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At least 793 records · Page 44Linked to original sources

PubMed2003

Identification of the key amino acids of glial cell line-derived neurotrophic factor family receptor alpha1 involved in its biological function.

Glial cell line-derived neurotrophic factor (GDNF) plays a critical role in neurodevelopment and survival of midbrain dopaminergic and spinal motor neurons in vitro and in vivo. The biological actions of GDNF are mediated by a two-receptor complex consisting of a glycosylphosphatidylinositol-linked cell surface molecule, the GDNF family receptor alpha1 (GFRalpha1), and receptor protein tyrosine kinase Ret. Although structural analysis of GDNF has been extensively examined, less is known about the structural basis of GFRalpha1 function. In this study, based on evolutionary trace method and relative solvent accessibility prediction of residues, a set of trace residues that are solvent-accessible was selected for site-directed mutagenesis. A series of GFRalpha1 mutations was made, and PC12 cell lines stably expressing different GFRalpha1 mutants were generated. According to the survival and differentiation responses of these stable PC12 cells upon GDNF stimulation and the GDNF-GFRalpha1-Ret interaction assay, residues 152NN153, Arg259, and 316SNS318 in the GFRalpha1 central region were found to be critical for GFRalpha1 binding to GDNF and eliciting downstream signal transduction. The single mutation R259A in the GFRalpha1 molecule simultaneously lost its binding ability to GDNF and Ret. However N152A/N153A or S316A/N317A/S318A mutation in the GFRalpha1 molecule still retained the ability to bind with Ret. These findings suggest that distinct structural elements in GFRalpha1 may be involved in binding to GDNF and Ret.

Amino Acid Substitution↗

PubMed2004

Acyl-CoA synthetase 2 overexpression enhances fatty acid internalization and neurite outgrowth.

During neurodevelopment neurons increase phospholipid synthesis to generate additional plasma membrane that makes up the growing neurites. Compared with most cell types, neurons contain a high percentage of the polyunsaturated fatty acids (PUFAs) arachidonic acid (AA) and docosahexaenoic acid (DHA). By utilizing PC12 cell lines as a model neuronal cell line, we examined the internalization rate of AA, DHA, and non-essential oleic acid (OA), as well as their effects on neurite outgrowth. When wild type cells were differentiated, the rate of AA and DHA internalization increased 50% more than the rate of OA internalization. When media were supplemented with AA or DHA, the average neurite length was increased by approximately 40%, but supplementation with the same amount of OA had no effect. We also increased the levels of acyl-CoA synthetase-1 (ACS1) and ACS2 proteins to determine whether they contribute to PUFA internalization or neurite outgrowth. Overexpression of ACS1 increased the rate of OA internalization by 55%, and AA and DHA uptake was increased by 25%, but there was no significant change in neurite outgrowth. In ACS2-overexpressing cells, in contrast, the rate of OA internalization increased by 90%, AA by 115%, and DHA by 70%. The average aggregate neurite length in ACS2-overexpressing cells was increased by approximately 40% when the media were supplemented with PUFAs, but there was no change with OA supplementation. Taken together, these results support the hypotheses that ACSs are rate-limiting for fatty acid internalization and that ACS2 enhances neurite outgrowth by promoting PUFA internalization.

3T3-L1 Cells↗

PubMed2004

Apolipoprotein E receptors are required for reelin-induced proteasomal degradation of the neuronal adaptor protein Disabled-1.

The cytoplasmic adaptor protein Disabled-1 (Dab1) is necessary for the regulation of neuronal positioning in the developing brain by the secreted molecule Reelin. Binding of Reelin to the neuronal apolipoprotein E receptors apoER2 and very low density lipoprotein receptor induces tyrosine phosphorylation of Dab1 and the subsequent activation or relocalization of downstream targets like phosphatidylinositol 3 (PI3)-kinase and Nckbeta. Disruption of Reelin signaling leads to the accumulation of Dab1 protein in the brains of genetically modified mice, suggesting that Reelin limits its own action in responsive neurons by down-regulating the levels of Dab1 expression. Here, we use cultured primary embryonic neurons as a model to demonstrate that Reelin treatment targets Dab1 for proteolytic degradation by the ubiquitin-proteasome pathway. We show that tyrosine phosphorylation of Dab1 but not PI3-kinase activation is required for its proteasomal targeting. Genetic deficiency in the Dab1 kinase Fyn prevents Dab1 degradation. The Reelin-induced Dab1 degradation also depends on apoER2 and very low density lipoprotein receptor in a gene-dose dependent manner. Moreover, pharmacological blockade of the proteasome prevents the formation of a proper cortical plate in an in vitro slice culture assay. Our results demonstrate that signaling through neuronal apoE receptors can activate the ubiquitin-proteasome machinery, which might have implications for the role of Reelin during neurodevelopment and in the regulation of synaptic transmission.

Amino Acid Sequence↗

PubMed2003

A global approach to childhood lead poisoning prevention.

Childhood lead poisoning is an important, preventable environmental disease affecting millions of children around the world. The effects of lead are well known and range from delayed and adversely affected neurodevelopment to severe health outcomes including seizures, coma, and death. This article reviews the childhood effects of lead poisoning, the approach being taken to the problem in the United States, and the obstacles faced by developing nations in dealing with lead exposure. The United States has attacked the childhood lead poisoning problem by attempting to eliminate sources of exposure, including gasoline, solder in water pipes and cans, and industrial emissions. These actions have resulted in a dramatic reduction in the number of children with elevated blood lead levels in the United States over the last two decades. However, many developing countries are just beginning to address the problem. Successful efforts will need to incorporate epidemiologic methods, source identification, enforced regulations, and a long-term government commitment to eliminating lead as a threat to the next generation of children.

Child, Preschool↗

PubMed1995

Essential fatty acid status in neonates after fish-oil supplementation during late pregnancy.

Healthy pregnant women (n 23) were supplemented with fish-oil capsules (2.7 g n-3 polyunsaturated fatty acids/d) from the 30th week of gestation until delivery. Subjects in a control group were either supplemented with olive-oil capsules (4 g/d, n 6) or received no supplementation (n 10). Fatty acid compositions of the phospholipids isolated from umbilical plasma and umbilical arterial and venous vessel walls were determined. Fatty acid compositions of maternal venous plasma phospholipids were determined as well. Maternal plasma phospholipids of the fish-oil-supplemented group contained more n-3 fatty acids and less n-6 fatty acids. Moreover, the amounts of the essential fatty acid deficiency markers Mead acid (20:3n-9) and Osbond acid (22:5n-6) were significantly lower. The extra amount of n-3 fatty acids consumed by the mothers resulted in higher contents of n-3 fatty acids, and of docosahexaenoic acid (22:6n-3) in particular, in the phospholipids of umbilical plasma and vessel walls. It is, indeed, possible to interfere with the docosahexaenoic acid status at birth: children born to mothers supplemented with fish oil in the last trimester of pregnancy start with a better docosahexaenoic acid status at birth, which may be beneficial to neonatal neurodevelopment.

Adult↗

PubMed2000

Evidence for progression of brain structural abnormalities in schizophrenia: beyond the neurodevelopmental model.

OBJECTIVE: Clinical, neuroimaging, neuropathological and neuropsychological evidence suggests that, in schizophrenia, there is structural and functional disturbance of the hippocampus. The purpose of this paper is to present published findings concerning the nature, timing and course of these putative disturbances of hippocampal function and the pathophysiological mechanisms involved, and to explore whether schizophrenia is a disorder of neurodevelopment, neurodegeneration or a combination of both processes. METHOD: The available cross-sectional and longitudinal evidence for hippocampal involvement in schizophrenia is reviewed and a model of hippocampal involvement in this disorder, which derives from our own cross-sectional and longitudinal hippocampal imaging data, is described. RESULTS: We propose a three-hit model in which an early neurodevelopmental lesion renders the hippocampus vulnerable to further insult later in life during the transition phase to active illness. The available evidence suggests that the left hippocampus is particularly vulnerable during these early stages, while further insult involving the hippocampus bilaterally occurs in those who develop a chronic form of the illness. CONCLUSIONS: Intervention strategies should target the most vulnerable stages of the illness, in particular the transition phase to psychosis, when novel treatments may prevent the illness or ameliorate its effects.

Brain↗

PubMed1994

Viruses and schizophrenia.

A viral hypothesis for the pathogenesis of schizophrenia has been under serious consideration for more than 70 years. To date, attempts have failed to identify a specific virus which contributes to the aetiology of the disorder. There has, however, been a recent resurgence of interest in a possible relationship between viral illness and schizophrenia. This renewed attention is the result of epidemiological evidence suggesting an excess of winter births in patients with schizophrenia, indications of foetal insults in persons who develop schizophrenia and an association between foetal exposure to the influenza virus and the subsequent development of schizophrenia. Advances in our understanding of the pathophysiology of viral diseases and the development of sophisticated techniques to study them have resulted in more complex viral hypotheses of schizophrenic aetiology, such as viral disruption of normal neurodevelopment, viral induced autoimmunity and retroviral integration. These hypotheses are now beginning to be tested experimentally.

Autoimmunity↗

PubMed1994

Evidence from two genetic syndromes for a dissociation between verbal and visual-spatial short-term memory.

Williams and Down syndromes, two genetic syndromes of abnormal neurodevelopment, are characterized by specific neuropsychological profiles and unique patterns of brain morphology. We find that the superior language ability of subjects with Williams syndrome is accompanied by significantly better performance on a verbal short-term memory task. Conversely, subjects with Down syndrome perform significantly better on a visual-spatial short-term memory task. This double dissociation provides neurogenetic evidence for the distinction between short-term storage for verbal and for visual-spatial stimuli.

Adolescent↗

PubMed2004

DISC1 and DISC2: discovering and dissecting molecular mechanisms underlying psychiatric illness.

A balanced (1;11)(q42;q14) translocation co-segregates with schizophrenia and major affective disorders in a large Scottish family. The translocation breakpoint on chromosome 1 is located within the Disrupted in Schizophrenia 1 and 2 genes (DISC1 and DISC2). Consequently loss of normal function of these genes is likely to underlie the susceptibility to developing psychiatric disorders that is conferred by inheritance of the translocation. Additionally, a number of independent genetic studies highlight the region of chromosome 1q containing DISC1 and DISC2 as a likely susceptibility locus for both schizophrenia and affective disorders. These genes are thus implicated in the aetiology of major psychiatric disorders in several populations. Although the function of DISC1 was initially unknown, several recent reports have made significant progress towards understanding its role in the central nervous system. Intriguingly, all data obtained to date point towards an involvement in processes critical to neurodevelopment and function. DISC2 has not been studied in detail, but is likely to modulate DISC1 expression. Overall, it is clear from the combination of genetic and functional data that DISC1 and/or DISC2 are emerging as important factors in the molecular genetics of psychiatric illness.

Brain↗

PubMed2000

Growth and neurodevelopmental outcome of very low birthweight infants with necrotizing enterocolitis.

UNLABELLED: The aim of the study was to assess the effect of necrotizing enterocolitis (NEC) on neurodevelopmental outcome and growth. Neurodevelopmental outcome of 20 out of 22 suriviving very low birthweight infants (VLBW) diagnosed with NEC between 1992 and 1996 was compared with 40 control infants matched for gestational age and year of admission. Follow-up studies were performed at 12 and 20 mo of corrected age. The German revision of the Griffiths' scales was used for development assessment. Neurodevelopment was significantly delayed in infants with NEC at 12 mo (median general developmental quotient: 90.0 vs 97.8; p = 0.04) and 20 mo (86.4 vs 97.7; p = 0.004) of age. Somatic growth did not differ between infants with and without NEC. Fifty-five percent of infants suffering from NEC but only 22.5% of the infants without NEC were severely retarded (developmental quotient < -2 SD of a control group of healthy newborns) at 20 mo of corrected age. CONCLUSION: Preterm infants developing NEC are at risk for neurodevelopmental impairment and need close neurodevelopmental follow-up for the first years of life.

Developmental Disabilities↗

PubMed2001

Cerebral proton magnetic resonance spectroscopy of neonates after extracorporeal membrane oxygenation.

UNLABELLED: During venoarterial extracorporeal membrane oxygenation the right carotid artery is ligated in a hypoxic neonate. The aim of the present study was to compare the morphology and metabolism of the left and right basal ganglia in 10 neonates after extracorporeal membrane oxygenation, using proton magnetic resonance imaging and spectroscopy. Data could be obtained in 9 neonates. No significant metabolic differences were found between either the left or right basal ganglia, despite a small right-sided thalamic infarct in one child. Metabolism was normal in all cases. All the infants showed symmetrical neurodevelopment. CONCLUSION: Ligation of the right carotid artery for venoarterial extracorporeal membrane oxygenation did not produce persistent changes in brain metabolism in the basal ganglia in this small group of patients.

Basal Ganglia↗

PubMed2002

Cerebral venous sinus thrombosis in a neonate due to factor V Leiden deficiency.

UNLABELLED: A case is described of cerebral venous sinus thrombosis due to factor V Leiden deficiency that occurred in the neonatal period, presenting with seizures. Diagnosis was based on ultrasonography, Doppler ultrasound (US) and magnetic resonance imaging (MRI). The aetiology was only recognized after blood-clotting tests, antithrombin III, C and S protein levels and factor V Leiden were studied. This situation was treated with intravenous heparin controlled by activated partial thromboplastin time (APTT). MRI angiography and Doppler US were important in the follow-up. It is important to assess periodically the neurological development of the baby and to prevent situations such as dehydration or severe infection, which can precipitate further thrombotic events. Molecular genetics allowed the identification of this trait in other family members. CONCLUSION: In every newborn with a thrombotic episode, coagulation studies must be performed, including testing for activated protein C (APC) resistance. Doppler US flow measurement and the MRI studies provide the best tools for diagnosis and follow-up. Heparin should be given to double the initial individual APTT. It is important to prevent any risk situation such as dehydration or severe infection, which could lead to a recurrence of a thrombotic episode. Regular assessment of the child's neurodevelopment is an important aspect of further care.

Activated Protein C Resistance↗

PubMed2004

Extrauterine growth restriction in very-low-birthweight infants.

UNLABELLED: Postnatal growth failure of very-low-birthweight (VLBW) infants may result from a complex interaction of genetic and environmental factors, including inadequate nutrition, morbidities affecting nutrient requirements, endocrine abnormalities and treatments. Among VLBW infants, those small for gestational age (SGA) at birth and those with postnatal growth restriction at the time of discharge are at higher risk of later growth failure and long-term consequences. Nutritional intervention with an "aggressive nutrition" during the first weeks of life may be able to minimize the interruption of nutrients that occurs at birth, and reduce as much as possible the incidence of growth restriction at the time of discharge and later. Even though aggressive parenteral and enteral nutrition appear to be effective and safe in VLBW infants, further evaluations of their long-term effect on growth and health consequences are needed. Several studies evaluating the effect of enriched nutrient formulas after hospital discharge on growth and neurodevelopment have produced conflicting results, whereas the potential deleterious long-term effects of prolonged use of high protein and/or of later catch-up growth have been questioned. In contrast, recent data seem to indicate that the use of human milk after hospital discharge could be the most beneficial diet for subsequent health and development. CONCLUSION: VLBW infants SGA at birth and those with early postnatal growth restriction are at high risk of later growth failure and long-term consequences. Therefore, the first objective of early nutrition should be to reduce the incidence of growth restriction at the time of discharge. Further studies on VLBW infants to evaluate the safety and beneficial effects of prolonged dietary manipulation during the first year of life are needed.

Body Composition↗

PubMed2005

Crystalloid or colloid for partial exchange transfusion in neonatal polycythemia: a systematic review and meta-analysis.

AIMS: To determine whether crystalloid solutions are as effective as colloid solutions when a partial exchange transfusion is performed in newborns with polycythemia. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Controlled Trials Register of the Cochrane Library (1966-2004). Keywords used were: polycythemia, partial exchange transfusion, hyperviscosity, and limited to newborn. Randomized studies in newborns with polycythemia were selected for evaluation. Outcomes examined were: long-term neurodevelopment; short-term physiological effects; improvement in clinical symptoms; reduction in haematocrit at 4-6 h; haematocrit at 24 h; and frequency of serious complications. RESULTS: Four randomized controlled clinical trials, including 200 patients in total, with evaluable data, which satisfied our criteria, were found. There were no data on long-term outcomes. There is no reported important difference in short-term physiologic effects. Use of crystalloid was as effective as colloid in both correction of haematological values and reduction of clinical symptoms following partial exchange transfusion. CONCLUSION: Crystalloid solutions are as effective as colloid solutions for partial exchange transfusion. When crystalloid solutions are used for this purpose, there is no risk of transmission of blood-borne diseases, there is no risk of anaphylaxis, they are rapidly and easily available, and are less expensive. The use of crystalloid should become the standard for partial exchange transfusion.

Colloids↗

PubMed2006

Does inadequate maternal iron or DHA status have a negative impact on an infant's functional outcomes?

UNLABELLED: Marginal intake of iron and omega-3 long-chain fatty acids (DHA) is prevalent among pregnant women. It is not clear to what extent poor iron or DHA status during pregnancy impacts on an infant's functional outcomes. A few studies suggest that inadequate maternal iron or DHA status may be associated with suboptimal functional outcomes in infants. In addition, there is a lack of prospective studies using randomized, double-blind design or experimental studies with appropriate animal models. Although both nutrients are involved in early brain development and their metabolism is interrelated, no study has examined the interaction between iron and omega-3 fatty acids during pregnancy. CONCLUSION: Long-term studies on large cohorts of pregnant women and their infants are needed to determine whether inadequate iron or DHA status during pregnancy is detrimental to infant neurodevelopment.

Brain↗

PubMed1998

Clinical application of the measurement of cord plasma lactate and pyruvate in the assessment of high-risk neonates.

Lactate levels in combination with lactate/pyruvate (L/P) ratio have been used to measure altered cellular redox states. We measured the cord plasma lactate levels and L/P ratios in 70 normal neonates (40 full-term and 30 preterm neonates) to set up the normal (control) ranges. The control cord plasma lactate levels and L/P ratios were 2660 [700 (SD)] micromol/l, 16 (3) in full-term neonates and 2750 (740) micromol/l, 17 (3) in preterm neonates, respectively. We also measured the lactate levels and L/P ratios in the high-risk full-term (n = 23) and preterm (n = 35) neonates, the results were 4500 (2600) micromol/l, 19 (13), and 5100 (2700) micromol/l, 26 (12), respectively. With the aid of elevated lactate levels and L/P ratios, the occurrence of neonatal encephalopathy can be predicted with a sensitivity of 100% and a specificity of 94.5% in this patient group. In our study, the six cases with abnormal neurodevelopment at 6-9 months of age all had both elevated lactate levels and L/P ratios at birth. We conclude that the measurement of lactate levels in combination with L/P ratios is a useful quantitative tool in assessing the existence and severity of perinatal hypoxia in the high-risk neonates.

Female↗

PubMed1998

The role of long chain polyunsaturated fatty acids (LCPUFA) in neonatal nutrition.

Exciting new research has shown that both preterm and term infants can actively convert the essential fatty acids linoleic acid (LA, 18:2n-6) and alpha-linolenic acid (ALA, 18:3n-3) to long chain polyunsaturated fatty acids (LCPUFA). However, the amount of LCPUFA being produced, particularly of docosahexaenoic acid (DHA, 22:6n-3), may not be sufficient to meet the developmental requirement of the infant. Because DHA is a major component of retinal and brain tissues, a number of studies have been initiated to test the effect of dietary LCPUFA on neural outcomes in infants. These studies have largely involved a comparison of neural responses from infants fed standard infant formula (no LCPUFA) with infants receiving LCPUFA from either supplemented formula or breast milk. The results have been equivocal and may be due to the variety of LCPUFA supplements and formula fat blends used, differing testing techniques as well as variations in clinical trial conduct, but are clearer in preterm than term infants. Overall the results indicate a possible role for LCPUFA in neurodevelopment.

Breast Feeding↗

PubMed1999

Duration of breastfeeding and developmental milestones during the latter half of infancy.

Several studies have suggested that breastfeeding has a long-term influence on brain development. However, interpretation of these findings is complicated by the presence of many potential confounding factors. Only a few studies have examined infants before 1 y of age, although very early assessment might reduce the role of environmental influence. We investigated the association between exclusive breastfeeding and three developmental milestones related to general and fine motor skills and early language development at the age of 8 mo. We followed 1656 healthy, singleton, term infants, with a birthweight of at least 2500 g, born between May 1991 and February 1992 in Aarhus, Denmark. Information was collected at 16 wk gestation, at delivery and when the infant was 8 mo old. Motor skills were evaluated by measurement of crawling and pincer grip. Early language development was defined as the ability to babble in polysyllables. The proportion of infants who mastered the specific milestones increased consistently with increasing duration of breastfeeding. The relative risk for the highest versus the lowest breastfeeding category was 1.3 (95% CI: 1.0-1.6) for crawling, 1.2 (95% CI: 1.1-1.3) for pincer grip and 1.5 (95% Cl: 1.3-1.8) for polysyllable babbling. Little change was found after adjustment for confounding. In conclusion, our data support the hypothesis that breastfeeding benefits neurodevelopment.

Breast Feeding↗