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PubMed2026

Tailless terminates the neural stem cell temporal cascade in both the optic lobe and central brain.

Temporal patterning is an evolutionarily conserved mechanism to produce neuronal and glial diversity from common cells of origin during neurodevelopment. This process is controlled by a series of temporal transcription factors that are transiently expressed and drive the sequential production of specific progeny subtypes. Intermediate neural progenitors (INPs) and optic lobe neural stem cells (OL NSCs) share striking similarities in temporal factor expression despite divergent cells of origin. Tailless (Tll) is a terminal temporal factor in the visual system in OL NSCs. Its expression coincides with the termination of neurogenesis and onset of gliogenesis. Here, we report that Tll also acts as a terminal factor in Drosophila INPs, demonstrating functional conservation. Tll expression is activated by the preceding temporal factor Scarecrow, and represses odd-paired and hamlet. tll also plays a partial role in promoting gliogenesis in gliogenic NSCs. We performed genome-wide binding analysis of Tll in the OL NSCs and INPs by Targeted DamID, revealing both conserved and divergent targets, reflecting differences in regulatory outcomes. We show that temporal patterning mechanisms are conserved between different brain regions, whilst facilitating lineage-specific outputs.

Animals↗

PubMed2026

Shielding the First 24 Postnatal Months of Life: A Proposal for a Prospective Cohort Study of Early-Life Electromagnetic Exposure and Autism Risk.

BACKGROUND: Autism Spectrum Disorder (ASD) involves Mirror Neuron System (MNS) dysfunction, driving core social and imitative impairments. Systemic physiological alterations such as autonomic dysregulation, mitochondrial dysfunction and neuroinflammation are known to impair synchronization and plasticity of neuronal clusters. A less-evident environmental cofactor, coinciding with rising ASD prevalence, is the considerable world-wide increase in electromagnetic radiation (EMR) overall exposure among children. Experimental evidence shows how low-intensity EMR influences cellular processes, via voltage-gated calcium channels (VGCCs), oxidative stress, and mitochondrial metabolism. The Resonant Convergence framework, allow to predict how chronic EMR exposure during the first 24 postnatal months of life can act as a factor in ASD pathogenesis. The best candidate mechanism is chronic Ion Cyclotron Resonance (ICR) detuning the Ca2+-calmodulin pathway, thus disrupting MNS synchronization. METHODS AND ANALYSIS: A prospective observational pilot cohort study (24-month follow-up) proposes to enroll 1000 full-term newborns into two arms: an EMR-reduced cohort (n = 500, rest and sleep-phase Faraday shielding) and a standard exposure cohort (n = 500). Exposure is quantified via radiofrequency (RF)/extremely low frequency(ELF) measurements, proximity analysis, device inventories and wearable dosimetry. The primary endpoint is a continuous neurodevelopmental trajectory score (joint attention, language, electroencephalogram (EEG) mu-rhythm); binary ASD diagnosis (Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), Autism Diagnostic Interview-Revised (ADI-R)) is a secondary, exploratory endpoint. Moreover, an optional genomic screening will evaluate gene-environment interactions within extremely low-frequency electromagnetic field (ELF-EMF) vulnerable pathways, including ASD-associated genes upregulated by RF via bromodomain and extraterminal protein (BET)-mediated epigenetic mechanisms. Analyses will employ risk ratios, Fisher's exact tests and logistic regression adjusted for confounders; mixed-effects and Bayesian modeling will evaluate longitudinal outcomes and exposure reduction effects. Given a 2-3% baseline prevalence, approximately 20-30 ASD cases are expected. The study is therefore powered for exploratory signal detection rather than definitive causal inference, providing the critical baseline data required to justify and design future confirmatory trials. Sex-stratified modeling will address the 4:1 male-to-female prevalence ratio. ETHICS AND DISSEMINATION: Ethics committee approval is not yet sought; full protocol review and approval will be obtained prior to the study initiation, in strict accordance with the Declaration of Helsinki. Written parental informed consent will be mandatory for all participants prior to enrollment. Study findings and methodological milestones will be disseminated through peer-reviewed international scientific publications. This protocol provides a structured methodological framework for the first prospective investigation of sleep-phase EMR reduction as a potential modulator of ASD incidence during early neurodevelopment. Results will inform adequately powered confirmatory trials in electromagnetic neurodevelopmental epidemiology.

autism spectrum disorder↗

PubMed2003

Are there opportunities to decrease nosocomial infection by choice of analgesic regimen? Evidence for immunity and pain interactions.

BACKGROUND: Interactions suggest that anesthetic and analgesic strategies could be used to modulate immune function and reduce nosocomial infection in critically ill pediatric patients. However, this theory has yet to be adequately tested. OBJECTIVE: To present the evidence for interactions between nociceptive and immune pathways. DATA SOURCES: The MEDLINE database and hand searches of the English-language biomedical literature for the 1985-2003 period. DATA SYNTHESIS: Substantial evidence exists for numerous bidirectional relationships between nociceptive and immune pathways. Some studies suggest that surgical pain and stress may alter immune function in adults. Limited evidence indicates that anesthetic and analgesic immunomodulation may boost immune function to prevent nosocomial infection. However, unique aspects of immune function maturation and neurodevelopment must be considered. CONCLUSION: Research is urgently needed to determine if the interactions between nociceptive and immune function pathways in critically ill infants and children are similar to those in adults and if host defenses can be enhanced by optimal anesthetic and analgesic strategies.

Analgesia↗

PubMed1997

Developmental precursors of affective illness in a general population birth cohort.

BACKGROUND: Recent evidence suggests that neurodevelopmental impairment may be a risk factor for later affective disorder. METHODS: Associations between childhood developmental characteristics and affective disorder were examined in a prospectively studied national British birth cohort of 5362 individuals born between March 3 and March 9, 1946. Mental state examinations by trained interviewers performed at ages 36 and 43 years identified 270 case subjects with adult affective disorder (AD). Teachers' questionnaires completed at age 13 and 15 years identified 195 case subjects who had shown evidence of childhood affective disturbance (CAD). RESULTS: Female gender and low educational test scores at ages 8, 11, and 15 years were a risk factor for AD, CAD, and AD without CAD. In addition, attainment of motor milestones was later in the CAD group (odds ratio [OR] = 1.2; 95% confidence interval [CI], 1.1-1.3), followed by, and independent of, greater risk for speech defects between the ages of 6 and 15 years (OR = 2.0; 95% CI, 1.3-3.0), decreased psychomotor alertness on medical examination between ages 4 and 11 years (OR = 4.6; 95% CI, 2.2-9.7), and an excess of twitching and grimacing motor behaviors in adolescence (OR = 3.9; 95% CI, 2.5-6.1). Persistent CAD was strongly associated with persistent AD (OR = 7.8; 95% CI, 2.6-23.2). CONCLUSION: The findings give credence to the suggestion that affective disorder, especially its early-onset form, is preceded by impaired neurodevelopment.

Adolescent↗

PubMed2003

Childhood head injury and expression of schizophrenia in multiply affected families.

BACKGROUND: The etiology of schizophrenia is believed to include genetic and nongenetic factors, with the pathogenesis involving abnormal neurodevelopment. We investigated whether mild head injury during brain maturation plays a role in the expression of schizophrenia in multiply affected families. METHODS: We compared the history and severity of head injuries in childhood (age, < or =10 years) and through adolescence (age, < or =17 years) in 67 subjects with narrowly defined schizophrenia and 102 of their unaffected siblings from 23 multiply affected families. In subjects with schizophrenia, only head injuries preceding the onset of psychosis were considered. RESULTS: Subjects in the schizophrenia group (n = 16 [23.9%]) were more likely than the unaffected siblings group (n = 12 [11.8%]) to have a history of childhood head injury (P =.04; odds ratio, 2.35 [95% confidence interval, 1.03-5.36]). Subjects in the schizophrenia group with a history of childhood head injury had a significantly younger median age at onset of psychosis (20 years) compared with those with no such history (25 years; z = -2.98; P =.003). The severity of head injury ranged from minimal to mild, including concussions, but within this narrow range, severity was correlated with younger age at onset (r(s) = -0.66; P =.005). Head injury occurred a median of 12 years before the onset of psychosis. Results were similar if head injuries during adolescence were included, but did not achieve statistical significance. CONCLUSIONS: Mild childhood head injury may play a role in the expression of schizophrenia in families with a strong genetic predisposition. Prospective studies of mild head injury should consider genetic predisposition for possible long-term neurobehavioral sequelae.

Adolescent↗

PubMed2003

Progressive structural brain abnormalities and their relationship to clinical outcome: a longitudinal magnetic resonance imaging study early in schizophrenia.

BACKGROUND: Many studies have shown that structural brain abnormalities in schizophrenia are already present by the time of index evaluation of first-episode patients. However, whether these abnormalities progressively worsen during the subsequent course of the disorder remains unresolved. METHODS: To study the longitudinal progression of structural brain abnormalities, high-resolution multispectral magnetic resonance images obtained on 73 recent-onset schizophrenic patients and 23 controls were analyzed using state-of-the-art, well-validated, and highly reliable neuroimaging tools. The mean duration between initial and follow-up MRIs was 3 years. Repeated-measures analysis of covariance was carried out to determine (1) whether brain volume changes differed between patients and controls and (2) the significance of regional brain changes on functional outcome in schizophrenia. RESULTS: We found accelerated enlargement in cortical sulcal cerebrospinal fluid spaces early in the course of schizophrenia. Instead of the usual trajectory of volume enlargement, patients showed progressive reduction in frontal lobe white matter volume. A reciprocal increase in frontal lobe cerebrospinal fluid volume also occurred at a more rapid rate in patients than in controls. In keeping with most of our a priori hypotheses, patients with poor outcome had greater lateral ventricular enlargement over time than patients with good outcome. Progressive decrement in frontal lobe white matter volume and enlargement in frontal lobe cerebrospinal fluid volume were associated with greater negative symptom severity. Reductions in frontal lobe gray and white matter volumes correlated with poorer executive functioning. CONCLUSIONS: There are ongoing changes in the brains of schizophrenic patients during the initial years after diagnosis despite ongoing antipsychotic drug treatment. These progressive changes seem to be most evident in the frontal lobes and to correlate with functional impairment. Disruptions in neurodevelopment or neural plasticity may act alone or in combination to bring about these progressive brain deficits in schizophrenia.

Adult↗

PubMed2006

Perinatal factors and the risk of developing anorexia nervosa and bulimia nervosa.

CONTEXT: Few prospective studies to date have investigated the role of obstetric complications in anorexia nervosa, and no study to our knowledge exists for this in bulimia nervosa. OBJECTIVE: To explore the role of obstetric complications in the development of eating disorders. DESIGN: A blind analysis of the obstetric records of a sample of subjects with anorexia nervosa, with bulimia nervosa, and normal subjects was performed. All of the subjects included in the study belong to the same population birth cohort and were born in the 2 obstetric wards of Padua Hospital, Padua, Italy, between January 17, 1971, and December 30, 1979. SETTINGS AND PARTICIPANTS: Part of the sample of subjects with eating disorders and all of the controls took part in a prevalence study carried out in 2 randomly selected areas of Padua. In addition, all of the subjects with anorexia nervosa and bulimia nervosa of the same birth cohort who were referred to an outpatient specialist unit were included. The final sample comprised 114 subjects with anorexia nervosa, 73 with bulimia nervosa, and 554 control subjects. RESULTS: Several complications, such as maternal anemia (P = .03), diabetes mellitus (P = .04), preeclampsia (P = .02), placental infarction (P = .001), neonatal cardiac problems (P = .007), and hyporeactivity (P = .03), were significant independent predictors of the development of anorexia nervosa. The risk of developing anorexia nervosa increased with the total number of obstetric complications. In addition, an increasing number of complications significantly anticipated the age at onset of anorexia nervosa (P = .03). The obstetric complications significantly associated with bulimia nervosa were the following: placental infarction (P = .10), neonatal hyporeactivity (P = .005), early eating difficulties (P = .02), and a low birth weight for gestational age (P = .009). Being shorter for gestational age significantly differentiated subjects with bulimia nervosa from both those with anorexia nervosa (P = .04) and control subjects (P = .05). CONCLUSIONS: A significantly higher risk of eating disorders was found for subjects with specific types of obstetric complications. An impairment in neurodevelopment could be implicated in the pathogenesis of eating disorders.

Adolescent↗

PubMedDate not supplied

Neurological development of 5-year-old children receiving a low-saturated fat, low-cholesterol diet since infancy: A randomized controlled trial.

CONTEXT: Early childhood introduction of nutritional habits aimed at atherosclerosis prevention is compatible with normal growth, but its effect on neurological development is unknown. OBJECTIVE: To analyze how parental counseling aimed at keeping children's diets low in saturated fat and cholesterol influences neurodevelopment during the first 5 years of life. DESIGN: Randomized controlled trial conducted between February 1990 and November 1996. SETTING: Outpatient clinic of a university department in Turku, Finland. PARTICIPANTS: A total of 1062 seven-month-old infants and their parents, recruited at well-baby clinics between 1990 and 1992. At age 5 years, 496 children still living in the city of Turku were available to participate in neurodevelopmental testing. INTERVENTION: Participants were randomly assigned to receive individualized counseling aimed at limiting the child's fat intake to 30% to 35% of daily energy, with a saturated:monounsaturated:polyunsaturated fatty acid ratio of 1:1:1 and a cholesterol intake of less than 200 mg/d (n = 540) or usual health education (control group, n = 522). MAIN OUTCOME MEASURES: Nutrient intake, serum lipid concentrations, and neurological development at 5 years, among children in the intervention vs control groups. RESULTS: Absolute and relative intakes of fat, saturated fatty acids, and cholesterol among children in the intervention group were markedly less than the respective values of control children. Mean (SD) percentages of daily energy at age 5 years for the intervention vs control groups were as follows: for total fat, 30.6% (4.5%) vs 33.4% (4.4%) (P<. 001); and for saturated fat, 11.7% (2.3%) vs 14.5% (2.4%) (P<.001). Mean intakes of cholesterol were 164.2 mg (60.1 mg) and 192.5 mg (71. 9 mg) (P<.001) for the intervention and control groups, respectively. Serum cholesterol concentrations were continuously 3% to 5% lower in children in the intervention group than in children in the control group. At age 5 years, mean (SD) serum cholesterol concentration of the intervention group was 4.27 (0.63) mmol/L (165 [24] mg/dL) and of the control group, 4.41 (0.74) mmol/L (170 [29] mg/dL) (P =.04). Neurological development of children in the intervention group was at least as good as that of children in the control group. Relative risks for children in the intervention group to fail tests of speech and language skills, gross motor functioning plus perception, and visual motor skills were 0.95 (90% confidence interval [CI], 0.60-1.49), 0.95 (90% CI, 0.58-1.55), and 0.65 (90% CI, 0.39-1.08), respectively (P =.85,.86, and.16, respectively, vs control children). CONCLUSION: Our data indicate that repeated child-targeted dietary counseling of parents during the first 5 years of a child's life lessens age-associated increases in children's serum cholesterol and is compatible with normal neurological development. JAMA. 2000;284:993-1000

Child Development↗

PubMed2003

Strategies for autism candidate gene analysis.

The identification of autism susceptibility genes has moved a step closer over the last four years with the completion of eight whole genome screens for linkage. Several overlapping areas of linkage have been reported, most notably on chromosomes 7q22-31 and 2q32. These regions of replicated linkage provide a focus to search for candidate genes whose normal functions in neurodevelopment are altered to increase the risk for autism. Strategies that aim to narrow further the rather broad size of these linkage regions, such as high density single nucleotide polymorphism (SNP)-based association studies, currently suffer from practical and statistical limitations. Alternatively, positional candidate genes can be screened for deleterious variants in autistic individuals selected from large samples such as those collected by the International Molecular Genetic Study of Autism Consortium (IMGSAC). Targeted genotyping of candidate gene variants in this large multiplex family sample will then be performed to confirm association with autism.

Animals↗

PubMed2001

Dopamine-synthesizing neurons include the putative H-cell homologue in the moth Manduca sexta.

The catecholamine dopamine (DA) plays a fundamental role in the regulation of behavior and neurodevelopment across animal species. Uncovering the embryonic origins of neurons that express DA opens a path for a deeper understanding of how DA expression is regulated and, in turn, how DA regulates the activities of the nervous system. In a well-established insect model, Manduca sexta, we identified the putative homologue of the embryonic grasshopper "H-cell" using intracellular techniques, laser scanning confocal microscopy, and immunohistochemistry. In both species, this neuron possesses four axons and has central projections resembling the letter H. The H-cell in grasshoppers is known to be derived from the midline precursor 3 cell (MP3) and to pioneer the pathways of the longitudinal connectives; in Drosophila, the H-cell is also known to be derived from MP3. In the current study, we demonstrate that the Manduca H-cell is immunoreactive to antibodies raised against DA and its rate-limiting synthetic enzyme, tyrosine hydroxylase (TH). In larvae and adults, one DA/TH-immunoreactive (-ir) H-cell per ganglion is present. In embryos, individual ganglia contain a single midline TH-ir cell body positioned along side its putative sibling. Such observations are consistent with the known secondary transformation (in grasshoppers) of only one of the two MP3 progeny during early development. Although a hallmark feature of invertebrate neurons is the fairly stereotypical position of neuronal somata, we found that the H-cell somata can "flip-flop" by 180 degrees between an anterior and posterior position. This variability appears to be random and is not restricted to any particular ganglion. Curiously, what is segment-specific is the absence of the DA/TH-ir H-cell in the metathoracic (T3) ganglion as well as the unique structure of the H-cell in the subesophageal ganglion. Because this is the first immunohistochemical study of DA neurons in Manduca, we have provided the distribution pattern and morphologies of dopaminergic neurons, in addition to the H-cells, within the ventral nerve cord during development.

Animals↗

PubMed2001

Prenatal exposure to anti-HIV drugs: neurobehavioral effects of zidovudine (AZT) + lamivudine (3TC) treatment in mice.

BACKGROUND: The new antiretroviral treatments that combine the zidovudine (AZT) regimen with lamivudine (3TC) appear as a cost-effective alternative to the current AZT monotherapy to prevent mother-to-fetus transmission of the HIV-1 virus. Recent evidence in uninfected children raised concern about the long-term effects of perinatal exposure to AZT and 3TC, especially when used in combination. Animal studies indicated behavioral changes in offspring exposed perinatally to both AZT and 3TC, whereas no animal data are available on the effects of the perinatal exposure to the AZT + 3TC combination on neurodevelopment. METHODS: Pregnant CD-1 mice received p.o. AZT + 3TC (160 and 500 mg/kg, respectively) or vehicle solution (NaCl 0.9%) twice daily from gestational day 10 to delivery. Maternal reproductive endpoints such as pregnancy length, abortion, litter size, sex ratio, and offspring viability were assessed. Pups were scored for different somatic and behavioral endpoints, including sensorimotor development, homing performance on postnatal day (PND) 10, passive-avoidance testing (PND 22-23), locomotor activity (PND 23), and social interaction (PND 35). RESULTS: While no effects were observed on maternal reproductive endpoints, treated pups showed a long-lasting reduction of body weight and a slightly delayed maturation of placing and grasping reflexes and pole grasping. No effects on passive-avoidance or locomotor activity were found. AZT + 3TC-treated mice showed selective alterations in the social interaction test; the treated female offspring also displayed a significant reduction of affiliative interactions. CONCLUSIONS: The combination of AZT and 3TC (1) induced small, but more marked, effects on somatic and sensorimotor development than either of these drugs administered separately; and (2) affected juvenile social behavior.

Animals↗

PubMed2000

Neurotrophins and the dynamic regulation of the neuronal cytoskeleton.

The morphology of neuronal axons and dendrites is dependent on the dynamics of the cytoskeleton. An understanding of neurodevelopment and adult neuroplasticity must therefore include a detailed description of the intrinsic and extrinsic mechanisms that regulate the organization and dynamics of actin filaments and microtubules. In this paper we review recent advances in the understanding of the dynamic regulation of neuronal morphology by interactions among cytoskeletal components and the regulation of the cytoskeleton by neurotrophins.

Animals↗

PubMed2000

Intravenous indomethacin for preventing mortality and morbidity in very low birth weight infants.

BACKGROUND: This section is under preparation and will be included in the next issue. OBJECTIVES: Indomethacin is used to treat symptomatic patent ductus arteriosus and may prevent or limit intraventricular haemorrhage in the neonatal period. This review examines the effectiveness of prophylactic intravenous indomethacin in reducing the mortality and morbidity associated with these conditions in infants weighing less than 1750 grams at birth. SEARCH STRATEGY: A literature search from January 1980 to October 1994 was made in three computerised data bases: Medline; Embase; and the Oxford Database of Perinatal Trials. The search was updated in February 1997. SELECTION CRITERIA: Strict selection criteria were applied to clinical trials: the population had to be newborn infants of birth weight < 1751 grams; the intervention had to be prophylactic intravenous indomethacin; the trial had to be randomised and controlled; and at least one of several prespecified outcomes had to be reported in the results. DATA COLLECTION AND ANALYSIS: The methodological quality of each study was assessed using explicit criteria. Data on relevant outcome measures were extracted on two separate occasions and, where appropriate, the results of individual trials were combined using meta-analysis techniques to provide a pooled estimate of effect. MAIN RESULTS: There is a trend towards reduced neonatal mortality in infants receiving prophylactic indomethacin, pooled relative risk (RR) = 0. 85 [95% CI 0.66 to 1.09]. The incidence of symptomatic patent ductus arteriosus is significantly reduced in treated infants, pooled RR = 0.35 [0.26 to 0.47] but there is no evidence that treatment affects respiratory outcomes. Prophylactic indomethacin significantly reduces the incidence of Grade 3 and 4 intraventricular haemorrhage in treated infants, pooled RR = 0.60 [0.43 to 0.83]. There is no evidence to suggest prophylactic indomethacin is associated with any long term adverse effect although there is a trend in treated infants towards an increased incidence of necrotizing enterocolitis, and some evidence that treatment may transiently impair renal function. There is no evidence that haemostasis is disturbed. REVIEWER'S CONCLUSIONS: Prophylactic treatment with indomethacin has a number of immediate benefits, in particular a reduction in symptomatic patent ductus arteriosus and severe intraventricular haemorrhage. There is no evidence at present of long-term harm. Further trials are needed to assess more precisely the effects, both beneficial and harmful, on short and long-term outcomes.

Cardiovascular Agents↗

PubMed2000

Routine ultrasound in late pregnancy (after 24 weeks gestation).

BACKGROUND: Diagnostic ultrasound is used selectively in late pregnancy where there are specific clinical indications. However, the value of routine late pregnancy ultrasound screening in unselected populations is controversial. The rationale for such screening would be the detection of clinical conditions which place the fetus or mother at high risk, which would not necessarily have been detected by other means such as clinical examination, and for which subsequent management would improve perinatal outcome. OBJECTIVES: To assess the effects on obstetric practice and pregnancy outcome of routine late pregnancy ultrasound, defined as greater than 24 weeks gestation, in women with either unselected or low risk pregnancies. SEARCH STRATEGY: The Cochrane Pregnancy and Childbirth Group Specialised Register of Controlled Trials and the Cochrane Controlled Trials Register were searched. SELECTION CRITERIA: All acceptably controlled trials of routine ultrasound in late pregnancy (defined as after 24 weeks). DATA COLLECTION AND ANALYSIS: The principal reviewer assessed trial quality and extracted data, under supervision of the co-reviewer. MAIN RESULTS: Seven trials recruiting 25,036 women were included. The quality of trials overall was satisfactory. There was no difference in antenatal, obstetric and neonatal intervention or morbidity in screened versus control groups. Routine late pregnancy ultrasound was not associated with improvements in overall perinatal mortality. Placental grading as an adjunct to third trimester examination scan was associated with a significant reduction in the stillbirth rate in the one trial that assessed it. There is a lack of data with regard to long term substantive outcomes such as neurodevelopment. There is a lack of data on maternal psychological effects. REVIEWER'S CONCLUSIONS: Based on existing evidence, routine late pregnancy ultrasound in low risk or unselected populations does not confer benefit on mother or baby. There is a lack of data about the potential psychological effects of routine ultrasound in late pregnancy, and the effects on both short and long term neonatal and childhood outcome. Placental grading in the third trimester may be valuable, but whether reported results are reproducible remains to be seen, and future research of late pregnancy ultrasound should include evaluation of placental textural assessment.

Female↗

PubMed2005

Glutamine supplementation to prevent morbidity and mortality in preterm infants.

BACKGROUND: Glutamine endogenous biosynthesis may be insufficient for tissue needs in states of metabolic stress. Trials in adults have suggested that glutamine supplementation improves clinical outcomes in critically ill adults. It has been suggested that glutamine supplementation may benefit preterm infants, particularly very low birth weight infants. OBJECTIVES: To determine the effects of glutamine supplementation on mortality and morbidity in preterm infants. SEARCH STRATEGY: We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2004), MEDLINE (1966 - August 2004), EMBASE (1980 - August 2004), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared glutamine supplementation versus no glutamine supplementation in preterm babies at any time from birth to discharge from hospital. DATA COLLECTION AND ANALYSIS: We extracted the data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two reviewers, and synthesis of data using relative risk, risk difference and weighted mean difference. MAIN RESULTS: More than 2300 infants have participated in six randomised controlled trials. All of the participating infants were of very low birth weight. Three trials assessed enteral glutamine supplementation, and three trials assessed parenteral glutamine supplementation. These trials were generally of good methodological quality with adequate allocation concealment, blinding of care-givers and assessors to the intervention, and complete or near-complete follow-up of recruited infants. We found that glutamine supplementation does not have a statistically significant effect on mortality: typical relative risk 0.98 (95% confidence interval 0.80 to 1.21); typical risk difference 0.00 (95% confidence interval -0.03 to 0.03). One of the trials assessed longer term neurodevelopmental outcomes (Poindexter 2004). The investigators reported that they did not find any statistically significant differences in various assessments of neurodevelopment (including Bayley scales) on follow up at 18 months corrected age. We found that glutamine supplementation does not have a statistically significant effect on the incidence of systemic infection (typical relative risk 1.02 (95% confidence interval 0.92 to 1.13); typical risk difference 0.01 (95% confidence interval -0.03 to 0.05)), necrotising enterocolitis (typical relative risk 1.02 (95% confidence interval 0.79 to 1.33); typical risk difference 0.00 (95% confidence interval -0.02 to 0.03)), days to full enteral nutrition (weighted mean difference -1.1 days (95% confidence interval -3.4 to 1.2)), or duration of hospital stay (weighted mean difference 0.65 days (95% confidence interval -2.9 to 4.2)). AUTHORS' CONCLUSIONS: The available data from good quality randomised controlled trials suggest that glutamine supplementation does not confer clinically significant benefits for preterm infants. The narrow confidence intervals for the effect size estimates suggest that a further trial of this intervention is not a research priority.

Dietary Supplements↗

PubMed2001

Formula milk versus term human milk for feeding preterm or low birth weight infants.

BACKGROUND: Term (mature) human breast milk, compared with artificial formula milks, may provide insufficient nutrition for growth and development in preterm or low birth weight infants. However, human milk may confer advantages to infants in terms of a decreased incidence of adverse outcomes. OBJECTIVES: To determine if formula milk compared with term human breast milk leads to improved growth and development without significant adverse effects in low birth weight or preterm infants. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used. This included electronic searches of the Cochrane Controlled Trials Register, MEDLINE, EMBASE and previous reviews including cross references. SELECTION CRITERIA: Randomised controlled trials comparing feeding with formula milk versus term human milk in low birth weight or preterm infants. DATA COLLECTION AND ANALYSIS: Data were extracted using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by each author and synthesis of data using relative risk, risk difference and weighted mean difference. MAIN RESULTS: Six trials, all initiated more than 20 years ago, fulfilled the pre-specified inclusion criteria. Four small trials compared feeding with standard calorie formula milk versus unfortified term human milk. Two trials compared feeding with calorie-enriched formula milk versus unfortified term human milk. No trials comparing feeding with formula milk versus nutrient-fortified term human milk were found. Only one trial reported longer term follow up of growth and development. In preterm and low birth weight infants, enteral feeding with formula milk compared with unfortified term human milk resulted in a greater rate of growth in the short term. We did not find a statistically significant difference in the incidence of necrotising enterocolitis, but this was evaluated as a pre-defined outcome in only one trial. The single trial that evaluated longer-term outcomes did not find evidence of an effect on longer-term growth and neurodevelopment. REVIEWER'S CONCLUSIONS: In preterm and low birth weight infants, feeding with formula milk, compared with unfortified term human milk, leads to a greater rate of growth in the short term. The limited data available do not allow definite conclusions on whether adverse outcomes, including necrotising enterocolitis, are increased in infants who receive formula milk compared with term human milk. There are no data from randomised trials on the comparison of feeding with formula milk versus nutrient-fortified breast milk. This limits the implications for practice of this review as nutrient fortification of breast milk is now a common practice in neonatal care. Future trials may compare growth, development and adverse outcomes in infants who receive adapted "preterm" formula milks versus nutrient-fortified human breast milk.

Humans↗

PubMed2003

Prophylactic intravenous antifungal agents to prevent mortality and morbidity in very low birth weight infants.

BACKGROUND: Invasive fungal infection is an increasingly common cause of mortality and morbidity in very low birth weight infants. As the diagnosis is often difficult, and treatment is often delayed, there is a need to assess whether antifungal prophylaxis is beneficial. OBJECTIVES: To assess whether prophylactic intravenous antifungal therapy reduces mortality and adverse neurodevelopmental outcomes in very low birth weight infants. SEARCH STRATEGY: We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Controlled Trials Register (The Cochrane Library, Issue 3, 2002), MEDLINE (1966 - September 2002), EMBASE (1980 - September 2002), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised controlled trials that compared the effect of prophylactic intravenous antifungal therapy versus placebo, or no drug, or another antifungal agent, in very low birth weight infants. DATA COLLECTION AND ANALYSIS: We extracted the data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by each author, and synthesis of data using relative risk and risk difference. The pre-specified outcomes were death prior to hospital discharge, longer term neurodevelopment, incidence of invasive fungal infection, emergence of antifungal resistance, and adverse drug reactions. MAIN RESULTS: We identified two eligible trials enrolling a total of 203 infants. Both trials compared the effect of prophylactic intravenous fluconazole versus placebo. 29 of the infants recruited to the two studies died. Meta-analysis revealed a statistically significantly reduced risk of death prior to hospital discharge for the infants who received fluconazole prophylaxis: typical relative risk: 0.44 (95% confidence interval 0.21, 0.91); typical risk difference: -0.11 (95% confidence interval -0.21, -0.02); number needed to treat: 9 (95% confidence interval 5, 50). There were not any data on longer term outcomes. REVIEWER'S CONCLUSIONS: We have found some evidence that prophylactic intravenous fluconazole reduces mortality prior to hospital discharge in very low birth weight infants. The meta-analysis suggests that there will be one fewer death in every nine infants treated with this intervention, but the 95% confidence interval around this estimate of effect is wide. The longer term neurodevelopmental consequences for infants exposed to this intervention remain to be determined. It will be important to identify any subgroups of very low birth weight infants that receive the most benefit from this intervention. There is also a need for further data on the effect of the intervention on the emergence of organisms with stable antifungal resistance.

Antifungal Agents↗

PubMed2004

Prophylactic intravenous antifungal agents to prevent mortality and morbidity in very low birth weight infants.

BACKGROUND: Invasive fungal infection is an increasingly common cause of mortality and morbidity in very low birth weight infants. As the diagnosis is often difficult, and treatment is often delayed, there is a need to assess whether antifungal prophylaxis is beneficial. OBJECTIVES: To assess whether prophylactic intravenous antifungal therapy reduces mortality and adverse neurodevelopmental outcomes in very low birth weight infants. SEARCH STRATEGY: We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2003), MEDLINE (1966 - October 2003), EMBASE (1980 - October 2003), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised controlled trials that compared the effect of prophylactic intravenous antifungal therapy versus placebo, or no drug, or another antifungal agent, in very low birth weight infants. DATA COLLECTION AND ANALYSIS: We extracted the data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by each author, and synthesis of data using relative risk and risk difference. The pre-specified outcomes were death prior to hospital discharge, longer term neurodevelopment, incidence of invasive fungal infection, emergence of antifungal resistance, and adverse drug reactions. MAIN RESULTS: We identified three eligible trials enrolling a total of 214 infants. Each of the trials compared the effect of prophylactic intravenous fluconazole versus placebo. Two of the trials reported death prior to hospital discharge as an outcome. 29 of the 203 infants recruited to these studies died. Meta-analysis revealed a statistically significantly reduced risk of death prior to hospital discharge for the infants who received fluconazole prophylaxis: typical relative risk: 0.44 (95% confidence interval 0.21, 0.91); typical risk difference: -0.11 (95% confidence interval -0.21, -0.02); number needed to treat: 9 (95% confidence interval 5, 50). None of the trials reported data on longer term outcomes. REVIEWER'S CONCLUSIONS: We have found some evidence that prophylactic intravenous fluconazole reduces mortality prior to hospital discharge in very low birth weight infants. The meta-analysis suggests that there will be one fewer death in every nine infants treated with this intervention, but the 95% confidence interval around this estimate of effect is wide. The longer term neurodevelopmental consequences for infants exposed to this intervention remain to be determined. It will be important to identify any subgroups of very low birth weight infants that receive the most benefit from this intervention. There is also a need for further data on the effect of the intervention on the emergence of organisms with stable antifungal resistance.

Antifungal Agents↗