Using guidelines of the Meta-analysis of Observational Studies in Epidemiology Group, we systematically reviewed the literature on neonatal jaundice (unconjugated hyperbilirubinemia) and Autism Spectrum Disorder (ASD) in term and preterm infants. Thirteen studies were included in a meta-analysis. Most used retrospective matched case–control designs. There was significant heterogeneity (Q = 31, p = 0.002) and no evidence of publication bias (p = 0.12). Overall, jaundice, assessed by total serum bilirubin (TSB), was associated with ASD (OR, 1.43, 95% CI 1.22–1.67, random effect model). This association was not found in preterms (OR 0.7, 95% CI 0.38–1.02) but deserves further investigation since other measures of bilirubin such as unbound unconjugated bilirubin may be better predictors of neurotoxicity than TSB in preterms.
Unconjugated hyperbilirubinemia; Free bilirubin; Premature infants; Meta-analysis
The lipid intake at which a significant bilirubin-displacing effect occurs as a function of gestational age (GA) is unclear.
To determine the effect of gradual increase in IL intake from 1.5 to 3 g/kg per day on bilirubin-albumin binding variables as a function of GA in premature infants with indirect hyperbilirubinemia.
Infants of 24 to 33 weeks’ gestation at birth who received IL (20% Intralipid [Fresenius Kabi, Uppsala, Sweden]) doses of 1.5, 2, 2.5, and 3 g/kg per day over 4 consecutive days were prospectively evaluated. The blood samples were drawn twice at least 8 hours apart on each IL intake to measure total serum bilirubin and free bilirubin by the peroxidase test. The highest free bilirubin on each IL intake, the corresponding total serum bilirubin, and serum albumin were used to calculate the bilirubin/albumin binding constant or binding affinity.
Sixty-two infants (median GA: 28 weeks) were studied during the first 10 days of life. None of the subjects had culture-proven sepsis, had triglyceride levels of >2.05 mmol/L, or were receiving steroids. Infants were grouped in 2-week GA intervals. The cumulative frequency of elevated free bilirubin concentration (≥90th percentile or Bf ≥ 32 nmol/L) as a function of IL intake was inversely related to GA and was significantly different among 2-week GA groups. There was significant decrease in binding affinity and increase in free bilirubin concentration with higher IL intake for ≤28 week but not for >28 week GA groups.
The IL intake may be associated with a significant fall in the binding affinity of bilirubin for plasma protein and a concomitant increase in free bilirubin concentration in premature infants. The lipid intake at which this occurs depends on GA.
free bilirubin; bilirubin-albumin binding; intravenous lipid emulsion; premature infants
The NLRP3 inflammasome plays key roles in inflammation and autoimmunity, and puriner-gic receptor P2X7 has been proposed to be upstream of NLRP3 activation. The aim of the present study, using murine models, was to investigate whether the P2X7/ NLRP3 inflammasome pathway contributes to the pathogenesis of lupus nephritis (LN).
MRL/lpr mice were treated with the selective P2X7 antagonist brilliant blue G (BBG) for 8 weeks. Following treatment, the severity of renal lesions, production of anti-double-stranded DNA (anti-dsDNA) antibodies, rate of survival, activation of the NLRP3/ ASC/caspase 1 inflammasome pathway, and ratio of Thl7 cells to Treg cells were evaluated. P2X7-targeted small interfering RNA (siRNA) was also used for in vivo intervention. Similar evaluations were carried out in NZM2328 mice, a model of LN in which the disease was accelerated by administration of adenovirus-expressing interferon-α (AdIFNα).
Significant up-regulation of P2X7/NLRP3 inflammasome signaling molecules was detected in the kidneys of MLR/lpr mice as compared with normal control mice. Blockade of P2X7 activation by BBG suppressed NLRP3/ASC/caspase 1 assembly and the subsequent release of interleukin-1β (IL-1β), resulting in a significant reduction in the severity of nephritis and circulating anti-dsDNA antibodies. The lifespan of the treated mice was significantly prolonged. BBG treatment reduced the serum levels of IL-1β and IL-17 and the Thl7:Treg cell ratio. Similar results were obtained by specific siRNA silencing of P2X7 in vivo. The effectiveness of BBG treatment in modulating LN was confirmed in NZM2328 mice with AdIFNα-accelerated disease.
Activation of the P2X7 signaling pathway accelerates murine LN by activating the NLRP3/ASC/caspase 1 inflammasome, resulting in increased IL-1β production and enhanced Thl7 cell polarization. Thus, targeting of the P2X7/NLRP3 pathway should be considered as a novel therapeutic strategy in patients with lupus.
The epidemiologic profile of infective endocarditis has changed substantially over the past few years, especially in industrialized countries. Our study evaluates the clinical and pathologic characteristics of infective endocarditis patients treated by cardiac surgery in China during a 12-year period.
We retrospectively evaluated 220 surgically treated infective endocarditis patients and analyzed their changes from the beginning of 1998 through 2009. The mean age of the patients increased from 36.9 to 42.7 years during those 12 years (P=0.036). The chief predisposing disease was congenital heart disease (32.8%), rather than rheumatic heart disease (13.2%); this rate did not change significantly during the 12 years. The prevalent congenital lesion was bicuspid aortic valve, the rate of which (55.6%) increased significantly over the 3 time intervals studied (P=0.016). The frequency of infective endocarditis after non-dental surgical and nonsurgical intervention was significantly greater (23.3%) during 1998 through 2001, compared with the 2 intervals that followed (9%; P=0.019). Streptococcus viridans was the most frequent causative agent overall (25.6%). Forty-seven of the 220 patients (21.4%) carried the clinical diagnosis of some other form of heart disease before surgery, but at surgery they were found to have infective endocarditis as the fundamental disease process. Of 47 patients, 33 (70.2%) had either very small or no vegetations but had focal necrosis and inflammation of valve tissue that supported the diagnosis of infective endocarditis.
Clinicopathology; endocarditis, infective; heart defects, congenital; heart valves/abnormalities; mitral valve prolapse; prosthesis-related infections; retrospective studies; rheumatic heart disease; staphylococcal infections; streptococcal infections
Umbilical cord blood has been used for a wide variety of immunologic investigations including assessments of developmental perturbations by antenatal exposures. Recent advances in multiparameter flow cytometry have allowed finer characterization of lymphocyte phenotype and function, revealing important differences between the fetal and adult immune systems. The degree of variability between human subjects confounds the ability to draw firm conclusions. Artifacts resulting from processing techniques exacerbate this variability. The unpredictable nature of deliveries, especially of premature infants, makes it difficult to control variables such as timing of umbilical cord mononuclear cell (UCMC) isolation and method of collection. Additionally, in multicenter studies dependent on central processing, delays are inevitable. However, little available literature describes systematic testing of the degree to which processing variations affect UCMC phenotype and function. Using multiparameter flow cytometry, we tested the effect of collection technique and length of time prior to UCMC isolation on T cell phenotype and function, with the goal of creating a standardized operating procedure for a multicenter investigation. The study also provides a benchmark data set including extensive surface and functional phenotyping of umbilical cord T cells. UCMC isolation delay of up to 24 h produced similar T cell phenotype and function as tested by in vitro SEB stimulation. There were few statistically significant differences between time points based on data medians. We conclude that, for the purpose of immunologic investigations, a 24-h time delay from sample collection to mononuclear cell isolation does not introduce a significant degree of variation in T cell phenotype and function when adhering to strict standard operating procedures.
umbilical cord blood; T-lymphocytes; phenotype; neonate; immunologic techniques; cell isolation; flow cytometry
The log-transformation is widely used in biomedical and psychosocial research to deal with skewed data. This paper highlights serious problems in this classic approach for dealing with skewed data. Despite the common belief that the log transformation can decrease the variability of data and make data conform more closely to the normal distribution, this is usually not the case. Moreover, the results of standard statistical tests performed on log-transformed data are often not relevant for the original, non-transformed data.We demonstrate these problems by presenting examples that use simulated data. We conclude that if used at all, data transformations must be applied very cautiously. We recommend that in most circumstances researchers abandon these traditional methods of dealing with skewed data and, instead, use newer analytic methods that are not dependent on the distribution the data, such as generalized estimating equations (GEE).
hypothesis testing; outliners; lon-normal distribution; normal distribution; skewness
Emerging evidence suggests that excess iron may be detrimental for brain development. However, little is known regarding the association between neonatal iron overload and subsequent neurodevelopment during infancy in vulnerable premature infants.
To evaluate the association between neonatal iron overload and neurodevelopment in premature infants.
Prospective cohort study
24–32 weeks gestational age infants who had serum ferritin (SF) measured at 34–35 weeks post-menstrual age (PMA) and did not meet exclusion criteria: SF < 76 ng/ml, toxoplasmosis, syphilis, rubella, cytomegalovirus, herpes infections, chromosomal disorders, or cranio-facial anomalies were eligible. In addition, infants with sepsis or elevated C-reactive protein within 10 days before their SF measurement were excluded.
Infants were evaluated for neurodevelopmental outcome at 8–12 months of age and were deemed to have neurodevelopmental impairment if they had one or more of the following: mental developmental index < 70, abnormal neurological examination, bilateral blindness, bilateral deafness, or required occupational, physical, or speech therapy.
95 infants were studied. 70 had normal iron status (SF 76–400 ng/ml) while 25 were deemed to have iron overload (SF >400 ng/ml) at 34–35 weeks PMA. There was a marginal increase in neurodevelopmental impairment among infants with iron overload compared to infants with normal iron status (64% vs. 41%, p = 0.05). However, after controlling for confounders, iron overload was not associated with neurodevelopmental impairment (Adjusted OR 0.71, 95% CI, 0.21 – 2.5).
Modest neonatal iron overload is not associated with neurodevelopmental impairment during infancy in premature infants.
premature infants; neurodevelopmental impairment; oxidative stress; iron overload; latent iron deficiency
Experimental animal studies and adult research consistently show that stress exposure and/or psychological symptoms are associated with poorer health and immune function. The application to children is not yet clear, however, and we lack developmental models for studies in this area. The objective of this paper was to test the hypothesis that self-reported self-efficacy and depression, two markers of psychological well-being in children, would predict immunity and rate of illnesses. The data are based on a prospective study of 141 healthy, normally developing children aged 7 – 13 years who were recruited from an ambulatory pediatric setting. Children completed self-efficacy and depression measures and had blood obtained for IL-6 plasma levels and natural killer (NK) cell functional assays on three occasions, six months apart. Parents maintained weekly child illness diaries over one year, using a thermometer to record fever. Parent psychiatric symptoms and income were used as covariates. Results indicated that, across the three occasions of measurement collected over the one-year period, higher perceived self-efficacy was significantly associated with lower plasma IL-6 concentrations. There was no overall main effect of depressive symptoms on immune measures; however, for older girls, higher depression was associated with elevated NK cell cytotoxicity and an increased rate of total illnesses and febrile illnesses. The findings provide some of the first evidence that psychological processes are associated with immunity and health in a normally developing sample of pre-adolescents. Furthermore, the pattern of results suggests a modified model of a link between psychological well-being and immunological processes in children. These results build on and expand research on the notion of allostatic load, and develop a groundwork for developmental studies in this area.
Self efficacy; depression; interleukin 6; children’s health
To evaluate the impact of the School-Based Asthma Therapy trial on asthma symptoms among urban children with persistent asthma.
Randomized trial, with children stratified by smoke exposure in the home and randomized to a school-based care group or a usual care control group.
Rochester, New York.
Children aged 3 to 10 years with persistent asthma.
Directly observed administration of daily preventive asthma medications by school nurses (with dose adjustments according to National Heart, Lung, and Blood Institute Expert Panel guidelines) and a home-based environmental tobacco smoke reduction program for smoke-exposed children, using motivational interviewing.
Main Outcome Measure
Mean number of symptom-free days per 2 weeks during the peak winter season (November-February), assessed by blinded interviews.
We enrolled 530 children (74% participation rate). During the peak winter season, children receiving preventive medications through school had significantly more symptom-free days compared with children in the control group (adjusted difference=0.92 days per 2 weeks; 95% confidence interval, 0.50-1.33) and also had fewer nighttime symptoms, less rescue medication use, and fewer days with limited activity (allP<.01). Children in the treatment group also were less likely than those in the control group to have an exacerbation requiring treatment with prednisone (12% vs 18%, respectively; relative risk=0.64; 95% confidence interval, 0.41-1.00). Stratified analyses showed positive intervention effects even for children with smoke exposure (n=285; mean symptom-free days per 2 weeks: 11.6 for children in the treatment group vs 10.9 for those in the control group; difference=0.96 days per 2 weeks; 95% confidence interval, 0.39-1.52).
The School-Based Asthma Therapy intervention significantly improved symptoms among urban children with persistent asthma. This program could serve as a model for improved asthma care in urban communities.
Influenza vaccine immunogenicity in premature infants is incompletely characterized.
To assess the immunogenicity of trivalent, inactivated influenza vaccine (TIV) in extremely low-birth-weight (ELBW, ≤1000 grams birth weight), premature (<30 weeks gestation) infants. We hypothesized that geometric mean titers (GMT) of influenza antibody would be lower in premature than in full-term (≥37 week) infants.
In this prospective, multicenter study, former premature and full-term infants ages, 6–17 months, received 2 doses of TIV during the 2006–7 or 2007–8 influenza seasons. Sera were drawn before dose 1 and 4–6 weeks after dose 2. Antibody was measured by hemagglutination inhibition.
Over two years, 41 premature and 42 full-term infants were enrolled; 36 and 33 of these infants, respectively, had post-vaccination titers available. Premature infants weighed less (mean 1.3 – 1.8 kg difference) at the time of immunization than full-term infants. Pre-vaccination titers did not differ between groups. Premature infants had higher post-vaccination antibody GMT than full-term infants to H1 (2006–7, 1:513 v. 1:91, P=0.03; 2007–8, 1:363 v. 1:189, P=0.02) and B/Victoria (2006–7, 1:51 v. 1:10, P=0.02). More premature than full-term infants had antibody titers ≥ 1:32 to B/Victoria (85% v. 60%, p=0.04) in 2007–8. Two (5%) premature and 8 (19%) full-term infants had adverse events, primarily fever, within 72 hours after vaccination. No child had medically-diagnosed influenza.
Former premature infants had antibody responses to two TIV doses greater than or equal to those of full-term children. Two TIV doses are immunogenic and well tolerated in ELBW, premature infants 6–17 months old.
Premature infant; very low birth weight infant; influenza vaccines; immunization; vaccines
Set-shifting is a neurocognitive concept defined as the ability to switch tasks flexibly. Set-shifting scores are worse in adults with Restrictive Anorexia Nervosa (AN-R) than in controls. Adolescence is a developmental period when young people must respond flexibly to new situations. The purpose of this study is to compare the set-shifting scores of 24 adolescent females with AN-R and 37 matched normal adolescent controls (ages 14–20).
Methods included sociodemographic, psychological and biologic data, and neurocognitive testing using the Behavior Rating of Executive Function – Self- and Parent-Reports, the Cambridge Neuropsychological Automated Battery, and the Wisconsin Card-Sorting Test. Statistical analyses included t-tests, multiple analysis of variance, and correlations.
Study and control subjects were similar on sociodemographic data and intelligence quotient. There were differences in Body Mass Index and the Eating Disorder-3 evaluation. Significant differences in the composite score of set-shifting between the study and control groups were found using multiple analysis of variance.
Adolescent females with AN-R had significantly worse set-shifting scores than did control subjects. Future studies of adolescent AN-R subjects should include biologic (fMRI) and neurocognitive measures to determine the mechanisms at the brain-behavioral interface so that treatment can be directed specifically to set-shifting deficits.
To determine the change in parental ratings of executive function and behavior in children with primary hypertension following antihypertensive therapy.
Parents of untreated hypertensive subjects and controls completed the Behavior Rating Inventory of Executive Function (BRIEF) to assess behavioral correlates of executive function and the Child Behavior Checklist (CBCL) to assess internalizing and externalizing behaviors. Hypertensive subjects subsequently received antihypertensive therapy to achieve casual BP < 95th percentile. After 12 months, all parents again completed the BRIEF and CBCL.
Twenty-two subjects with hypertension and 25 normotensive control subjects had both baseline and 12-month assessments. Hypertensive subject’s blood pressure improved (24-hr systolic BP load: mean baseline vs. 12-months, 60 vs. 25%, p < 0.001). Parent ratings of executive function improved from baseline to 12-months in the hypertensives (BRIEF Global Executive Composite T-score, Δ = −5.9, p = 0.001) but not in the normotensive controls (Δ = −0.36, p = 0.83). In contrast, T-scores on the Child Behavior Checklist Internalizing and Externalizing summary scales did not change significantly from baseline to 12-months in either hypertensive or control subjects.
Children with hypertension demonstrated improvement in parental ratings of executive function after 12 months of antihypertensive therapy.
Neurocognitive function; blood pressure; treatment
Human herpesvirus 6 (HHV-6) causes ubiquitous infection in early childhood with lifelong latency or persistence. Reactivation of HHV-6 has been associated with multiple diseases including encephalitis. Chromosomal integration of HHV-6 also occurs. Previous studies have suggested that the detection of HHV-6 DNA in plasma is an accurate marker of active viral replication.
We sought to determine whether PCR assays on plasma could correctly differentiate between primary HHV-6 infection, chromosomal integration of HHV-6 and latent HHV-6 infection.
We performed qualitative PCR, real-time quantitative PCR (RQ-PCR), and reverse-transcriptase PCR (RT-PCR) assays on samples of peripheral and cord blood mononuclear cells, as well as plasma, from groups of subjects with well defined HHV-6 infection, including subjects with chromosomally integrated HHV-6.
Results and Conclusions
The detection of HHV-6 DNA in plasma was 92% sensitive compared to viral isolation for the identification of primary infection with HHV-6. All plasma samples from infants with chromosomally integrated HHV-6 had HHV-6 DNA detectable in plasma while only 5.6% were positive by RT-PCR. The specificity of plasma PCR for active replication of HHV-6 was 84% compared to viral culture while the specificity of RT-PCR was 98%. Our results demonstrate that qualitative or quantitative PCR of plasma is insufficient to distinguish between active viral replication and chromosomal integration with HHV-6. We found a higher specificity of RT-PCR performed on PBMC samples compared to PCR or RQ-PCR performed on plasma when evaluating samples for active HHV-6 replication.
Human herpesvirus 6; chromosomally integrated HHV-6 (CI-HHV-6); polymerase chain reaction; real time quantitative polymerase chain reaction (RQ-PCR); reverse transcriptase polymerase chain reaction (RT-PCR)
Prader-Willi syndrome is a genetic disorder characterized by obesity. The Figure Rating Scale (Stunkard, Sorensen, & Schulsinger, 1983) was completed by 43 individuals with this syndrome to determine their level of dissatisfaction with their body. Their parents also completed this scale regarding their child to determine whether they were dissatisfied with their child’s body status. Results showed that individuals with Prader-Willi syndrome were dissatisfied with their body. Parents also were dissatisfied with their child’s body. Results of this study demonstrate that the responses of persons with Prader-Willi syndrome on the Figure Rating Scale show significant discrepancies between how they think they look and how they wished they looked.
To determine the relations between hypertension and parental ratings of behavior and executive functions in children with primary hypertension and to examine the potential moderating influence of obesity.
Hypertensive and normotensive control groups were matched for age, sex, race, intelligence quotient, maternal education, household income, and obesity. Parents completed the Child Behavior Checklist (CBCL) to assess Internalizing and Externalizing problems and the Behavior Rating Inventory of Executive Function (BRIEF) to assess behavioral correlates of executive function.
Thirty-two hypertensive subjects and 32 normotensive controls (10 –18y) were enrolled. On the CBCL, hypertensives had higher Internalizing T-scores (53 vs. 44.5, p = 0.02) with 37% falling within the clinically significant range vs. 6% of controls (p = 0.005). Internalizing score increased with increasing BMI percentile in hypertensive, but not normotensive, subjects. Hypertensives had worse BRIEF Global Executive Composite (GEC) T-scores compared with controls (50 vs. 43, p = 0.009).
Children with both hypertension and obesity demonstrate higher rates of clinically significant internalizing problems, and hypertensives (irrespective of obesity) demonstrate lower parental ratings of executive function compared with normotensive controls.
Neurocognitive function; anxiety; depression; blood pressure
Family processes have a substantial impact on children’s social and emotional well-being, but little is known about the effects of family stress on children’s physical health. To begin to identify potential links between family stress and health in children, we examined associations between specific aspects of family psychosocial stress and the frequency of illnesses in children, measures of innate and adaptive immune function, and human herpesvirus 6 (HHV-6) reactivation.
Prospective study of 169 ambulatory school-age children and parents. Parents completed multiple assessments of stress at 7 sequential six-month visits and maintained weekly illness diaries for their children over three years using a thermometer to record fever. Children had blood obtained for HHV-6 and immune function studies at each visit including natural killer (NK) cell function and the percentage of CD4 and CD8 cells associated with immune control of cytomegalovirus (CMV).
Parental psychiatric symptoms were associated with a higher frequency of illnesses: for each 1 unit increase in symptom score children had an increased 1-year rate of total illnesses of 40% (rate ratio, 1.40; 95% CI, 1.06–1.85) and febrile illnesses of 77% (rate ratio, 1.77, 95% CI, 1.00–3.13). Parental psychiatric symptom scores were also associated with enhanced NK cell function (estimate, 0.15; 95% CI, 0.05–0.26) and increased percentages of CD8+CD28-CD57+ cells in the blood of CMV seropositive children (estimate, 2.57; 95% CI, 0.36–4.79). HHV-6 reactivation was not detected.
There is an association between specific psychosocial stress exposure and rates of illness and immune function in normally developing children.
To determine if children with white coat hypertension (WCH) have evidence of target-organ damage by comparing left ventricular mass index (LVMI) of subjects with WCH to that of matched normotensive and hypertensive controls.
Each WCH subject was matched by body mass index (± 10%), age (± 1 year), and sex to a normotensive control and to a hypertensive control. Echocardiograms were reviewed to determine LVMI for each subject. These triple matches were analyzed using repeated measures analysis of variance to detect differences in LVMI between the three groups.
Twenty-seven matched triplets were established. The groups were comparable for sex, age, and body mass index (BMI). Mean LVMI was 29.2, 32.3, and 35.1 g/m2.7, for normotensives, WCH, and sustained hypertensives, respectively (normotensive vs. WCH, p = 0.028; WCH vs. sustained hypertensive, p = 0.07). Left ventricular hypertrophy was not present in any subject in the normotensive or WCH groups, but was present in 26% of the sustained hypertensive subjects (p < 0.001).
After controlling closely for BMI, children with WCH had a LVMI which was intermediate between that of normotensives and sustained hypertensives, suggesting that WCH may be associated with hypertensive end-organ effects.