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PubMed2026

Gut microbiome composition and predicted functions relate to growth and behavior in a Japanese preschool cohort.

Early childhood is a period of rapid brain maturation and gut microbiome assembly, when emerging behavioral difficulties can shape later mental health and learning trajectories. Microbiota-gut-brain communication has been implicated in neurodevelopment through microbial metabolites and immune signaling. However, most pediatric evidence comes from high-risk or clinically referred cohorts, and gut microbiome-related correlates of typical behavioral variation in community-based preschool children remain poorly defined. In a cross-sectional sample of typically developing Japanese preschool children, we observed exploratory nominal associations between behavioral variation within normative ranges and gut microbiome composition and predicted functions. Internalizing domains showed candidate links with taxa and predicted pathways related to inflammatory potential and nucleotide biosynthesis, whereas somatic complaints and withdrawn behavior showed nominal associations with lower predicted respiratory and fermentative activity. Sleep-related difficulties showed multiple representative nominal pathway-level associations, including pathways related to methyl-donor and heme biosynthesis, while externalizing domains showed candidate links with predicted cell-envelope and carbohydrate-remodeling pathways. In contrast, age, height, and weight tracked expected maturation-related microbiome features, indicating that behavioral associations were not simple proxies of growth. Together, these findings provide an exploratory profile of microbiome-behavior correlations in a low-risk Japanese preschool cohort and highlight pathway-level candidates that may interface with neurodevelopment.

Humans↗

PubMed2026

A novel iPSC model of Bryant-Li-Bhoj neurodevelopmental/neurodegenerative syndrome demonstrates the role of histone H3.3 in chromatin dynamics, neuronal differentiation, and maturation.

BACKGROUND: Bryant-Li-Bhoj neurodevelopmental syndrome (BLBS) is neurogenetic disorder caused by variants in H3-3A and H3-3B, the two genes that encode histone H3.3. Ninety-nine percent of individuals with BLBS show developmental delay/intellectual disability, but the mechanism by which variants in H3.3 result in these phenotypes is not yet understood, limiting the therapeutic interventions available to individuals living with BLBS. METHODS: Here, we investigate how one BLBS-causative variant, H3-3B p.Leu48Arg (L48R), affects neurodevelopment using an induced pluripotent stem cell model differentiated to 2D neural progenitor cells (NPCs), 2D forebrain neurons (FBNs), and 3D dorsal forebrain organoids (DFBOs). We employ a multi-omic approach in the 2D models to quantify the resulting changes in gene expression and chromatin accessibility. We used immunofluorescence (IF) staining to define the identities of cells in the 3D DFBOs and whole-cell patch clamp to investigate the electrophysiological properties of neurons in DFBOs. RESULTS: In the 2D systems, we found dysregulated gene expression and chromatin accessibility affecting neuronal fate, adhesion, neurotransmission, and excitatory/inhibitory balance. Immunofluorescence of DFBOs corroborated altered proportions of radial glia and mature neuronal populations. Patch clamp recordings revealed decreased electrical activity in neurons from L48R DFBOs compared to control DFBOs. CONCLUSIONS: These data provide the first mechanistic insights into the pathogenesis of BLBS from a human-derived model of neurodevelopment, which suggest that H3.3 L48R increases H3-3B expression, resulting in the hyper-deposition of H3.3 into the nucleosome, which underlies changes in gene expression and chromatin accessibility. Functionally, this causes dysregulation of cell adhesion, neurotransmission, and the balance between excitatory and inhibitory signaling. These results are a crucial step towards preclinical development and testing of targeted therapies for this and related disorders.

Histones↗

PubMed2001

Dysregulation of olfactory receptor neuron lineage in schizophrenia.

BACKGROUND: Growing evidence implicates abnormal neurodevelopment in schizophrenia. While neuron birth and differentiation is largely completed by the end of gestation, the olfactory epithelium (OE) is a unique part of the central nervous system that undergoes regeneration throughout life, thus offering an opportunity to investigate cellular and molecular events of neurogenesis and development postmortem. We hypothesized that OE neurons exhibit deviant progress through neurodevelopment in schizophrenia characterized by an increase in immature neurons. METHODS: Olfactory epithelium was removed at autopsy from 13 prospectively assessed elderly subjects who had schizophrenia and 10 nonpsychiatric control subjects. Sections were immunolabeled with antibodies that distinguish OE neurons in different stages of development, including basal cells (low-affinity nerve growth factor receptor, p75NGFR), postmitotic immature neurons (growth-associated protein 43 [GAP43]), and mature olfactory receptor neurons (olfactory marker protein). Absolute and relative densities of each cell type were determined. RESULTS: We observed a significantly lower density of p75NGFR basal cells (37%) in schizophrenia and increases in GAP43 + postmitotic immature neurons (316%) and ratios of GAP43 + postmitotic immature neurons to p75NGFR + cells (665%) and olfactory marker protein + mature neurons to p75NGFR + basal cells (328%). Neuroleptic-free schizophrenia subjects exhibited the highest GAP43 + postmitotic immature neuron values. CONCLUSIONS: Abnormal densities and ratios of OE neurons at different stages of development indicate dysregulation of OE neuronal lineage in schizophrenia. This could be because of intrinsic factors controlling differentiation or an inability to gain trophic support from axonal targets in the olfactory bulb. While caution is necessary in extrapolating developmental findings in mature OE to early brain development, similarities in molecular events suggest that such studies may be instructive.

Aged↗

PubMed2006

Fish intake, contaminants, and human health: evaluating the risks and the benefits.

CONTEXT: Fish (finfish or shellfish) may have health benefits and also contain contaminants, resulting in confusion over the role of fish consumption in a healthy diet. EVIDENCE ACQUISITION: We searched MEDLINE, governmental reports, and meta-analyses, supplemented by hand reviews of references and direct investigator contacts, to identify reports published through April 2006 evaluating (1) intake of fish or fish oil and cardiovascular risk, (2) effects of methylmercury and fish oil on early neurodevelopment, (3) risks of methylmercury for cardiovascular and neurologic outcomes in adults, and (4) health risks of dioxins and polychlorinated biphenyls in fish. We concentrated on studies evaluating risk in humans, focusing on evidence, when available, from randomized trials and large prospective studies. When possible, meta-analyses were performed to characterize benefits and risks most precisely. EVIDENCE SYNTHESIS: Modest consumption of fish (eg, 1-2 servings/wk), especially species higher in the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduces risk of coronary death by 36% (95% confidence interval, 20%-50%; P<.001) and total mortality by 17% (95% confidence interval, 0%-32%; P = .046) and may favorably affect other clinical outcomes. Intake of 250 mg/d of EPA and DHA appears sufficient for primary prevention. DHA appears beneficial for, and low-level methylmercury may adversely affect, early neurodevelopment. Women of childbearing age and nursing mothers should consume 2 seafood servings/wk, limiting intake of selected species. Health effects of low-level methylmercury in adults are not clearly established; methylmercury may modestly decrease the cardiovascular benefits of fish intake. A variety of seafood should be consumed; individuals with very high consumption (> or =5 servings/wk) should limit intake of species highest in mercury levels. Levels of dioxins and polychlorinated biphenyls in fish are low, and potential carcinogenic and other effects are outweighed by potential benefits of fish intake and should have little impact on choices or consumption of seafood (women of childbearing age should consult regional advisories for locally caught freshwater fish). CONCLUSIONS: For major health outcomes among adults, based on both the strength of the evidence and the potential magnitudes of effect, the benefits of fish intake exceed the potential risks. For women of childbearing age, benefits of modest fish intake, excepting a few selected species, also outweigh risks.

Animals↗

PubMed1999

Developmental intervention for preterm infants diagnosed with periventricular leukomalacia.

Preterm infants with periventricular leukomalacia (PVL) were evaluated to determine whether multi-sensory stimulation is safe and to assess whether it improved neurobehavior and neurodevelopment. Thirty preterm infants with documented PVL were randomly assigned to control (n= 15) or experimental (Group E) (n= 15) groups at 33 weeks post-conceptional age. Group E infants received 15 minutes of auditory, tactile, visual, and vestibular (ATVV) intervention twice a day, five days a week, for four weeks during hospitalization. Repeated measures ANOVA demonstrated that Group E infants experienced significant increases in heart and respiratory rate and a 0.72% drop in hemoglobin saturation, coinciding with a significant behavioral state shift from sleep to alertness during intervention. No differences were identified in neurobehavioral function and neurodevelopment, indicating that Group E suffered no injury. Group E had an average hospital stay nine days shorter than that of controls, with the associated cost savings of $213,840. The earlier hospital discharge indicates that ATVV intervention promotes alertness without compromising physiologic status in vulnerable infants.

Analysis of Variance↗

PubMed2000

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants.

BACKGROUND: Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although intermittent positive pressure ventilation (IPPV) saves lives, lung distortion during its use is associated with lung injury and chronic lung disease (CLD). Conventional IPPV is provided at 30-80 breaths per minute while a newer form of ventilation called high frequency oscillatory ventilation (HFOV) provides 'breaths' at 10-15 seconds. This has been shown to result in less lung injury in experimental studies. OBJECTIVES: The objective of this review is to determine whether the elective use of high frequency oscillatory ventilation (HFOV) as compared to conventional ventilation in preterm infants who are mechanically ventilated for the respiratory distress syndrome decreases the incidence of chronic lung disease (CLD) without adverse effects. SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal handsearching by the Cochrane Collaboration, mainly in the English language. Expert informant's search in the Japanese language was made by Prof. Y. Ogawa. SELECTION CRITERIA: Randomized controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who are to be given IPPV. Randomization and commencement of treatment should have been as soon as possible after the start of IPPV and usually in the first 12 hours of life. DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was independently reviewed by the various authors. Each author extracted data separately; they were compared and differences were resolved. The standard method of the Cochrane Neonatal Review Group was used to synthesize the data using relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) for benefits, and number needed to harm (NNH) for adverse effects, were calculated. MAIN RESULTS: Meta-analysis of the six eligible studies comparing HFOV with CV revealed that there is no difference in mortality. There are trends toward decreases in CLD in survivors at 28-30 days, 'death or CLD at 28-30 days' and CLD in survivors at 36-37 weeks postmenstrual age or discharge in the HFOV group. However, there are trends towards increases in severe (grades 3 & 4) intraventricular hemorrhage (IVH) and in periventricular leukomalacia (PVL) in the HFOV group. HFOV results in a small increase in any air leak syndrome (ALS), [summary RR 1.20 (1.03, 1.39)]. Only 2 trials have included neurodevelopmental follow up and more survivors in the HFOV group are abnormal [summary RR 1.26 (1.01, 1.58)]. In the subgroup of four trials where a high volume strategy (HVS) was used, HFOV results in more favourable pulmonary outcomes. There are significantly lower rates of CLD in survivors at 28-30 days [summary RR 0.53 (0.36, 0.76)] and of 'death or CLD at 28-30 days' [summary RR 0.56 (0.40, 0.77) with a non-significant trend towards a reduction in oxygen use at 36-37 weeks postmenstrual age or discharge [summary RR 0.74 (0.55, 1.01)]. There were no differences in the rates of IVH or PVL. Of the four trials in the subgroup using surfactant routinely, three also used the HVS. The trends in results were similar with surfactant to those for the HVS subgroup analysis. One trial suggests that HFOV may reduce the cost of in-hospital care. In the subgroup of two trials (HIFI 1989, Rettwitz-Volk 1998) not using a HVS there is no effect of HFOV on the rate of CLD; however, there is an increase in the rate of PVL [summary RR 1.64 (1.02, 2.64). REVIEWER'S CONCLUSIONS: The overall meta-analyses is dominated by the large HIFI study which did not use the HVS recommended on the basis of animal studies, and in which surfactant was not available. Studies which used HVS have shown some benefits in short term measures of CLD without an in

High-Frequency Ventilation↗

PubMed2000

Restricted versus liberal oxygen exposure for preventing morbidity and mortality in preterm or low birth weight infants.

BACKGROUND: This section is under preparation and will be included in the next issue. OBJECTIVES: In preterm or low birth weight infants, does targeting ambient oxygen concentration to achieve a lower versus higher blood oxygen range, or administering restricted versus liberal supplemental oxygen, influence mortality, retinopathy of prematurity, lung function, growth or development? SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was used. An additional literature search was conducted of the MEDLINE, EMBASE, and CINAHL databases in order to locate any trials in addition to those provided by the Cochrane Controlled Trials Register (CENTRAL/CCTR). SELECTION CRITERIA: All trials in preterm or low birth weight infants utilising random or quasi-random patient allocation, in which ambient oxygen concentrations were targeted to achieve a lower versus higher blood oxygen range, or restricted versus liberal oxygen was administered, were eligible for inclusion. DATA COLLECTION AND ANALYSIS: The methodological quality of the eligible trials was assessed independently by each author for the degree selection, performance, attrition and detection bias. Data were extracted and reviewed independently by the each author. Data analysis was conducted according to the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: The restriction of oxygen significantly reduced the incidence and severity of retinopathy of prematurity without unduly increasing death rates in the meta-analysis of the five trials included in this review. The one trial that specifically addressed the question of lower versus higher PaO2 found no effect on death, but did not report (in sufficient detail to warrant inclusion) the effect of this intervention on eye or other outcomes. The effects of either of these oxygen administration policies on other clinically meaningful outcomes including chronic lung disease and long term growth, neurodevelopment, lung or visual function were not reported in any of the available trials. REVIEWER'S CONCLUSIONS: The results of this meta-analysis confirm the commonly held view of today's clinicians that a policy of unrestricted, unmonitored oxygen therapy has potential harms, without clear benefits. However, the question of what is the optimal target range for maintaining blood oxygen levels in preterm/LBW infants was not answered by the data available for inclusion in this review.

Humans↗

PubMed2000

Routine doppler ultrasound in pregnancy.

BACKGROUND: Doppler ultrasound study of umbilical artery waveforms helps identify the compromised fetus in 'high risk' pregnancies and, therefore, deserves assessment as a screening test in 'low risk' pregnancies. One of the main aims of routine antenatal care is to identify the 'at risk' fetus in order to apply clinical interventions which could result in reduced perinatal morbidity and mortality. OBJECTIVES: To assess the effects on obstetric practice and pregnancy outcome of routine Doppler ultrasound in unselected and low risk pregnancies. SEARCH STRATEGY: The Cochrane Pregnancy and Childbirth Group Specialised Register of Controlled Trials and the Cochrane Controlled Trials Register were searched. Date of last search: September 1999 SELECTION CRITERIA: Acceptably controlled trials of routine Doppler ultrasound (umbilical circulation and/or uterine circulation) in unselected or low risk pregnancies. DATA COLLECTION AND ANALYSIS: Both reviewers assessed trial quality and extracted data. Authors of two trials were contacted for additional information. MAIN RESULTS: Five trials were included which recruited 14,338 women. The methodological quality of the trials was generally good. Based on existing evidence, routine Doppler ultrasound examination in low risk or unselected populations did not result in increased antenatal, obstetric and neonatal interventions, and no overall differences were detected for substantive short term clinical outcomes such as perinatal mortality. There is no available evidence to assess the effect on substantive long term outcomes such as childhood neurodevelopment. There is no available evidence to assess maternal outcomes, particularly psychological effects. In two studies there were unexpected findings suggesting possible harmful effects, but the explanation for this is not clear, and further evaluation regarding the safety of Doppler ultrasound is required. REVIEWER'S CONCLUSIONS: Based on existing evidence, routine Doppler ultrasound in low risk or unselected populations does not confer benefit on mother or baby. Future research should be powerful enough to address small changes in perinatal outcome, and should include evaluation of maternal psychological effects, long term outcomes such as neurodevelopment, and issues of safety.

Female↗

PubMed2002

Sedatives for opiate withdrawal in newborn infants.

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opiate withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss and seizures. Treatments used to ameliorate symptoms and reduce morbidity include opiates, sedatives and non-pharmacological treatments. OBJECTIVES: To assess the effectiveness and safety of using a sedative compared to a non-opiate control for NAS due to withdrawal from opiates, and to determine which type of sedative is most effective and safe. SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was used. This included searches of the Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2002) and MEDLINE 1966-2002. SELECTION CRITERIA: Trials enrolling infants with NAS born to mothers with an opiate dependence, with > 80% follow up and using random or quasi-random allocation to sedative or control. Control could include another sedative or non-pharmacological treatment. DATA COLLECTION AND ANALYSIS: Each author assessed study quality and extracted data independently. Primary outcomes included treatment failure (failure to achieve symptom control or use of additional drug treatment), seizure occurrence, mortality and neurodevelopment. Treatment effect was expressed using (RR), risk difference (RD), mean difference (MD) and weighted mean difference (WMD). Meta-analysis was performed using a fixed effect model. MAIN RESULTS: Five studies enrolling a total of 285 patients met inclusion criteria (Finnegan 1984, Kahn 1969, Kaltenbach 1986, Khoo 1995, Madden 1977); however, two (Finnegan 1984, Kaltenbach 1986) may be sequential reports that include some identical patients. Methodological concerns included the use of quasi-random rather than random patient allocation methods in three studies, and sizeable, largely unexplained differences in reported numbers allocated to each group in three studies. Phenobarbital compared to supportive care alone has not been shown to reduce treatment failure or time to regain birthweight (one study). However, the duration of supportive care required to be given to infants each day was significantly reduced (MD -162.1 minutes/day, 95% CI -249.2, -75.1). Comparing phenobarbital to diazepam, meta-analysis of two studies found that phenobarbital produced a significant reduction in treatment failure (typical RR 0.39, 95% CI 0.24, 0.62). There was no significant difference in duration of treatment or duration of hospital stay. Comparing phenobarbital with chlorpromazine, one study found no significant difference in treatment failure rate. No data for neurodevelopment were available, reported by treatment group as allocated. No trials were eligible that assessed clonidine for NAS. REVIEWER'S CONCLUSIONS: In newborn infants with NAS, there is no evidence that phenobarbital, compared with supportive care alone, reduces treatment failure; however, phenobarbital may reduce the daily duration of supportive care needed. Phenobarbital, compared to diazepam, reduces treatment failure. There is insufficient evidence to support the use of chlorpromazine or clonidine in newborn infants with NAS. Clonidine and chlorpromazine should only be used in the context of a randomised clinical trial. The results of this review, taken in conjunction with the related review, Opiate treatment for opiate withdrawal in newborn infants (Osborn 2002), indicate that treatment with opiates is the preferred initial therapy for NAS. It is hypothesised that this is particularly true for infants whose mothers have used only opiates during pregnancy. If a sedative is used, phenobarbital is preferred to diazepam. The results of an ongoing trial of the addition of phenobarbital to an opiate are awaited.

Chlorpromazine↗

PubMed2005

Sedatives for opiate withdrawal in newborn infants.

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opiate withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss and seizures. Treatments used to ameliorate symptoms and reduce morbidity include opiates, sedatives and non-pharmacological treatments. OBJECTIVES: To assess the effectiveness and safety of using a sedative compared to a non-opiate control for NAS due to withdrawal from opiates, and to determine which type of sedative is most effective and safe. SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was used. This update included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2005), MEDLINE 1966-March 2005 and abstracts of conference proceedings. SELECTION CRITERIA: Trials enrolling infants with NAS born to mothers with an opiate dependence, with > 80% follow up and using random or quasi-random allocation to sedative or control. Control could include another sedative or non-pharmacological treatment. DATA COLLECTION AND ANALYSIS: Each author assessed study quality and extracted data independently. Primary outcomes included treatment failure (failure to achieve symptom control or use of additional drug treatment), seizure occurrence, mortality and neurodevelopment. Treatment effect was expressed using (RR), risk difference (RD), mean difference (MD) and weighted mean difference (WMD). Meta-analysis was performed using a fixed effect model. MAIN RESULTS: Six studies enrolling a total of 305 patients met inclusion criteria (Coyle 2002; Finnegan 1984; Kahn 1969; Kaltenbach 1986; Khoo 1995; Madden 1977); however, two (Finnegan 1984; Kaltenbach 1986) may be sequential reports that include some identical patients. Methodological concerns included the use of quasi-random allocation methods in four studies, and sizeable, largely unexplained differences in reported numbers allocated to each group in three studies. Phenobarbitone compared to supportive care alone has not been shown to reduce treatment failure or time to regain birthweight (one study). However, the duration of supportive care given to infants was significantly reduced (MD -162.1 mins/day, 95% CI -249.2, -75.1). Comparing phenobarbitone to diazepam, meta-analysis of two studies found phenobarbitone produced a significant reduction in treatment failure (typical RR 0.39, 95% CI 0.24, 0.62). There was no significant difference in duration of treatment or hospital stay. Comparing phenobarbitone with chlorpromazine, one study found no significant difference in treatment failure rate. No data for neurodevelopment reported by treatment group of allocation were available. No trials were eligible that assessed clonidine for NAS. In infants treated with an opiate, a small quasi-random study reported a reduced severity of withdrawal. Infants were weaned from an opiate more quickly which allowed earlier hospital discharge and reduced hospital costs. These findings may reflect the low dose of opiate used for initial treatment and the policy of discharging infants home on phenobarbitone but not morphine. AUTHORS' CONCLUSIONS: In newborn infants with NAS, there is no evidence that phenobarbitone compared with supportive care alone reduces treatment failure; however, phenobarbitone may reduce the daily duration of supportive care needed. Phenobarbitone, compared to diazepam, reduces treatment failure. In infants treated with an opiate, the addition of phenobarbitone may reduce withdrawal severity. Further trials are required to determine if this finding is applicable when a higher initial dose of opiate is used, and determine the effects of phenobabritone on infant development. There is insufficient evidence to support the use of chlorpromazine or clonidine in newborn infants with NAS. Clonidine and chlorpromazine should only be used in the context of a randomised clinical trial. This review should be taken in conjunction with the review "Opiate treatment for opiate withdrawal in newborn infants" (Osborn 2002a) which indicates that an opiate is the preferred initial therapy for NAS.

Chlorpromazine↗

PubMed2002

Opiate treatment for opiate withdrawal in newborn infants.

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opiate withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss and seizures. Treatments used to ameliorate symptoms and reduce morbidity include opiates, sedatives and non-pharmacological treatments. OBJECTIVES: To assess the effectiveness and safety of using an opiate, compared to a sedative or non-pharmacological treatment, for treatment of NAS due to withdrawal from opiates. The evidence for use of different opiates was assessed in subgroup analyses. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group including searches (up to March 2002) of the Oxford Database of Perinatal Trials, Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2002), MEDLINE (1966-March 2002), previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal handsearching mainly in the English language. SELECTION CRITERIA: Trials enrolling infants with NAS born to mothers with an opiate dependence, with > 80% follow up and using random or quasi-random allocation to opiate or control. Control could include an opiate, sedative or non-pharmacological treatment. DATA COLLECTION AND ANALYSIS: Each author assessed study quality and extracted data independently. Primary outcomes included control of symptoms, seizure occurrence, mortality and neurodevelopment. Treatment effect was expressed using relative risk (RR), risk difference (RD), mean difference (MD) and weighted mean difference (WMD). Meta-analysis was performed using a fixed effect model. MAIN RESULTS: Six studies enrolling a total of 511 infants met inclusion criteria (Carin 1983, Finnegan 1984, Kaltenbach 1986, Kandall 1983, Khoo 1995, Madden 1977); however, two (Finnegan 1984, Kaltenbach 1986) may be sequential reports that include some identical patients. The studies enrolled infants of mothers who had used opiates with or without other drugs during pregnancy. Methodological concerns included the use of quasi-random rather than random patient allocation methods in three studies, and sizeable, largely unexplained differences in reported numbers allocated to each group in four studies. Opiate (morphine) vs supportive care only: One study (Khoo 1995) found no significant effect on treatment failure (RR 1.29, 95% CI 0.41, 4.07), a significant increase in hospital stay (MD 15.0 days, 95% CI 8.9, 21.1) and significant reductions in time to regain birthweight (MD -2.8 days, 95% -5.3, -0.3) and duration of supportive care (MD -197.2 minutes/day, 95% CI -274.2, -120.3). Opiate vs phenobarbital: Meta-analysis of three studies found no significant difference in treatment failure (typical RR 0.78, 95% CI 0.46, 1.32). One of these studies (Finnegan 1984) reported that opiate treatment resulted in a significant reduction in treatment failure among infants of mothers who had used only opiates; however, as this was a post-hoc analysis, this result should be interpreted with caution. One study (Kandall 1983) reported a reduction in seizures, of borderline statistical significance, with the use of opiate. Opiate vs diazepam: Meta-analysis of two studies found a significant reduction in treatment failure (RR 0.43, 95% CI 0.23, 0.80) with the use of opiate. No study reported neurodevelopment by allocated treatment group. REVIEWER'S CONCLUSIONS: Opiates, as compared to supportive care only, appear to reduce the time to regain birth weight and reduce the duration of supportive care, but increase the duration of hospital stay; there is no evidence of effect on treatment failure. When compared to phenobarbital, opiates may reduce the incidence of seizures but, overall, there is no evidence of effect on treatment failure. When compared to diazepam, opiates reduce the incidence of treatment failure. A post-hoc analysis generates the hypothesis that treatment effects may vary according to whether the population includes infants born to all opiate users (i.e. with or without other drug exposure) or is restricted to infants of mothers who used opiates only. In view of the methodologic limitations of the included studies the conclusions of this review should be treated with caution. Further research is needed.

Humans↗

PubMed2005

Opiate treatment for opiate withdrawal in newborn infants.

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opiate withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss and seizures. Treatments used to ameliorate symptoms and reduce morbidity include opiates, sedatives and non-pharmacological treatments. OBJECTIVES: To assess the effectiveness and safety of using an opiate, compared to a sedative or non-pharmacological treatment, for treatment of NAS due to withdrawal from opiates. SEARCH STRATEGY: The previous review was updated with additional searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2005), MEDLINE (1966-December 2004) and EMBASE (1980-December 2004) supplemented by searches of conference abstracts and citation lists of published articles. SELECTION CRITERIA: Trials enrolling infants with NAS born to mothers with an opiate dependence, with > 80% follow up and using random or quasi-random allocation to opiate or control. Control could include an opiate, sedative or non-pharmacological treatment. DATA COLLECTION AND ANALYSIS: Each author assessed study quality and extracted data independently. Primary outcomes included control of symptoms, seizure occurrence, mortality and neurodevelopment. Treatment effect was expressed using relative risk (RR), risk difference (RD), mean difference (MD) and weighted mean difference (WMD). Meta-analysis was performed using a fixed effect model. MAIN RESULTS: Seven studies enrolling a total of 585 infants met inclusion criteria (Carin 1983; Finnegan 1984; Jackson 2004; Kaltenbach 1986; Kandall 1983; Khoo 1995; Madden 1977); however, two (Finnegan 1984; Kaltenbach 1986) may be sequential reports that include some identical patients. The studies enrolled infants of mothers who had used opiates with or without other drugs during pregnancy. Methodological concerns included the use of quasi-random rather than random patient allocation methods in three studies; sizeable, largely unexplained differences in reported numbers allocated to each group in four studies; and imbalances in group characteristics after randomisation in one study. Opiate (morphine) vs supportive care only: One study (Khoo 1995) found no significant effect on treatment failure (RR 1.29, 95% CI 0.41, 4.07), a significant increase in hospital stay (MD 15.0 days, 95% CI 8.9, 21.1) and significant reductions in time to regain birthweight (MD -2.8 days, 95% -5.3, -0.3) and duration of supportive care (MD -197.2 minutes/day, 95% CI -274.2, -120.3). Opiate vs phenobarbitone: Meta-analysis of four studies found no significant difference in treatment failure (typical RR 0.76, 95% CI 0.51, 1.11). One of these studies (Finnegan 1984) reported that opiate treatment resulted in a significant reduction in treatment failure among infants of mothers who had used only opiates; however, as this was a post-hoc analysis, this result should be interpreted with caution. One study (Jackson 2004) reported a significant reduction in duration of treatment and admission to the nursery for infants receiving morphine compared to phenobarbitone. One study (Kandall 1983) reported a reduction in seizures, of borderline statistical significance, with the use of opiate. Opiate vs diazepam: Meta-analysis of two studies found a significant reduction in treatment failure (RR 0.43, 95% CI 0.23, 0.80) with the use of opiate. No study reported neurodevelopment by allocated treatment group. AUTHORS' CONCLUSIONS: Opiates, as compared to supportive care only, appear to reduce the time to regain birth weight and reduce the duration of supportive care, but increase the duration of hospital stay; there is no evidence of effect on treatment failure. When compared to phenobarbitone, opiates may reduce the incidence of seizures but, overall, there is no evidence of effect on treatment failure. One study reported a reduction in duration of treatment and nursery admission for infants on morphine. When compared to diazepam, opiates reduce the incidence of treatment failure. A post-hoc analysis generates the hypothesis that treatment effects may vary according to whether the population includes infants born to all opiate users (i.e. with or without other drug exposure) or is restricted to infants of mothers who used opiates only. In view of the methodologic limitations of the included studies the conclusions of this review should be treated with caution.

Diazepam↗

PubMed2000

Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for apnea of prematurity.

BACKGROUND: Apnea of prematurity is almost universal in infants who are born before 34 weeks gestation. Previous randomised trials and systematic reviews have found methylxanthines to be effective in preventing apnea of prematurity. However, recent concerns about potential long term side effects of methylxanthines on the neurodevelopment of low birth weight infants have led to an increased interest in alternate methods of treating apnea of prematurity. Nasal continuous positive airway pressure (NCPAP) is a useful method of respiratory support which reduces the incidence of obstructive or mixed apnea. However, apneic infants managed with NCPAP, with or without methylxanthines, sometimes require endotracheal intubation with its attendant morbidity and cost. Nasal intermittent positive pressure ventilation (NIPPV) is a simple, effective mode of respiratory support for older children and adults. It has been used to treat apnea in preterm infants but case reports of gastrointestinal perforations have limited its widespread use. OBJECTIVES: In preterm infants with recurrent apnea, does treatment with NIPPV lead to a greater reduction in apnea and need for intubation and mechanical ventilation, as compared with treatment with NCPAP? Does NIPPV increase the incidence of gastrointestinal complications, i.e. gastric distension leading to cessation of feeds, or perforation? SEARCH STRATEGY: Medline was searched (1966-2000) using the MeSH terms: infant, newborn (exp) and positive-pressure respiration (exp). Other sources included the Cochrane Controlled Trials Register and CINAHL (search terms: infant, newborn and intermittent positive pressure ventilation); also used were expert informants, previous reviews including cross-references, and conference and symposia proceedings. SELECTION CRITERIA: All randomised and quasi-randomised trials were included. Participants included unventilated preterm infants experiencing apnea of prematurity. Interventions compared were intermittent positive pressure ventilation administered via the nasal route, either by short nasal prongs or nasopharyngeal tube, and nasal CPAP delivered by the same methods. Types of outcome measures: - failure of therapy as defined by apnea that is frequent or severe requiring additional ventilatory support - rates of endotracheal intubation - rates of apnea and bradycardia expressed as events per hour - gastrointestinal complications i.e. abdominal distension requiring cessation of feeds, or GI perforation DATA COLLECTION AND ANALYSIS: Data were extracted independently by the three reviewers. The trials were analysed using relative risk (RR), risk difference (RD) and number needed to treat (NNT) for dichotomous data; means and weighted mean difference (WMD) were used for continuous data. MAIN RESULTS: Two trials, enrolling 54 infants in total, fulfilled the inclusion criteria. Both reported only the short term results (4 to 6 hours) of the interventions. Only one infant (randomised to NCPAP) required intubation during this period. Ryan (1989), in a cross over study of 20 infants, showed no significant difference in rates of apnea (events/hr) between the 2 interventions (WMD -0.10 (-0.53,0. 33)). Lin (1998) randomised 34 infants and demonstrated a greater reduction in frequency of apneas (events/hr) with NIPPV compared to NCPAP (WMD -1.19 (-2.31,-0.07)). Meta-analysis of both trials showed no difference in pCO2 (mmHg) at the end of the 4-6 hour study period (WMD 0.95 (-3.05,4.94)). No data were reported on gastrointestinal complications. REVIEWER'S CONCLUSIONS IMPLICATIONS FOR PRACTICE: NIPPV may be a useful method of augmenting the beneficial effects of NCPAP in preterm infants with apnea that is frequent or severe. Its use appears to reduce the frequency of apneas more effectively than NCPAP. Additional safety and efficacy data are required before recommending NIPPV as standard therapy for apnea. IMPLICATIONS FOR RESEARCH: Future trials with sufficient power should assess the efficacy (reduction in failure of therapy) and safety (GI complications) of NIPPV. Outcomes should be assessed throughout the entire period during which the infant requires assisted ventilation. The recent ability to synchronise NIPPV with an infant's spontaneous respirations is a promising development requiring further assessment.

Apnea↗

PubMed2005

Population-based and family-based association study of 5'UTR polymorphism of the reelin gene and schizophrenia.

Reelin is a glycoprotein involved in the migration and positioning of proliferating neurons and synaptic connectivity during neurodevelopment. It may also modulate neuronal plasticity throughout life. Therefore, the reelin gene is a candidate gene for schizophrenia. We examined the association of the CGG repeat polymorphism in the 5'-untranslated region of the reelin gene with schizophrenia in 266 unrelated French Caucasian patients, 156 of their parents, and 103 controls. We found no difference in the allele distribution between patients and controls although there was a significant higher prevalence of the genotype 8-8 in controls (CLUMP T3: chi(2) = 6.3, P = 0.035). There was no significant transmission disequilibrium in intrafamilial analysis. To refine our phenotypic characterization and in accordance with converging evidence suggesting that treatment resistance is associated with indices of abnormal neurodevelopment, we studied the association between reelin gene polymorphism and response to antipsychotics. Patients who responded to antipsychotics had a higher frequency of both the (CGG)(10) allele and (CGG)(10)-containing genotypes (P = 0.02; P = 0.006, respectively), with an odd ratio for genotypes of 4.2 (CI = [1.4;12.4]). Our results weakly support an association of reelin gene variants with schizophrenia as a whole, yet suggest that reelin could be associated with treatment-resistant schizophrenia.

5' Flanking Region↗

PubMed2007

Association between the 5q31.1 gene neurogenin1 and schizophrenia.

Multiple lines of evidence suggest that schizophrenia results from aberrant neurodevelopment. The neurogenin1 gene (neurog1) consists of a single 1,666 bp exon that encodes a basic helix-loop-helix (bHLH) transcription factor that causes neuronal differentiation and induces cortical and glutamatergic differentiation programs. Because of its function and its location in 5q31.1, which has been linked to schizophrenia in multiple samples, we tested it for association with the disorder. We sequenced neurog1 in 25 affected subjects from the Irish Study of High-Density Schizophrenia Families. We observed a 5'-UTR SNP at position -60, already present in databases as rs8192558, and tested it along with rs2344485, rs8192559, and rs2344484. Narrow, intermediate, and broad diagnostic definitions were used. The major alleles of rs8192558 and rs2344484 were over-transmitted to affected subjects using both Pedigree Disequilibrium Test (PDT) (0.01 < or = P < or = 0.06) and FBAT (0.02 < or = P < or = 0.07). A haplotype consisting of the major alleles of all four SNPs was significantly over-transmitted in FBAT to the broad definition (P = 0.049), with trend significance to the narrow and intermediate definitions, and with trend significance in PDT. In confirmatory tests using 657 cases and 411 controls, this haplotype was slightly but not significantly over-represented in cases (81% vs. 77%, P = 0.21). These results, along with a priori evidence for the involvement of neurog1 in neurodevelopment, suggest that variants in neurog1 might have a small effect on susceptibility to schizophrenia. This gene should be tested in additional and larger samples.

Basic Helix-Loop-Helix Proteins↗

PubMed1996

Successful early copper therapy in Menkes disease associated with a mutant transcript containing a small In-frame deletion.

Classical Menkes disease is a fatal X-linked neurodegenerative disorder caused by defects in a gene (MNK) that encodes a copper-transporting ATPase. Treatment with parenteral copper has been proposed for patients identified before symptoms develop. We recently described suboptimal outcomes despite early copper replacement in two classical Menkes patients whose mutation predicts little if any functional copper transporter. Here, we describe successful copper replacement therapy in a patient with Menkes disease with a splice acceptor site mutation (IVS8,AS,dup5) that causes exon-skipping and generates a mutant transcript with a small in-frame deletion in a noncritical region. The patient was diagnosed by analysis of neurochemical levels in cord blood, and parenteral copper replacement was begun at 8 days of life. Throughout infancy, he showed normal head growth, brain myelination, and age-appropriate neurodevelopment, including independent walking at 14 months of age. In contrast, his affected half-brother and first cousin with the same mutation, but who were not diagnosed and treated from an early age, showed arrested head growth, cerebral atrophy, delayed myelination, and abnormal neurodevelopment. We propose that the successful neurological outcome in this patient was related to early repletion of circulating copper levels, in combination with residual copper transport by a partially functional MNK ATPase containing the small deletion. We hypothesize that raising plasma copper concentrations in patients with Menkes disease with some residual functional gene product can increase the ligand: transporter ratio and thus alter favorably the kinetics of copper transport into and within the brain.

Adenosine Triphosphatases↗

PubMed2001

Molecular neuropathology of transgenic mouse models of Down syndrome.

Down syndrome (DS) is a complex, clinically heterogeneous disorder which shows both impairment of neurodevelopement and the neurodegenerative changes of Alzheimer's disease (AD). The phenotype of DS is caused by triplication of chromosome 21 and transgenic mouse models have been developed, and are being created, that carry single genes and chromosomal segments to excess. For example, transgenic mice containing additional copies of the amyloid precursor protein (APP) gene, have been useful in producing the Abeta deposition characteristic of AD and DS, but not the cytoskeletal changes that are the hallmarks of these human disorders. Such models are useful in replicating aspects of pathogenesis and allow for the testing of therapeutic agents to restore impaired function. Segmental trisomic mouse models, which survive to adulthood and possess three copies of multiple genes responsible for the DS phenotype, such as Ts1Cje and Ts65Dn, have been used to explore aspects of neurodevelopment and neurodegeneration. These animal models show some but not all the pathological, biochemical, and transcriptional changes seen in DS. They also have the advantage of allowing for the testing of therapeutic agents to restore impaired function. Analysis of the transcriptome and proteome of fetal and adult DS indicates that there is a complex relationship between gene dosage, gene and protein expression, and that data from animal models will need to be compared and evaluated in the light of data obtained from DS tissue.

Animals↗

PubMed1991

Breast mild jaundice: natural history, familial incidence and late neurodevelopmental outcome of the infant.

Jaundice associated with breast feeding is a frequent problem facing the paediatrician. Despite numerous reports on this subject, the natural history, familial occurrence and late neurodevelopment of children with breast milk jaundice remain unclear. The follow up of 60 infants with breast milk jaundice showed that there are two bilirubin peaks, on the 4th and 5th day and on the 14th-15th day of life. In the infants with uninterrupted breast feeding, the hyperbilirubinaemia disappeared slowly and could still be detected 12 weeks after birth. The familial incidence of 13.9%, indicating that in some cases a unique genetic factor is expressed. Late neurodevelopment or hearing defects were not observed, thus enabling the paediatrician to encourage continuation of breast feeding in most cases of healthy infants with breast milk jaundice.

Bilirubin↗