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Salmonella meningitis and its complications in infants.

OBJECTIVE: To review the presenting features, complications and outcome of infants with Salmonella meningitis. METHODOLOGY: Retrospective review of all cultures of cerebrospinal fluid positive for bacteria in children below 12 years of age, processed at the Department of Medical Microbiology, University of Malaya Medical Centre, Kuala Lumpur from 1973 to 1997. Records of all cases positive for Salmonella species were retrieved and studied. RESULTS: Thirteen infants aged 3 days to 9 months with Salmonella meningitis were included. The median age of onset of symptoms was 4 months. The clinical and laboratory features were similar to other causes of bacterial meningitis. Salmonella enteritidis was the commonest serotype isolated. Nine infants developed fits, six of which were difficult to control. Other complications noted were hydrocephalus (five), subdural effusions (four), empyema (three), ventriculitis (two), intracranial haemorrhage and cerebral abscess (one each). The use of ampicillin and/or chloramphenicol and inadequate duration of therapy resulted in recrudescence or relapse in five infants. The overall mortality was 18%. The presence of empyema, intracerebral abscess, ventriculitis, hydrocephalus, and intracranial haemorrhage were associated with adverse neurodevelopmental sequelae or death. More than half of those who survived had normal long-term outcome. CONCLUSION: Infants who developed neurological complications as a result of Salmonella meningitis had significant mortality and adverse long-term neurodevelopment outcome.

Anti-Bacterial Agents↗

Repeated adverse fetal outcome in pregnancy complicated by uncontrolled maternal phenylketonuria.

Phenylketonuria in pregnancy carries with it an increased risk of spontaneous abortion and development of a fetus that is affected by the maternal phenylketonuria syndrome. This syndrome is characterized by low birthweight, congenital heart disease, microcephaly, childhood growth failure, and cognitive impairment. It is the result of the hyperphenylalaninemia that accompanies the phenylketonuric state, and may therefore be avoided by maintaining maternal serum phenylalanine levels within the normal range. Phenylalanine is an essential amino acid and may be controlled by dietary manipulation. Presented here is a case history of a woman with phenylketonuria who was unable to satisfactorily control her serum phenylalanine levels in each of her three pregnancies. All three children were adversely affected by the fetopathy of the maternal phenylketonuria syndrome, each with evidence of growth failure and impaired neurodevelopment. This patient illustrates the difficulties that may be encountered when providing obstetric care to the woman with phenylketonuria who is not able or not willing to restrict her dietary intake of phenylalanine. The discussion includes consideration of management strategies, including dietary therapy and legal intervention.

Adult↗

Giant glioependymal cyst resembling holoprosencephaly on prenatal ultrasound: case report and review of the literature.

We report the earliest in utero presentation of a 'giant' glioependymal cyst detected on routine prenatal ultrasound at 22 weeks estimated gestational age. The clinicopathologic features of these rare lesions are reviewed as well as previous reports of glioependymal cysts detected in utero. The effects of large intracranial cysts on neurodevelopment are discussed as well as the differential diagnosis of infantile intracranial cysts and therapeutic alternatives.

Adult↗

An analysis of maternal and fetal hair lead levels.

Lead contamination of the environment is an important public health consideration. There is evidence of declining blood lead levels in Britain, however, there is still concern about chronic exposure of the fetus and young children to low levels of lead and the effect that this has on neurodevelopment. Hair lead levels have been found to correlate well with body lead contamination. This study is the first to document the level of hair lead in pregnant women and their babies from an urban British population. There was no evidence of toxic maternal lead levels and the fetus is protected by the placental barrier.

Adult↗

ortho-substituted PCB95 alters intracellular calcium signaling and causes cellular acidification in PC12 cells by an immunophilin-dependent mechanism.

ortho-Substituted PCBs mobilize Ca2+ from isolated brain microsomes by interaction with FKBP12/RyR complexes. Investigation into the cellular importance of this mechanism was undertaken using PC12 cells by fluoroimaging the actions of specific PCB congeners on [Ca2+]i and pH. RyR and IP3R share a common intracellular Ca2+ store in PC12 cells. Perfusion of nM to low microM PCB95 caused a transient rise of [Ca2+]i that was not completely dependent on extracellular Ca2+. Pre-incubation of the cells with ryanodine or FK506 completely eliminated PCB95 responses, suggesting a primary action on the FKPP12/RyR-sensitive store. PCB95, but not PCB126, induced a gradual decrease in cytosolic pH that could be completely eliminated by FK506 pre-incubation of the cells. Direct respiration measurement using isolated brain mitochondria demonstrated that neither of the PCBs directly altered any stage of mitochondrial respiration. These results revealed that PCB95 disrupts intracellular Ca2+ signaling in PC12 cells by interaction with the FKBP12/RyR complex that in turn accelerated cellular metabolism, possibly affecting signaling between ER and mitochondria. Since ortho-substituted PCBs have been shown to be neurotoxic and may affect neurodevelopment, studies on the molecular mechanism by which they alter cellular signaling may provide valuable information on the physiological roles of FKPB12 and RyR on neuronal functions.

Acidosis↗

Synaptic concentration of type-I adenylyl cyclase in cerebellar neurons.

Specific subcellular targeting and spatial arrangement of signaling molecules are important for efficient signal transduction. The neuro-specific type-I adenylyl cyclase (AC1) is stimulated by Ca2+, and plays an essential role in neurodevelopment and neuroplasticity. We generated hemagglutinin (HA)-tagged AC1 to study its subcellular localization in cultured neurons. The HA-tagged AC1 has similar enzymatic activity and regulatory properties to that of non-tagged protein. HA-AC1 targeted to both apical and basolateral domains in the epithelial Madin-Darby canine kidney (MDCK) cells, and it was found in both axons and dendrites in cultured hippocampal neurons as well as in cerebellar granule neurons. Interestingly, AC1 showed a distinct punctate form of immunostaining in MDCK cells and transfected neurons, suggesting it targets to specific subcellular domains. By immunostaining with different synaptic markers, we found that AC1 puncta were located at the excitatory synapses in cerebellar granule neurons. Our data provide a possible cellular mechanism for the physiological role of AC1 in neuroplasticity.

Adenylyl Cyclases↗

Heme oxygenase-1 and heme oxygenase-2 have distinct roles in the proliferation and survival of olfactory receptor neurons mediated by cGMP and bilirubin, respectively.

Heme oxygenase (HO) is implicated in protection against oxidative stress, proliferation and apoptosis in many cell types, including neurons. We utilized olfactory receptor neurons (ORNs) as a model to define the roles of HO-1 and HO-2 in neuronal development and survival, and to determine the mediators of these effects. The olfactory system is a useful model as ORNs display neurogenesis post-natally and do not contain nitric oxide synthase (NOS) activity, which could confound results. HO isoforms were expressed in ORNs during embryogenesis and post-natally. Mice null for either HO-1 or HO-2 displayed decreased proliferation of neuronal precursors. However, apoptosis was increased only in HO-2 null mice. Cyclic GMP immunostaining was reduced in ORNs in both genotypes, providing direct evidence that HO mediates cGMP production in vivo. Bilirubin immunostaining was reduced only in HO-2 null mice. These roles for HO-1 and HO-2 were confirmed using detergent ablation of the epithelium to observe increased neurogenesis of ORNs after target disruption in HO null mice. Primary cultures of ORNs revealed that proliferative and survival effects of HO were mediated through cGMP and bilirubin, respectively. These results support a role for HO, the CO-cGMP signaling system and bilirubin in neurodevelopment and in response to injury.

Animals↗

Recovery of brain docosahexaenoate leads to recovery of spatial task performance.

Infants fed vegetable oil-based formulas may have poorer visual function, lower cognitive scores and acquire learning tasks more slowly in comparison with those breast fed or those fed formulas supplemented with docosahexaenoate. The aim of the present study was to determine the reversibility of losses in brain function associated with the loss of brain DHA. Rats were fed very low or adequate levels of n-3 fatty acids through three generations. The n-3 fatty acid deficient animals of the F3 generation were then given an n-3 adequate diet containing alpha-linolenic and docosahexaenoic acids (DHA) at birth, weaning (3 weeks) or young adulthood (7 weeks). The spatial task performance of these animals returned to the n-3 adequate diet was then compared using the Morris water at two different ages, at 9 or 13 weeks. Our results indicate that animals repleted since birth or at weaning were able to achieve nearly the same level of brain DHA and spatial task performance as animals maintained for three generations on an n-3 adequate diet. In the case of young adult animals, the degree of DHA and behavioral performance recovery depended upon the duration of dietary repletion with substantial recovery in animals after 6 weeks but little recovery of function after two weeks. The significance of these findings is that they indicate that at least some of the adverse effects of DHA deficiency during neurodevelopment may be reversible with an n-3 fatty acid supplemented diet.

Animals↗

[Neurobiological impact of separating mothers from newborns in rodents].

Numerous animal models of early stress are currently being developed because early stress results in long-term disruptions of neuronal functions and the development of long-term behavioral disorders. These models should allow to study the concept of vulnerability applied to psychiatric disorders. The fundamental importance of the bond between the mother and the offsprings, in all mammalian species, for the development of the new-born, point to the great interest of animal models of mother/pups separation. Long periods of deprivation tend to result in anxiety, depressive-like behaviors and drug addiction in adult rats. Neurobiological studies have shown that several neuronal systems, in particular neuropeptidergic systems in the limbic structures of the brain, are disrupted, possibly due to the effects of early stress on neurodevelopment. Models evaluating the impact of early environmental factors should help to improve the prevention and prediction of psychiatric disorders and to develop new therapeutic strategies.

Animals↗

Distilling the evidence on developmental care: a systematic review.

PURPOSE: To determine whether developmental care interventions reduce neurodevelopmental delay, poor weight gain, length of hospital stay, length of mechanical ventilation, physiologic stress, and other clinically relevant adverse outcomes in preterm infants. SUBJECTS: Infants born at less than 37 weeks postconceptional age. This review consisted of 31 studies in 4 categories of developmental care interventions, 19 subgroups, and multiple clinical outcomes. The total sample sizes in the individual studies ranged from 16 to 259; the sample size in 18 of the studies was less than 50. DESIGN AND METHODS: A systematic review, based on the Cochrane Collaboration format, of all randomized trials in which elements of developmental care are compared with routine nursery care and that measured clinically relevant outcomes. Searches were made of MEDLINE from 1966 to July 2000. Additional databases were also searched electronically. Reference lists and bibliographies of relevant articles were hand-searched. Experts in the field were contracted. If more than one study in an outcome category existed, a meta-analysis was conducted. PRIMARY OUTCOME MEASURES: Outcome measures included the following: length of hospital stay, weight at discharge, neurodevelopment, physiologic parameters, feeding growth, sleep/wake states, age at discharge, neonatal outcomes, cost of hospital stay, and death. PRINCIPAL RESULTS: Developmental care interventions showed some benefit to preterm infants with respect to improved short-term growth outcomes, decreased respiratory support, decreased incidence of moderate to severe chronic lung disease, decreased length and cost of hospital stay, and improved neurodevelopmental outcomes to 24 months corrected age. These findings were based on 2 or 3 small trials for each outcome. Although a number of other benefits were shown, those results were from single studies with small sample sizes. The lack of blinding of the assessors of the outcome variables was a significant methodological flaw in half of the studies. The costs of the interventions and personnel were not considered in any of the studies. CONCLUSIONS: In most studies, the inclusion of multiple interventions made the determination of the effect of any single intervention difficult. Although there is evidence of some benefit of developmental care interventions overall and no major harmful effects reported, there were a large number of outcomes for which no or conflicting effects were shown. The single trials that did show a significant effect of an intervention on a major clinical outcome were based on small sample sizes, and the findings often were not supported in other small trials. Before a clear direction for practice can be supported, evidence showing more consistent effects of developmental care interventions on important short- and long-term clinical outcomes is needed. The economic impact of the implementation and maintenance of developmental care practices should be considered by individual institutions.

Birth Weight↗

Resective surgery in infants and young children with intractable epilepsy.

Despite the relatively high incidence of epilepsy during the first few years of life, and its documented adverse impact on development, few studies have documented the long term outcomes following epilepsy surgery in infants and young children. We report a consecutive series of 11 patients under 3 years of age who underwent excisional surgery for intractable seizures. A total of 16 resective procedures were performed, and comprised functional hemispherectomy, temporal lobectomy, and lesionectomy. The mean follow-up period was 3 years. At follow-up, 73% (8/11) were seizure-free, with over half of these patients able to cease anti-epileptic medications. Acceleration of neurodevelopment was seen in all patients in whom preoperative developmental delay was present. Quality of life was enhanced in all patients. This series confirms that excellent results can be obtained following excisional surgery in well-selected infants and young children with intractable seizures.

Child Development↗

New genetic hypothesis of schizophrenia.

Lack of complete concordance for schizophrenia in monozygotic twins has been interpreted as indicative of non-genetic cofactors in transmission of the illness. We present an alternative hypothesis that can parsimoniously explain, using known genetic mechanisms, the heredity pattern, the phenotypic spectrum and the biological abnormalities found in schizophrenia. The inheritance of a single recessive mutated allele of a gene crucial in brain development if followed by a somatic mutation in the normal allele during critical periods of brain development could result in developmental abnormalities that are expressed behaviorally as schizophrenic illness. Acquisition of this somatic mutation is likely enhanced during periods of intense cell division; therefore, the window of opportunity would be restricted to key periods in neurodevelopment. The somatic mutation may not always occur, thus explaining the variability of expression seen in the clinical population. Because the single allele mutation is still transmissible, the equal incidence of schizophrenia in the offspring of monozygotic twins discordant for the disease could also be explained. This possibility has implications for the development of genetic models and the source of genetic material for studies isolating the gene(s) of schizophrenia.

Brain↗

The marine toxin domoic acid may affect the developing brain by activation of neonatal brain microglia and subsequent neurotoxic mediator generation.

Amnesic shellfish poisoning, one of the shellfish poisoning syndromes, is caused by the marine diatom toxin domoic acid (DOM). While in adult rats, mice, monkeys and humans DOM poorly penetrates the blood-brain barrier, DOM has been shown to be very toxic to fetal in newborn mice, because the blood-brain barrier is incomplete during neurodevelopment. This fact may explain why neonates show a higher sensitivity to neurotoxins like DOM as compared to adult animals. Mechanistic studies on DOM's neurotoxicity have mainly concentrated on the investigation of DOM's effect on neuronal tissue. Recent studies have shown that glia is also involved in DOM's neurotoxicity to the adult as well as the developing nervous system. The scientific literature strongly supports the hypothesis that the microglia may play a critical role in mediating DOM's neurotoxic effects. However, the effect of DOM on microglia has not been systematically investigated. The literature supporting our hypothesis is presented and discussed.

Animals↗

Potential diagnostic aids for abnormal fatty acid metabolism in a range of neurodevelopmental disorders.

Disorders of neurodevelopment include attention deficit hyperactivity disorder, dyspraxia, dyslexia and autism. There is considerable co-morbidity of these disorders and their identification often presents difficulties to those making a diagnosis. This is especially difficult when a multidisciplinary approach is not adopted. All of these disorders have been reported as associated with fatty acid abnormalities ranging from genetic abnormalities in the enzymes involved in phospholipid metabolism to symptoms reportedly improved following dietary supplementation with long chain fatty acids. If definitive disorders of lipid metabolism could be defined then the diagnosis and subsequent management of neurodevelopmental disorders might be transformed. In the identification of those disorders of development which involve lipid metabolism, there are now several tests, measures of lipid metabolism, which could be useful.

Apraxias↗

Transient hypothyroxinemia of prematurity is associated with abnormal cranial ultrasound and illness severity.

Transient hypothyroxinemia without elevated thyroid-stimulating hormone (TSH) levels is common in prematurity, especially in very-low-birth-weight (VLBW) infants. The transient hypothyroxinemia of prematurity (THOP) has been seen as a "benign" condition not requiring medical treatment. However, some recent large observational studies have revealed a relationship between THOP and abnormal neurodevelopment. Furthermore, one study showed THOP had twice the risk of brain echolucency, which was the best predictable neurodevelopmental dysfunction, than the premature infants with normal or higher thyroxine levels. The relationships among THOP, illness severity, and neurodevelopmental dysfunction remain unclear. We propose a hypothesis that THOP is associated with abnormal ultrasound and illness severity. We studied 54 infants who were admitted more than 14 days at our neonatal intensive care unit (NICU) with a birth weight <2000 g from March 1999 to March 2000. The infants received serum thyroxine (T4), free-T4, and TSH measurement during the first weeks of life. Most of them had serum thyroxine levels measured at approximately 2 weeks of age. The infants enrolled in the study were examined by at least 1 of 3 cranial ultrasounds during the first weeks of life, illness severity evaluation according to the neonatal therapeutic intervention scoring system (NTISS) score, as well as NICU hospital stay period. Infant were classified as THOP by T4 value <5.3 microg/dL (68 nmol/L), which is 2.6 SD below the mean for term infants in Massachusetts, without elevated TSH value (<20 microIU/mL). After adjusting for some confounding factors, such as gestational age, birth weight, duration of mechanical ventilation, infants with THOP were associated with abnormal cranial ultrasound, illness severity, and lower 1-minute Apgar score. In our studies, THOP was related with brain ultrasound anomaly, neonatal illness, and lower Apgar score at 1 minute. Does early thyroxine intervention improve the prognosis and neurodevelopmental dysfunction? This question requires further investigation.

Age Distribution↗

[Clinical and molecular genetic findings in four girls with Rett syndrome].

We report on four mental retarded girls with typical clinical signs of Rett syndrome. Rett syndrome is an X-linked neurodevelopment disorder which develops after a period of normal development at the age of 6 to 18 months, affecting 1/10 000 - 15 000 girls. Recently, the MeCP2-gene encoding the methyl-CpG-binding protein 2 has been shown to be mutated in 80 percent of girls with Rett Syndrome, studied so far. In our patients with Rett syndrome two common mutations of the MeCP2-gene, R168X (n=2) and T158M were found. In the 4th patient a novel "missense" mutation R294G was identified.

Child↗

Growth and development until 18 months of children exposed to tocolytics indomethacin or nylidrin.

Indomethacin, a prostaglandin synthesis inhibitor, is a more efficient tocolytic than the beta-sympathomimetic nylidrin, but causes more frequent unwanted effects in the neonatal period. In order to elucidate the effects on neurodevelopment, infants randomly exposed in utero to either compound were followed up to 18 months. A total of 93 children (40 exposed to nylidrin and 53 exposed to indomethacin) were examined at the age of 12 months. A detailed neurological examination was carried out in 44 of these infants at the age of 18 months. At the age of 12 months the children in the indomethacin group showed poor outcome (death or severe BPD and/or CP and/or severe ROP) in 23% and the children in the nylidrin group in 5% (p = 0.039, Fisher Exact Test). Concerning the children born during tocolysis the corresponding figures were 73% and 13% respectively (p = 0.002, Fisher Exact Test). The growth of the children did not differ significantly between the two treatment groups. Neurological assessment at the age of 18 months revealed more subnormally scoring children in the indomethacin group, but the differences were not significant. It was concluded that the higher incidence of poor outcome and a lest favourable neurological development in the indomethacin group do not support indomethacin's position as the drug of choice for tocolysis.

Child Development↗

Prenatally acquired cytomegalovirus encephalopathy.

A case is reported of congenital cytomegalovirus infection. A baby girl was born at an estimated gestational age of 35 weeks to a 26-year-old Hispanic women. There was maternal cocaine abuse and poor prenatal care, and variable decelerations, abruptio placentae, and meconium-stained fluid occurred in the intrapartum period. Cytomegalovirus was isolated from the urine, with growth occurring in 48 hours, and the neonate had characteristic neurodevelopment handicaps.

Cytomegalovirus Infections↗