胎龄40 w NBNA得分为(31.02±3.51)分,对照组为(35.21±4.02)分,差异具有统计学意义(P<0.05);胎龄3个月,MDI得分在观察组与对照组间差异无具有统计学意义(P>0.05),但其PDI得分低于对照组(P<0.05);胎龄6个月,观察组MDI及PDI得分均低于对照组(P<0.05)。结论:绒毛膜羊膜炎与未足月胎膜早破后早产儿的脑部损伤情况具有一定相关性,可以作为预测早产儿脑损伤程度的一项指标。     

Preterm Birth,Age at School Entry and Educational Performance

Objective

To investigate if the lack of gestational age correction may explain some of the school failure seen in ex-preterm infants.

Design

A cohort study based on the Avon Longitudinal Study of Parents and Children (ALSPAC). The primary outcome was a low Key Stage 1 score (KS1) score at age 7 or having special educational needs (SEN). Exposure groups were defined as preterm (<37 weeks gestation, n = 722) or term (37–42 weeks, n = 11,268). Conditional regression models were derived, matching preterm to term infants on date of birth (DOB), expected date of delivery (EDD) or expected date of delivery and year of school entry. Multiple imputation was used to account for missing covariate data.

Results

When matching for DOB, infants born preterm had an increased odds of a low KS1 score (OR 1.73 (1.45–2.06)) and this association persisted after adjusting for potential confounders (OR 1.57 (1.25–1.97)). The association persisted in the analysis matching for EDD (fully adjusted OR 1.53 (1.21–1.94)) but attenuated substantially after additionally restricting to those infants who entered school at the same time as the control infants (fully adjusted OR 1.25 (0.98–1.60)). A compatible reduction in the population attributable risk fraction was seen from 4.60% to 2.12%, and year of school entry appeared to modify the association between gestational age and the risk of a poor KS1 score (p = 0.029).

Conclusions

This study provides evidence that the school year placement and assessment of ex-preterm infants based on their actual birthday (rather than their EDD) may increase their risk of learning difficulties with corresponding school failure.     

Mortality, Neonatal Morbidity and Two Year Follow-Up of Extremely Preterm Infants Born in the Netherlands in 2007

Background

Extremely preterm infants are at high risk of neonatal mortality and adverse outcome. Survival rates are slowly improving, but increased survival may come at the expense of more handicaps.

Methodology/Principal Findings

Prospective population-based cohort study of all infants born at 23 to 27 weeks of gestation in the Netherlands in 2007. 276 of 345 (80%) infants were born alive. Early neonatal death occurred in 96 (34.8%) live born infants, including 61 cases of delivery room death. 29 (10.5%) infants died during the late neonatal period. Survival rates for live born infants at 23, 24, 25 and 26 weeks of gestation were 0%, 6.7%, 57.9% and 71% respectively. 43.1% of 144 surviving infants developed severe neonatal morbidity (retinopathy of prematurity grade ≥3, bronchopulmonary dysplasia and/or severe brain injury). At two years of age 70.6% of the children had no disability, 17.6% was mild disabled and 11.8% had a moderate-to-severe disability. Severe brain injury (p = 0.028), retinopathy of prematurity grade ≥3 (p = 0.024), low gestational age (p = 0.019) and non-Dutch nationality of the mother (p = 0.004) increased the risk of disability.

Conclusions/Significance

52% of extremely preterm infants born in the Netherlands in 2007 survived. Surviving infants had less severe neonatal morbidity compared to previous studies. At two years of age less than 30% of the infants were disabled. Disability was associated with gestational age and neonatal morbidity.     

Rat Brain Type II 5'-Iodothyronine Deiodinase Activity Is Extremely Sensitive to Stress

Abstract: The effects of different kinds of acute stressor on thyroid hormone concentrations and deiodinase activities were investigated in four brain regions (frontal cortex, amygdala, hypothalamus, and cerebellum) and in the pituitaries and livers of adult male rats. Five groups of rats were killed after each of the following stressors: (a) an intraperitoneal injection of saline, (b) intragastric intubation, (c) and (d) two different forms of handling, being grasped as for intraperitoneal injection and being moved from one cage to another, and (e) a 2-h period spent in a slowly rotating drum. Two other groups were placed in the rotating drums for 10 and 19 h (sleep deprivation experiment), respectively. All stressors induced significant (in some cases up to 200%) increases in the activity of type II 5′-iodothyronine deiodinase, which catalyzes the deiodination of the prohormone l -thyroxine (T₄) to the active metabolite 3,3′,5-triiodo-l -thyronine (T₃). As a consequence, the tissue concentrations of T₄ fell, and those of T₃ rose (sometimes by up to 300%). However, these changes were limited to selected areas of the brain that were specific for each stressor and were not seen in all brain regions investigated in any group. No clear-cut effects of stress were seen on the activities of the type III 5-iodothyronine deiodinase isoenzyme, which catalyzes the inactivation of T₃, on liver or serum thyroid hormone concentrations or on liver of brain type I 5′-iodothyronine deiodinase activities. In summary, our results show that even mild and very brief stress can induce marked increases in T₃ concentrations specifically in brain but not in liver or blood. Thus, contrary to common opinion, thyroid hormones may play an important physiological role in stress reactions, at least in tissues that contain type II 5′-iodothyronine deiodinase, such as brain and pituitary.     

Decreased and Increased Anisotropy along Major Cerebral White Matter Tracts in Preterm Children and Adolescents

Premature birth is highly prevalent and associated with neurodevelopmental delays and disorders. Adverse outcomes, particularly in children born before 32 weeks of gestation, have been attributed in large part to white matter injuries, often found in periventricular regions using conventional imaging. To date, tractography studies of white matter pathways in children and adolescents born preterm have evaluated only a limited number of tracts simultaneously. The current study compares diffusion properties along 18 major cerebral white matter pathways in children and adolescents born preterm (n = 27) and full term (n = 19), using diffusion magnetic resonance imaging and tractography. We found that compared to the full term group, the preterm group had significantly decreased FA in segments of the bilateral uncinate fasciculus and anterior segments of the right inferior fronto-occipital fasciculus. Additionally, the preterm group had significantly increased FA in segments of the right and left anterior thalamic radiations, posterior segments of the right inferior fronto-occipital fasciculus, and the right and left inferior longitudinal fasciculus. Increased FA in the preterm group was generally associated with decreased radial diffusivity. These findings indicate that prematurity-related white matter differences in later childhood and adolescence do not affect all tracts in the periventricular zone and can involve both decreased and increased FA. Differences in the patterns of radial diffusivity and axial diffusivity suggest that the tissue properties underlying group FA differences may vary within and across white matter tracts. Distinctive diffusion properties may relate to variations in the timing of injury in the neonatal period, extent of white matter dysmaturity and/or compensatory processes in childhood.     

Perinatal Clinical Antecedents of White Matter Microstructural Abnormalities on Diffusion Tensor Imaging in Extremely Preterm Infants

Objective

To identify perinatal clinical antecedents of white matter microstructural abnormalities in extremely preterm infants.

Methods

A prospective cohort of extremely preterm infants (N = 86) and healthy term controls (N = 16) underwent diffusion tensor imaging (DTI) at term equivalent age. Region of interest-based measures of white matter microstructure - fractional anisotropy and mean diffusivity - were quantified in seven vulnerable cerebral regions and group differences assessed. In the preterm cohort, multivariable linear regression analyses were conducted to identify independent clinical factors associated with microstructural abnormalities.

Results

Preterm infants had a mean (standard deviation) gestational age of 26.1 (1.7) weeks and birth weight of 824 (182) grams. Compared to term controls, the preterm cohort exhibited widespread microstructural abnormalities in 9 of 14 regional measures. Chorioamnionitis, necrotizing enterocolitis, white matter injury on cranial ultrasound, and increasing duration of mechanical ventilation were adversely correlated with regional microstructure. Conversely, antenatal steroids, female sex, longer duration of caffeine therapy, and greater duration of human milk use were independent favorable factors. White matter injury on cranial ultrasound was associated with a five weeks or greater delayed maturation of the corpus callosum; every additional 10 days of human milk use were associated with a three weeks or greater advanced maturation of the corpus callosum.

Conclusions

Diffusion tensor imaging is sensitive in detecting the widespread cerebral delayed maturation and/or damage increasingly observed in extremely preterm infants. In our cohort, it also aided identification of several previously known or suspected perinatal clinical antecedents of brain injury, aberrant development, and neurodevelopmental impairments.     

Glutamate Decarboxylase-Dependent Acid Resistance in Brucella spp.: Distribution and Contribution to Fitness under Extremely Acidic Conditions

Brucella is an expanding genus of major zoonotic pathogens, including at least 10 genetically very close species occupying a wide range of niches from soil to wildlife, livestock, and humans. Recently, we have shown that in the new species Brucella microti, the glutamate decarboxylase (Gad)-dependent system (GAD system) contributes to survival at a pH of 2.5 and also to infection in mice by the oral route. In order to study the functionality of the GAD system in the genus Brucella, 47 isolates, representative of all known species and strains of this genus, and 16 strains of the closest neighbor genus, Ochrobactrum, were studied using microbiological, biochemical, and genetic approaches. In agreement with the genome sequences, the GAD system of classical species was not functional, unlike that of most strains of Brucella ceti, Brucella pinnipedialis, and newly described species (B. microti, Brucella inopinata BO1, B. inopinata-like BO2, and Brucella sp. isolated from bullfrogs). In the presence of glutamate, these species were more acid resistant in vitro than classical terrestrial brucellae. Expression in trans of the gad locus from representative Brucella species in the Escherichia coli MG1655 mutant strain lacking the GAD system restored the acid-resistant phenotype. The highly conserved GAD system of the newly described or atypical Brucella species may play an important role in their adaptation to acidic external and host environments. Furthermore, the GAD phenotype was shown to be a useful diagnostic tool to distinguish these latter Brucella strains from Ochrobactrum and from classical terrestrial pathogenic Brucella species, which are GAD negative.     

Cell Size and the Heat-Shock Response in Rat Brain

Abstract: The expression of mRNAs encoding two members of the heat-shock protein 70 family, the constitutively-expressed heat-shock cognate (hsc70) mRNA and the strictly heat-inducible (hsp70) mRNA, was quantitated in cerebellar and hippocampal cells of rats 3 h after amphetamine-induced or heat-induced hyperthermia. Intracellular heat-shock mRNA levels in specific cell types were compared with those of total polyadenylic acid [poly(A)] mRNA or 18S rRNA in the same cell type. Levels of poly(A) mRNAs, 18S rRNAs, and hsc70 mRNAs were highest in large neurons and lowest in glia. hsp70 mRNAs were also present at highest levels in large neurons, suggesting that hsp70 mRNAs accumulated as rapidly in these cell types as they did in small neurons and glia. However, compared with levels of intracellular poly(A) mRNAs or levels of rRNAs, large neurons contained two- to 12-fold lower levels of hsp70 mRNAs than neurons of intermediate size and five- to 30-fold lower levels than glia. These results suggest that hsp70 mRNAs accumulated as rapidly in large neurons as in small neurons and glia, but that the large size of these neurons precluded intracellular hsp70 mRNA concentrations increasing as quickly. The susceptibility of large neurons to stress-induced cell death could be due, in part, to their inability to synthesize rapidly hsp70 in sufficient amounts to protect these cells from the initial molecular consequences of stress.     

Brain Size Growth and Life History in Human Evolution

Increases in endocranial volume (a measure of brain size) play a major role in human evolution. Despite the importance of brain size increase, the developmental bases of human brain size evolution remain poorly characterized. Comparative analyses of endocranial volume size growth illustrate that distinctions between humans and other primates are consequences of differences in rates of brain size growth, with little evidence for differences in growth duration. Evaluation of available juvenile fossils shows that earliest hominins do not differ perceptibly from chimpanzees (Pan). However, rapid and human-like early brain growth apparently characterized Homo erectus at about 1?Ma before present. Neandertals show patterns of brain growth consistent with modern humans during infancy, but reach larger sizes than modern humans as a result of differences in later growth. Growth analyses reveal commonalities in patterns of early brain size growth during the last million years human evolution, despite major increases in adult size. This result implies consistency across hominins in terms of maternal metabolic costs of infancy. Continued size growth past infancy in Neandertals and modern humans, when compared to earlier hominins, may have cognitive implications. Differences between Neandertals and modern humans are implied, but difficult to define with certainty.