Personality in Adults Who Were Born Very Preterm

Aim

To investigate the personality in very preterm individuals (VPT; gestational age, GA, <32 weeks) at adult age in two cohorts born in 1974–76 and 1980–82, respectively, and to illuminate the effect of increased survival rates and the clinical implications of deviations in personality.

Method

Demographic data were extracted for all individuals born in Denmark in 1974–76 and 1980–82. From each period one index-group each comprising 150 individuals with the lowest gestational age was selected. Thereafter two control groups born at term were matched by gender, age and residential area. Personality was assessed with the short version of NEO PI-R, and psychiatric diagnoses were obtained from the Danish Psychiatric Central Research Register.

Results

Of all the individuals born <32 weeks of gestation in 1980–82 67% were alive in 2006 vs. 43% of those born in 1974–76 (p<0.0001). A total of 433 individuals participated in the study, 76% of the VPT groups (n = 227, mean GA = 27.9) and 69% of the control groups (n = 206). There were no significant differences on personality scores between the two VPT groups. Compared to the control groups, the combined VPT groups scored higher on neuroticism (p = 0.005) and agreeableness (p = 0.012), but lower on extraversion (p = 0.002). Psychiatric disorder was strongly associated with higher scores on neuroticism and lower scores on extraversion.

Interpretation

Improved survival of VPT infants was not associated with increased deviances in the personality as adults. The personality traits in VPT individuals differ moderately from those of term born controls. High scores in neuroticism and low scores in extraversion were associated with increased risk psychiatric disorders. VPT adults also showed signs of positive adaptation in the form of an agreeable and confident attitude towards others.

What this paper adds

The much improved survival rate in very preterm infants during the early years of active neonatology was not associated with increased risk of personality deviation. There are signs of positive adaptation in the form of increased agreeableness in young adults born very preterm.     

Subregional Hippocampal Morphology and Psychiatric Outcome in Adolescents Who Were Born Very Preterm and at Term

Background

The hippocampus has been reported to be structurally and functionally altered as a sequel of very preterm birth (<33 weeks gestation), possibly due its vulnerability to hypoxic–ischemic damage in the neonatal period. We examined hippocampal volumes and subregional morphology in very preterm born individuals in mid- and late adolescence and their association with psychiatric outcome.

Methods

Structural brain magnetic resonance images were acquired at two time points (baseline and follow-up) from 65 ex-preterm adolescents (mean age = 15.5 and 19.6 years) and 36 term-born controls (mean age=15.0 and 19.0 years). Hippocampal volumes and subregional morphometric differences were measured from manual tracings and with three-dimensional shape analysis. Psychiatric outcome was assessed with the Rutter Parents’ Scale at baseline, the General Health Questionnaire at follow-up and the Peters Delusional Inventory at both time points.

Results

In contrast to previous studies we did not find significant difference in the cross-sectional or longitudinal hippocampal volumes between individuals born preterm and controls, despite preterm individual having significantly smaller whole brain volumes. Shape analysis at baseline revealed subregional deformations in 28% of total bilateral hippocampal surface, reflecting atrophy, in ex-preterm individuals compared to controls, and in 22% at follow-up. In ex-preterm individuals, longitudinal changes in hippocampal shape accounted for 11% of the total surface, while in controls they reached 20%. In the whole sample (both groups) larger right hippocampal volume and bilateral anterior surface deformations at baseline were associated with delusional ideation scores at follow-up.

Conclusions

This study suggests a dynamic association between cross-sectional hippocampal volumes, longitudinal changes and surface deformations and psychosis proneness.     

Neonatal Pain-Related Stress Predicts Cortical Thickness at Age 7 Years in Children Born Very Preterm

Background

Altered brain development is evident in children born very preterm (24–32 weeks gestational age), including reduction in gray and white matter volumes, and thinner cortex, from infancy to adolescence compared to term-born peers. However, many questions remain regarding the etiology. Infants born very preterm are exposed to repeated procedural pain-related stress during a period of very rapid brain development. In this vulnerable population, we have previously found that neonatal pain-related stress is associated with atypical brain development from birth to term-equivalent age. Our present aim was to evaluate whether neonatal pain-related stress (adjusted for clinical confounders of prematurity) is associated with altered cortical thickness in very preterm children at school age.

Methods

42 right-handed children born very preterm (24–32 weeks gestational age) followed longitudinally from birth underwent 3-D T1 MRI neuroimaging at mean age 7.9 yrs. Children with severe brain injury and major motor/sensory/cognitive impairment were excluded. Regional cortical thickness was calculated using custom developed software utilizing FreeSurfer segmentation data. The association between neonatal pain-related stress (defined as the number of skin-breaking procedures) accounting for clinical confounders (gestational age, illness severity, infection, mechanical ventilation, surgeries, and morphine exposure), was examined in relation to cortical thickness using constrained principal component analysis followed by generalized linear modeling.

Results

After correcting for multiple comparisons and adjusting for neonatal clinical factors, greater neonatal pain-related stress was associated with significantly thinner cortex in 21/66 cerebral regions (p-values ranged from 0.00001 to 0.014), predominately in the frontal and parietal lobes.

Conclusions

In very preterm children without major sensory, motor or cognitive impairments, neonatal pain-related stress appears to be associated with thinner cortex in multiple regions at school age, independent of other neonatal risk factors.     

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.     

Radial Glial Fibers Promote Neuronal Migration and Functional Recovery after Neonatal Brain Injury

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Increased Adiposity in Adults Born Preterm and Their Children

Background

Preterm birth is associated with abnormalities in growth, body composition, and metabolism during childhood, but adult data are scarce and none exist for their offspring. We therefore aimed to examine body composition and cardiovascular risk factors in adults born preterm and their children.

Methods

A cohort of 52 adults (aged 35.7 years, 54% female, 31 born preterm) and their term-born children (n=61, aged 8.0 years, 54% female, 60% from a preterm parent) were studied. Auxology and body composition (whole-body dual-energy X-ray absorptiometry) were measured, and fasting blood samples taken for metabolic and hormonal assessments.

Results

Adults born preterm had greater abdominal adiposity, displaying more truncal fat (p=0.006) and higher android to gynoid fat ratio (p=0.004). Although women born preterm and at term were of similar weight and BMI, men born preterm (n=8) were on average 20 kg heavier (p=0.010) and of greater BMI (34.2 vs 28.4 kg/m²; p=0.021) than men born at term (n=16). Adults born preterm also displayed a less favourable lipid profile, including lower HDL-C concentrations (p=0.007) and greater total cholesterol to HDL-C ratio (p=0.047). Children of parents born preterm tended to have more body fat than the children of parents born at term (21.3 vs 17.6%; p=0.055). Even after adjustment for mean parental BMI, children of parents born preterm had altered fat distribution, with more truncal fat (p=0.048) and greater android to gynoid fat ratio (p=0.009).

Conclusions

Adults born preterm, particularly men, have markedly increased fat mass and altered fat distribution. A similar increase in abdominal adiposity was observed in the term born offspring of parents born preterm, indicating that adverse outcomes associated with preterm birth may extend to the next generation.     

Salivary Telomere Length and Lung Function in Adolescents Born Very Preterm: A Prospective Multicenter Study

Preterm birth is associated with abnormal respiratory functions throughout life. The mechanisms underlying these long-term consequences are still unclear. Shortening of telomeres was associated with many conditions, such as chronic obstructive pulmonary disease. We aimed to search for an association between telomere length and lung function in adolescents born preterm. Lung function and telomere length were measured in 236 adolescents born preterm and 38 born full-term from the longitudinal EPIPAGE cohort. Associations between telomere length and spirometric indices were tested in univariate and multivariate models accounting for confounding factors in the study population. Airflows were significantly lower in adolescents born preterm than controls; forced expiratory volume in one second was 12% lower in the extremely preterm born group than controls (p<0.001). Lower birth weight, bronchopulmonary dysplasia and postnatal sepsis were significantly associated with lower airflow values. Gender was the only factor that was significantly associated with telomere length. Telomere length correlated with forced expiratory flow 25–75 in the extremely preterm adolescent group in univariate and multivariate analyses (p = 0.01 and p = 0.02, respectively). We evidenced an association between telomere length and abnormal airflow in a population of adolescents born extremely preterm. There was no evident association with perinatal events. This suggests other involved factors, such as a continuing airway oxidative stress leading to persistent inflammation and altered lung function, ultimately increasing susceptibility to chronic obstructive pulmonary disease.     

Outcome at Two Years of Very Preterm Infants Born after Rupture of Membranes before Viability

PurposeTo compare the respiratory and neurological outcomes at two years of age of preterm children born before 33 weeks of gestation (WG) after early preterm premature rupture of membranes (EPPROM) between 14 and 24 WG with preterm children without EPPROM.ResultsNinety-four cases with EPPROM before 24WG have been included. The 31 children born from 26WG to 32WG were matched with 62 controls. The EPPROM group had poorer clinical evaluation at one year for motor (p = 0.003) and cognitive developmental scores (p = 0.016). Neuromotor rehabilitation was performed more often (p = 0.013). However, there was no difference at 2 years of age. Children born after EPPROM were hospitalized more often for bronchiolitis (p<0.001) during their first 2 years, which correlates with increased incidence of pneumothorax (p = 0.017), pulmonary hypoplasia (p = 0.004) and bronchopulmonary dysplasia (p = 0.005) during neonatal period.ConclusionAt two years, despite an increase in severe bronchiolitis and the need for more neuromotor rehabilitation during the first month of the life after discharge, there was no difference in neurological outcomes in the very preterm children of the EPPROM group compared to those born at a similar GA without EPPROM.     

Duration of Cord Clamping and Neonatal Outcomes in Very Preterm Infants

Background

Delayed cord clamping (DCC, ≥30s) increases blood volume in newborns and is associated with fewer blood transfusions and short-term neonatal complications. The optimal timing of cord clamping for very preterm infants should maximize placental transfusion without interfering with stabilization and resuscitation.

Aim

We compared the effect of different durations of DCC, 30-45s vs. 60-75s, on delivery room (DR) and neonatal outcomes in preterm infants <32 weeks gestational age (GA).

Methods

This is a single-center prospective observational study. Data were collected prospectively from eligible infants from two groups: 30-45s DCC group (January 2008 to February 2011, n = 187) and 60-75s DCC group (March 2011 to April 2014, n = 166).

Results

The 60-75s DCC group compared to the 30-45s DCC group had higher hematocrits at <2 hours (49.2% vs. 47.4%, p = 0.02). In infants <28 weeks GA, the 12–36 hours hematocrit was higher in the 60-75s DCC group compared to the 30-45s DCC group (47.9% vs. 42.1%, p = 0.002). The 60-75s DCC group had reductions in DR intubation (11% vs. 22%, p = 0.004), hypothermia on admission (1% vs. 5%, p = 0.01), surfactant therapy (13% vs. 28%, p = 0.001), intubation in the first 24 hours (20% vs. 34%, p = 0.004), any intubation (27% vs. 40%, p = 0.007), and any red blood cell transfusion (20% vs. 33%, p = 0.008) during the hospitalization compared to the 30-45s DCC group. These reductions remained significant after adjusting for GA, gender and >48 hours of antenatal steroid exposure. There was no difference between the two groups in neonatal death, intraventricular hemorrhage, chronic lung disease, late onset sepsis, necrotizing enterocolitis and severe retinopathy of prematurity.

Conclusion

In this study cohort increasing DCC duration from 30-45s to 60-75s is associated with decreased hypothermia on admission, neonatal respiratory interventions and red blood cell transfusions without increase in neonatal mortality and morbidities.     

Multi-Modal Assessment of Long-Term Erythropoietin Treatment after Neonatal Hypoxic-Ischemic Injury in Rat Brain

Erythropoietin (EPO) has been recognized as a neuroprotective agent. In animal models of neonatal brain injury, exogenous EPO has been shown to reduce lesion size, improve structure and function. Experimental studies have focused on short course treatment after injury. Timing, dose and length of treatment in preterm brain damage remain to be defined. We have evaluated the effects of high dose and long-term EPO treatment in hypoxic-ischemic (HI) injury in 3 days old (P3) rat pups using histopathology, magnetic resonance imaging (MRI) and spectroscopy (MRS) as well as functional assessment with somatosensory-evoked potentials (SEP). After HI, rat pups were assessed by MRI for initial damage and were randomized to receive EPO or vehicle. At the end of treatment period (P25) the size of resulting cortical damage and white matter (WM) microstructure integrity were assessed by MRI and cortical metabolism by MRS. Whisker elicited SEP were recorded to evaluate somatosensory function. Brains were collected for neuropathological assessment. The EPO treated animals did not show significant decrease of the HI induced cortical loss at P25. WM microstructure measured by diffusion tensor imaging was improved and SEP response in the injured cortex was recovered in the EPO treated animals compared to vehicle treated animals. In addition, the metabolic profile was less altered in the EPO group. Long-term treatment with high dose EPO after HI injury in the very immature rat brain induced recovery of WM microstructure and connectivity as well as somatosensory cortical function despite no effects on volume of cortical damage. This indicates that long-term high-dose EPO induces recovery of structural and functional connectivity despite persisting gross anatomical cortical alteration resulting from HI.     

Decreased Resting Functional Connectivity after Traumatic Brain Injury in the Rat

Traumatic brain injury (TBI) contributes to about 10% of acquired epilepsy. Even though the mechanisms of post-traumatic epileptogenesis are poorly known, a disruption of neuronal networks predisposing to altered neuronal synchrony remains a viable candidate mechanism. We tested a hypothesis that resting state BOLD-fMRI functional connectivity can reveal network abnormalities in brain regions that are connected to the lesioned cortex, and that these changes associate with functional impairment, particularly epileptogenesis. TBI was induced using lateral fluid-percussion injury in seven adult male Sprague-Dawley rats followed by functional imaging at 9.4T 4 months later. As controls we used six sham-operated animals that underwent all surgical operations but were not injured. Electroencephalogram (EEG)-functional magnetic resonance imaging (fMRI) was performed to measure resting functional connectivity. A week after functional imaging, rats were implanted with bipolar skull electrodes. After recovery, rats underwent pentyleneterazol (PTZ) seizure-susceptibility test under EEG. For image analysis, four pairs of regions of interests were analyzed in each hemisphere: ipsilateral and contralateral frontal and parietal cortex, hippocampus, and thalamus. High-pass and low-pass filters were applied to functional imaging data. Group statistics comparing injured and sham-operated rats and correlations over time between each region were calculated. In the end, rats were perfused for histology. None of the rats had epileptiform discharges during functional imaging. PTZ-test, however revealed increased seizure susceptibility in injured rats as compared to controls. Group statistics revealed decreased connectivity between the ipsilateral and contralateral parietal cortex and between the parietal cortex and hippocampus on the side of injury as compared to sham-operated animals. Injured animals also had abnormal negative connectivity between the ipsilateral and contralateral parietal cortex and other regions. Our data provide the first evidence on abnormal functional connectivity after experimental TBI assessed with resting state BOLD-fMRI.     

Leukocyte Telomere Length in Young Adults Born Preterm: Support for Accelerated Biological Ageing

Background

Subjects born preterm have an increased risk for age-associated diseases, such as cardiovascular disease in later life, but the underlying causes are largely unknown. Shorter leukocyte telomere length (LTL), a marker of biological age, is associated with increased risk of cardiovascular disease.

Objectives

To compare LTL between subjects born preterm and at term and to assess if LTL is associated with other putative cardiovascular risk factors at young adult age.

Methods

We measured mean LTL in 470 young adults. LTL was measured using a quantitative PCR assay and expressed as T/S ratio. We analyzed the influence of gestational age on LTL and compared LTL between subjects born preterm (n = 186) and at term (n = 284). Additionally, we analyzed the correlation between LTL and potential risk factors of cardiovascular disease.

Results

Gestational age was positively associated with LTL (r = 0.11, p = 0.02). Subjects born preterm had shorter LTL (mean (SD) T/S ratio = 3.12 (0.44)) than subjects born at term (mean (SD) T/S ratio = 3.25 (0.46)), p = 0.003). The difference remained significant after adjustment for gender and size at birth (p = 0.001). There was no association of LTL with any one of the putative risk factors analyzed.

Conclusions

Young adults born preterm have shorter LTL than young adults born at term. Although we found no correlation between LTL and risk for CVD at this young adult age, this biological ageing indicator may contribute to CVD and other adult onset diseases at a later age in those born preterm.     

Systemic Evaluation of Hypoxic-Ischemic Brain Injury in Neonatal Rats

The objective of the study was to evaluate the systematically rat model of neonatal hypoxic-ischemic brain damage. The right carotid arteries of 7-day-old healthy Wistar rats were ligated, and then, the rats were subjected to an environment with 8 % of oxygen. Four weeks after the birth, neurobehavioral test, water maze test, and motor-evoked potential and neuropathologic examinations were performed. The footprint analysis showed significantly larger and instable paces in the hypoxic-ischemic group (P < 0.05); the time that rats crossed the balance beam in the hypoxic-ischemic group was longer than the control group (P < 0.05). The water maze test showed that the escape latency of hypoxic-ischemic group was significantly longer than that of control group (P < 0.05). The hindlimb quadriceps compound muscle-evoked potential CMEP of rats in hypoxic-ischemic group showed that the wave amplitude was lower than that of control group (P < 0.05). HE staining showed visible periventricular leukomalacia in hypoxic-ischemic groups; disrupted nuclear membrane was detected in the IH group with transelectronmicroscopy; Immunohistochemistry: compared with control group, MBP-positive neurocytes decreased, glial fibrillary acidic protein positive neurocytes increased in the periventricular zone (P < 0.05). Carotid artery ligation combining the hypoxic chamber created a reliable and stable rat model of neonatal hypoxic-ischemic brain damage and can be used for experimental research related to management of cerebral palsy.     

Comparison in Outcomes at Two-Years of Age of Very Preterm Infants Born in 2000, 2005 and 2010

ObjectiveTo investigate alteration in 2-year neurological/behavioral outcomes of very preterm infants born in a French level three neonatal intensive care unit.MethodsWe conducted a prospective, comparative study of very preterm infants born before 33 weeks’ gestation at 5-year intervals in 2000, 2005 and 2010 at Rouen University Hospital. Neonatal mortality/morbidities, ante- and neonatal treatments, and at age 2 years motor, cognitive and behavioral data were collected by standardized questionnaires.ResultsWe included 536 very preterm infants. Follow-up rates at two years old were 78% in 2000, 93% in 2005 and 92% in 2010 respectively. No difference in gestational age, birthweight, neonatal mortality/morbidities was observed except a decrease in low grade subependymal/intraventricular hemorrhages. Care modifications concerned use of antenatal magnesium sulfate, breast-feeding and post-natal corticosteroid therapy. Significant improvement in motor outcome and dramatic decrease in cerebral palsy rates (12% in 2000, 6% in 2005, 1% in 2010, p<0.001) were observed, as were improvements in feeding behavior. Although a non significant difference to better psychosocial behavior was reported, there was no difference in cognitive outcome.ConclusionsImprovement in neuromotor outcome and behavior was reported. This could be due to multiple modifications in care: including administration of magnesium sulfate to women at risk of preterm birth, increase in breast-feeding, decrease in low grade subependymal/intraventricular hemorrhages, and decrease in post-natal corticosteroid therapy, all of which require further investigation in other studies. Extended follow-up until school age is mandatory for better detection of cognitive, learning and behavioral disorders.     

Neonatal White Matter Abnormalities an Important Predictor of Neurocognitive Outcome for Very Preterm Children

Background

Cerebral white matter abnormalities on term MRI are a strong predictor of motor disability in children born very preterm. However, their contribution to cognitive impairment is less certain.

Objective

Examine relationships between the presence and severity of cerebral white matter abnormalities on neonatal MRI and a range of neurocognitive outcomes assessed at ages 4 and 6 years.

Design/Methods

The study sample consisted of a regionally representative cohort of 104 very preterm (≤32 weeks gestation) infants born from 1998–2000 and a comparison group of 107 full-term infants. At term equivalent, all preterm infants underwent a structural MRI scan that was analyzed qualitatively for the presence and severity of cerebral white matter abnormalities, including cysts, signal abnormalities, loss of white matter volume, ventriculomegaly, and corpus callosal thinning/myelination. At corrected ages 4 and 6 years, all children underwent a comprehensive neurodevelopmental assessment that included measures of general intellectual ability, language development, and executive functioning.

Results

At 4 and 6 years, very preterm children without cerebral white matter abnormalities showed no apparent neurocognitive impairments relative to their full-term peers on any of the domain specific measures of intelligence, language, and executive functioning. In contrast, children born very preterm with mild and moderate-to-severe white matter abnormalities were characterized by performance impairments across all measures and time points, with more severe cerebral abnormalities being associated with increased risks of cognitive impairment. These associations persisted after adjustment for gender, neonatal medical risk factors, and family social risk.

Conclusions

Findings highlight the importance of cerebral white matter connectivity for later intact cognitive functioning amongst children born very preterm. Preterm born children without cerebral white matter abnormalities on their term MRI appear to be spared many of the cognitive impairments commonly associated with preterm birth. Further follow-up will be important to assess whether this finding persists into the school years.     

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.     

Decreased Bone Mineral Density in Adults Born with Very Low Birth Weight: A Cohort Study

Background

Very-low-birth-weight (VLBW, <1,500 g) infants have compromised bone mass accrual during childhood, but it is unclear whether this results in subnormal peak bone mass and increased risk of impaired skeletal health in adulthood. We hypothesized that VLBW is associated with reduced bone mineral density (BMD) in adulthood.

Methods and Findings

The Helsinki Study of Very Low Birth Weight Adults is a multidisciplinary cohort study representative of all VLBW births within the larger Helsinki area from 1978 to 1985. This study evaluated skeletal health in 144 such participants (all born preterm, mean gestational age 29.3 wk, birth weight 1,127 g, birth weight Z score 1.3), and in 139 comparison participants born at term, matched for sex, age, and birth hospital. BMD was measured by dual energy X-ray absorptiometry at age 18.5 to 27.1 y. Adults born with VLBW had, in comparison to participants born at term, a 0.51-unit (95% confidence interval [CI] 0.28–0.75) lower lumbar spine Z score and a 0.56-unit (95% CI 0.34–0.78) lower femoral neck Z score for areal BMD. These differences remained statistically significant after adjustment for the VLBW adults'' shorter height and lower self-reported exercise intensity.

Conclusions

Young adults born with VLBW, when studied close to the age of peak bone mass, have significantly lower BMD than do their term-born peers. This suggests that compromised childhood bone mass accrual in preterm VLBW children translates into increased risk for osteoporosis in adulthood, warranting vigilance in osteoporosis prevention. Please see later in the article for the Editors'' Summary     

Valproate Administered after Traumatic Brain Injury Provides Neuroprotection and Improves Cognitive Function in Rats

Background

Traumatic brain injury (TBI) initiates a complex series of neurochemical and signaling changes that lead to pathological events including neuronal hyperactivity, excessive glutamate release, inflammation, increased blood-brain barrier (BBB) permeability and cerebral edema, altered gene expression, and neuronal dysfunction. It is believed that a drug combination, or a single drug acting on multiple targets, may be an effective strategy to treat TBI. Valproate, a widely used antiepileptic drug, has a number of targets including GABA transaminase, voltage-gated sodium channels, glycogen synthase kinase (GSK)-3, and histone deacetylases (HDACs), and therefore may attenuate a number of TBI-associated pathologies.

Methodology/Principal Findings

Using a rodent model of TBI, we tested if post-injury administration of valproate can decrease BBB permeability, reduce neural damage and improve cognitive outcome. Dose-response studies revealed that systemic administration of 400 mg/kg (i.p.), but not 15, 30, 60 or 100 mg/kg, increases histone H3 and H4 acetylation, and reduces GSK-3 activity, in the hippocampus. Thirty min post-injury administration of 400 mg/kg valproate improved BBB integrity as indicated by a reduction in Evans Blue dye extravasation. Consistent with its dose response to inhibit GSK-3 and HDACs, valproate at 400 mg/kg, but not 100 mg/kg, reduced TBI-associated hippocampal dendritic damage, lessened cortical contusion volume, and improved motor function and spatial memory. These behavioral improvements were not observed when SAHA (suberoylanilide hydroxamic acid), a selective HDAC inhibitor, was administered.

Conclusion/Significance

Our findings indicate that valproate given soon after TBI can be neuroprotective. As clinically proven interventions that can be used to minimize the damage following TBI are not currently available, the findings from this report support the further testing of valproate as an acute therapeutic strategy.