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PubMed2003

Can breast-feeding protect against schizophrenia? Case-control Study.

BACKGROUND: Human milk, unlike formula feeds, contains long-chain polyunsatured fatty acids, such as docosahexaenoic acid and arachidonic acid which are essential in the development of the central nervous system. If human milk is the optimal food for brain development, and if schizophrenia is a neurodevelopment disorder, might people who become schizophrenic in adult life be less likely to have been breast-fed? AIMS: To compare the incidence and length of breast-feeding in patients, siblings and normal controls and to examine the relationship between the duration of breast-feeding and age at onset of schizophrenia. METHOD: 113 schizophrenic patients were recruited, as were 140 siblings of the patients and 113 nonschizophrenic controls. The breast-feeding history of the patients, their siblings and controls was obtained through interviews with the mothers of the patients and controls. RESULTS: There were no significant differences between groups in the incidence of breast- feeding. The duration of breast-feeding was positively correlated with the age at onset of illness (r = +0.25, p < 0.02). CONCLUSION: Breast-feeding is no less common in those who develop schizophrenia in later life. However, breast milk might postpone the onset of the illness in schizophrenic patients.

Adult↗

PubMedDate not supplied

Effect of protein phosphorylation on neurite outgrowth in cultured embryonic Xenopus spinal neurons.

Intracellular signaling pathways involved in neurite outgrowth have been extensively studied in a variety of cell systems. While most of these studies utilized continuous neuronal-like cell lines, fewer studies have been conducted in primary neuronal culture. One primary culture system that has recently been used to dissect the signaling pathways involved in axon guidance consists of spinal neurons derived from embryonic Xenopus laevis. In this study, we used Xenopus to study neurite outgrowth by treating neuronal cultures with pharmacological agents that activate or inhibit various protein kinases or that inhibit protein phosphatases. We found that agents which affected signaling via cAMP-dependent protein kinase, calmodulin, cyclin-dependent kinase 5, or protein phosphatases had effects on Xenopus neurite outgrowth that were similar to those reported in other primary neurons or in neuronal-like cell lines. However, agents which affected protein kinase C signaling had effects on Xenopus neurite outgrowth that were distinct from those reported in neuronal-like cell lines. Although continuous cell lines have several advantages for the dissection of signaling pathways involved in neurodevelopment, these observations underscore the importance of also using primary neurons to examine these pathways.

Animals↗

PubMed2003

Early arterial lactate and prediction of outcome in preterm neonates admitted to a neonatal intensive care unit.

AIM: In the present study early arterial lactate samples were examined to predict adverse outcome in preterm neonates. SUBJECTS AND METHODS: 88 preterm neonates (mean gestational age 29.8 weeks, mean birth weight 1,225 g) had arterial lactate levels measured from indwelling arterial catheters within the first 3 h of life. An adverse outcome was defined as death or abnormal neurodevelopment. The positive (PPV) and negative predictive value (NPV) of early arterial lactate levels for an adverse outcome (death or neurodevelopmental abnormalities) were calculated using receiver operating characteristic analysis. RESULTS: PPV and NPV of arterial lactate within 3 h after birth were 0.47 and 0.92, respectively, with a cutoff value of 5.7 mmol/l. Umbilical blood gas values and 1 and 5 min Apgar scores had much lower PPVs. CONCLUSION: Arterial lactate levels within 3 h of life can be used to select preterm neonates who are at risk of an adverse outcome.

Apgar Score↗

PubMed2002

A computational model for neocortical neuronogenesis predicts ethanol-induced neocortical neuron number deficits.

We have developed a computational model that allows for the evaluation of normal and perturbed neurodevelopmental processes. This mathematical construct is used to test the hypothesis that reduced neuronal production is the critical mechanism behind fetal alcohol syndrome. Model predictions of normal neurodevelopment match independent stereological measures but challenge estimates generated using a previously published model of normal neocortical neuronogenesis. Evaluation of data showing an increased cell cycle length after prenatal exposure to ethanol during neocortical neuronogenesis yields predictions of cellular deficits that can account for the permanent neocortical neuronal loss seen in rodents exposed to ethanol concentrations of public health relevance.

Animals↗

PubMed2003

Nutritionally regulated hormonal factors in prolonged postnatal growth retardation and its associated adverse neurodevelopmental outcome in extreme prematurity.

Recent published data show that at hospital discharge, most infants born at <30 weeks of gestation would not achieve the median birth weight of the reference fetus at the same postconceptional age, and many would be less than the 10th centile. Estimating from the current recommendations of calorie and protein intakes, these infants accrue large deficits in intakes of protein and calorie during the first weeks of life. Postnatal growth retardation over a prolonged period of time is related to neurodevelopmental delays. While a total energy intake of 120 kcal/kg/day has generally been considered adequate, protein requirement in low gestation infants remains a matter for debate. Increasing the dietary protein:calorie ratio has previously been proposed as a strategy to enhance growth and to achieve a body composition similar to that of the reference fetus. Previous study data reveal that serum insulin-like growth factor I (IGF-I) concentration is positively correlated with protein intake, and nitrogen retention, in turn, is positively correlated with serum IGF-I concentration. Remarkably, elevated serum growth hormone but low serum IGF-I concentrations have been reported in low gestation infants and in infants with intrauterine growth retardation, suggesting IGF-I being a nutritionally regulated hormonal factor in the postnatal growth retardation. As neurodevelopment in extreme prematurity is likely affected by multiple factors, we hypothesize that a combined strategy of the previously proposed hormonal supplement with hydrocortisone and tri-iodothyronine together with increased dietary protein intake (progressively increasing from 1.5 g/kg/day intravenously administered amino acids immediately after birth, then 3.6 g/100 kcal at approximately 125 kcal/kg/day when enterally fed till the infant reaches a body weight of >or=1.8 kg and at >or=50th centile weight of the reference fetus at the same postconceptional age) would likely be synergistic and more effective in improving neurodevelopmental outcome.

Amino Acids↗

PubMed2004

Hypocapnia induces caspase-3 activation and increases Abeta production.

BACKGROUND: At least half of all cases of early onset (<60) familial Alzheimer's disease (FAD) are caused by any of over 150 mutations in three genes: the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2). Mutant forms of PS1 have been shown to sensitize cells to apoptotic cell death. OBJECTIVE: We investigated the effects of hypocapnia, a risk factor for both cognitive and neurodevelopment deficits, on caspase-3 activation, apoptosis, and amyloid beta-protein (Abeta) production, and assessed the influence of the PS1Delta9 FAD mutation on these effects. METHOD: For this purpose, we exposed stably transfected H4 human neuroglioma cells to conditions consistent with hypocapnia (PCO2<40 mm Hg) and hypocapnia plus hypoxia (PO2<21%). RESULTS: Hypocapnia (20 mm Hg CO2 for 6 h) induced caspase-3 activation and apoptosis; the PS1Delta9 FAD mutation significantly potentiated these effects. Moreover, the combination of hypocapnia (20 mm Hg CO2) and hypoxia (5%O2) induced caspase-3 activation and apoptosis in a synergistic manner. Hypocapnia (5 and 20 mm Hg CO2 for 6 h) also led to an increased Abeta production. CONCLUSION: The findings suggest that hypocapnia (e.g. during general anesthesia) could exacerbate AD neuropathogenesis.

Alzheimer Disease↗

PubMed2005

Antenatal glucocorticoids increase early total thyroxine levels in premature infants.

BACKGROUND: Hypothyroxinemia is associated with adverse neonatal outcomes including white matter damage, cerebral palsy, poor neurodevelopment and death. It has become increasingly important to understand the natural history and modifiers of thyroid function in the premature infant. It is standard obstetrical practice to offer antenatal glucocorticoids to pregnant women with threatened preterm delivery. Few studies have investigated the effect of antenatal glucocorticoids on neonatal thyroid function. OBJECTIVE: To examine the association between antenatal exposure to glucocorticoids and early total thyroxine (T4) levels among extremely premature infants. METHODS: We studied 521 infants born at 4 medical centers. Entry criteria included a gestational age of 23-28 weeks and a serum thyroxine level obtained in the first postnatal week. Receipt of antenatal glucocorticoids was recorded as none, partial, or complete. A complete course consisted of two doses of betamethasone or four doses of dexamethasone within a 48-hour period between 2 and 7 days of delivery. Early total T4 levels were obtained from state-mandated newborn screening programs. RESULTS: Controlling for potential maternal, perinatal and neonatal confounding variables, infants exposed to a complete course of antenatal glucocorticoids had total T4 levels 0.8 microg/dl higher than their peers who were not exposed to a complete course of antenatal glucocorticoids (p = 0.03). CONCLUSIONS: Extremely premature infants who received a complete course of antenatal glucocorticoids had significantly higher total thyroxine levels in the first postnatal week. Maternal, perinatal, and early neonatal variables did not completely explain this association. We speculate that antenatal glucocorticoids influence early neonatal thyroid function.

Adult↗

PubMed2005

Catechol-O-methyltransferase Val158Met polymorphism in schizophrenia: associations with cognitive and motor impairment.

Cognitive and motor deficits have been proposed as markers of abnormal neurodevelopment in schizophrenia and have been associated with genetic liability. In a multicenter study involving 106 subjects, 56 with deficit schizophrenia and 50 with nondeficit schizophrenia, we tested the hypothesis that the catechol-O-methyltransferase (COMT) Val(158)Met polymorphism is associated with cognitive and motor deficits either in schizophrenia as a whole or in its deficit subtype. The COMT Val(158)Met polymorphism shared 6.6% of the executive/attention dysfunction variance in patients with schizophrenia and 15.6% of the motor impairment variance in patients with deficit schizophrenia. These results support the hypothesis that the COMT Val(158)Met polymorphism influences executive functions in schizophrenia and the neuromotor performance in the deficit subtype only.

Adolescent↗

PubMed2005

Early diffusion-weighted MRI and 1H-Magnetic Resonance Spectroscopy in asphyxiated full-term neonates.

AIM: To assess the predictive value of early MRI and proton MR spectroscopy ((1)H-MRS), 11 full-term neonates with severe perinatal asphyxia were studied within 48 h after birth. METHODS: T(1)- and T(2)-weighted MRI, diffusion-weighted MRI (DW-MRI), apparent diffusion coefficient of water (ADC) of the basal ganglia and parietal white matter, as well as (1)H-MRS of the basal ganglia were performed in a 1.5-Tesla magnetic field. Neurodevelopment was assessed in the survivors for at least 24 months. RESULTS: Nine of the 11 neonates had a poor outcome (7 died, 2 developed cerebral palsy). All examinations were normal in the 2 neonates with a good outcome. T(1)- and T(2)-weighted MRI were abnormal in 7, DWI was abnormal in 7, ADC was abnormal in 5, and elevated lactate/N-acetylaspartate ratios using (1)H-MRS were seen in 7 of the 9 neonates with a poor outcome. None of these 9 had completely normal MRI or (1)H-MRS findings. CONCLUSIONS: Using a combination of T(1)- and T(2)-weighted MRI, DW-MRI, ADC measurements and (1)H-MRS within 48 h after severe perinatal asphyxia, no abnormalities were seen with any of these techniques in both neonates with a good outcome.

Asphyxia Neonatorum↗

PubMed1994

Hypoglycaemia in the neonate: how and when is it important?

Cerebral metabolism is known to be highly dependent upon glucose utilisation. In the neonate, severe hypoglycaemia is now recognized to be associated with subsequent adverse neurodevelopment and in extremis glial and neuronal cell death. However, the level at which hypoglycaemia becomes clinically important is not well understood. Clinical methods for assessing effects of hypoglycaemia are at best crude. Noninvasive assessment of neuronal function suggests that cerebral dysfunction occurs at blood glucose levels well above clinical action levels. Thus, we appear to ignore apparently asymptomatic hypoglycaemia at our and indeed the patient's peril. Furthermore, glycaemic status invariably is interpreted with scant regard to alternative catabolic substrates. In the neonate, recent evidence suggests this approach is unfounded. This presentation will review evidence that glycaemic status in neonates should no longer be considered as an entity in itself, but rather in the light of compensatory metabolic processes and treated accordingly.

Humans↗

PubMed1995

Sleep EEG changes in psychotic disorders: gender and age effects.

The aim of this study was to examine gender-related differences in electroencephalographic (EEG) sleep in inpatients with psychotic disorders. We investigated the effects of gender and age as well as gender-by-age interactions on sleep continuity, architecture and intranight distributions in 38 male and 23 female patients with functional psychoses. No gender effects were seen for any sleep parameters. However, older psychotic males had less slow-wave sleep than older psychotic females. On the other hand, female psychotic patients showed a significant decline in automated REM counts with age. It is possible that gender-related differences in neurodevelopment and/or aging could account for these findings.

Adolescent↗

PubMed1991

Febrile convulsions induced by microwaves and the alteration in behavior of albino mouse OF1.

We studied the effects of microwave (2,440 MHz) induced febrile convulsions (FCs) on the behavior and development of 31 albino mice (OF1 strain), between 25 and 30 days old, in comparison with a group of 33 animals from the same litters. Previously a string test was adapted to measure the neurodevelopment of mice in the first 6 months of life with 82 animals of the same characteristics. The animals submitted to convulsions (fit temperature = 39.2 +/- 0.96 degrees C) showed normal growth, in fact they obtained better results in the test than the control mice (2-way ANOVA, p less than 0.01). FCs have no negative influence on the normal behavior of the mouse.

Animals↗

PubMed1996

Gene-environment interaction in schizophrenia: season-of-birth effect reveals etiologically different subgroups.

Compared to the general population, one consistent finding in schizophrenia research is a significant surplus of schizophrenic births in the winter/spring months. There is little evidence that this is attributed to statistical artefacts. The "harmful effects' hypothesis offers the most plausible explanation for this phenomenon. Exogenous harmful effects, predominant during the cold season, may affect the developing immature fetal brain and thus constitute some of the factors predisposing to schizophrenic breakdown in adulthood. Neuropathological and epidemiological studies point to the second trimenon of gestation as the crucial period of fetal brain maturation. Recently, some studies found that the surplus in schizophrenic winter/spring births is mainly due to sporadic forms. In contrast, patients with high genetic risk of the disease even tended to have a birth deficit during this period. This suggests that schizophrenia is not a disease entity but consists of etiologically distinct subgroups on which the influence of genes and/or environment has to be weighted differently. On the one hand, in sporadic forms of the disease exogenous noxious agents may be of major etiological importance. On the other hand, in fetuses at high genetic risk neurodevelopment may already be disturbed due to a genetic defect and additional environmentally noxious agents can cause abortions, stillbirths and sudden infant deaths.

Embryonic and Fetal Development↗

PubMed2026

The Thyroid-Brain Network: Exploring Inflammation, Immune Mechanisms and Common Triggers in Thyroid-Related Neurological Dysfunction.

Autoimmune thyroid diseases (AITD), including Hashimoto's thyroiditis and Graves' disease, represent the most prevalent endocrine disorders worldwide, affecting hundreds of millions with profound but often under recognized neurological consequences. There are emerging lines of evidence establishing inflammation and immunity as the critical missing link connecting peripheral thyroid dysfunction to central nervous system manifestations. Thyroid hormones function as essential neuromodulators governing neurodevelopment, synaptic plasticity, and cognitive processing through integrated genomic and non-genomic mechanisms, with region-specific cerebral metabolic disturbances correlating with distinct neuropsychiatric symptoms. The immunological perspective reveals that AITD propagates neuroinflammation through convergent pathways: molecular mimicry enabling cross-reactivity between thyroid and neural antigens, cytokine-mediated disruption of neurotransmitter metabolism, HMGB1-driven glial activation, and blood-brain barrier compromise facilitating immune cell infiltration. The thyroid-gut-microbiota axis emerges as a critical mediator wherein dysbiosis perpetuates both thyroid autoimmunity and neuroinflammation through impaired serotonin precursor availability and increased intestinal permeability. Mitochondrial dysfunction represents an energetic common denominator, as thyroid hormone dysregulation directly impairs oxidative phosphorylation, producing region-specific cerebral metabolic disturbances. Simultaneous compromise of monoamine systems, cholinergic signaling abnormalities, and glutamate excitotoxicity creates a particularly toxic neurochemical state in untreated thyroid dysfunction. Common triggers such as psychological stress, gut dysbiosis, and mitochondrial impairment may activate interconnected pathways that simultaneously compromise thyroid and brain function, revealing that these disorders share fundamental mechanistic origins. These insights have been discussed in the current review to enhance the understanding of thyroid-brain function, the core mechanisms and consequences of functional deficits.

Journal Article↗

PubMed1996

Genetic association of the HLA DRB1 gene locus on chromosome 6p21.3 with schizophrenia.

OBJECTIVE: The authors investigated the human leukocyte antigen (HLA) DRB1*04 gene in schizophrenic patients because it is positively associated with rheumatoid arthritis, an autoimmune disease that exhibits a strong negative association with schizophrenia. The HLA DQB1*0602 allele was also studied because of previous reports of genetic association between it and schizophrenia. Maternal HLA was investigated because of the reported association between prenatal influenza and schizophrenia and the central role of HLA molecules in the immune response to viral infections. METHOD: Polymerase chain reactions and sequence-specific oligonucleotide probes were used to genotype 94 unrelated patients with DSM-III-R schizophrenia, 92 mothers of schizophrenic offspring who were not related either to each other or to the 94 patients, and 177 healthy comparison subjects. RESULTS: The frequency of DRB1*04 alleles was significantly lower in both the schizophrenic patients and the unrelated mothers of schizophrenic offspring than in the healthy comparison subjects. No significant differences were found for DQB1*0602. CONCLUSIONS: DRB1*04 alleles may partially account for the genetic predisposition to schizophrenia. The association reported here may be explained by genetic linkage or by an autoimmune pathophysiology for a proportion of schizophrenia cases. Alternatively, it may be that maternal B lymphocytes that do not express the DR4 antigen encoded by DRB1*04 respond to influenza virus by producing antibodies that perturb neurodevelopment, thus underpinning a proportion of schizophrenia cases.

Chromosomes, Human, Pair 6↗

PubMed1998

Is schizophrenia a progressive neurodevelopmental disorder? Toward a unitary pathogenetic mechanism.

OBJECTIVE: The author 1) reassesses the case against a neuronal degeneration hypothesis for schizophrenia; 2) demonstrates that the hypothesis that schizophrenia is a disorder caused by early (i.e., pre- or perinatal) and static (i.e., fixed, nonprogressive) damage to the brain is unsatisfactory because it cannot readily account for brain imaging results from schizophrenic patients and lacks both satisfactory clinical examples and experimental models of early, static developmental disorders resulting in the late spontaneous functional deterioration that characterizes schizophrenia; and 3) offers an alternative pathogenetic hypothesis for schizophrenia that is consistent with the available imaging and neuropathological data. METHOD: Published data on schizophrenia and relevant clinical and experimental studies of neurodevelopment and its disorders are reviewed. RESULTS: The neuropathological studies provide strong evidence against a classic neurodegenerative pathogenesis of schizophrenia and moderate support for prenatal developmental abnormalities. The imaging data provide strong evidence that excessive brain volume loss occurs after maximum brain volume expansion and equivocal evidence that it continues after onset of overt illness. The available clinical and experimental models of late deterioration after static, early brain lesions are unconvincing. A progressive developmental mechanism can reconcile the neuropathological and imaging data, while being compatible with both early onset and late deterioration. CONCLUSIONS: It matters whether the pathogenetic agent in schizophrenia is static or progressive, since if it is the latter it is worthwhile to search not only for means of prevention but also for interventions that will arrest progression as early as possible.

Apoptosis↗

PubMed1998

MRI study of cavum septi pellucidi in schizophrenia, affective disorder, and schizotypal personality disorder.

OBJECTIVE: A cavum between the septi pellucidi may reflect neurodevelopmental anomalies in midline structures of the brain. The authors examined cavum septi pellucidi in subjects with schizophrenia, affective disorder, and schizotypal personality disorder and in normal subjects. METHOD: Thirty schizophrenic patients (15 chronic, 15 first-episode), 16 patients with affective disorder (first-episode), 21 patients with schizotypal personality disorder, and 46 normal subjects were evaluated with magnetic resonance imaging. Cavum septi pellucidi was assessed by counting the number of 1.5-mm slices containing cavum septi pellucidi. RESULTS: The presence or absence of cavum septi pellucidi did not differentiate among groups. However, the prevalence of abnormal cavum septi pellucidi (i.e., cavum septi pellucidi contained on four or more slices) was 30.4% for schizophrenic patients (36.4% for chronic, 25.0% for first-episode), 20.0% for patients with affective disorder, 18.8% for patients with schizotypal personality disorder, and 10.3% for normal subjects. When the authors used the Nopoulos et al. criteria for rating cavum septi pellucidi, which omitted borderline cases with cavum septi pellucidi on three slices, the prevalence of abnormal cavum septi pellucidi increased to 35.0% for schizophrenia (40.0% for chronic, 30.0% for first-episode), 25.0% for affective disorder, 27.3% for schizotypal personality disorder, and 13.0% for normal subjects. There was a statistically significant difference in ratings between schizophrenic and normal subjects. CONCLUSIONS: The results suggest that alterations in midline structures during the course of neurodevelopment may play a role in the pathogenesis of schizophrenia.

Adult↗

PubMed1999

Clinical and neurobiological correlates of cytogenetic abnormalities in childhood-onset schizophrenia.

OBJECTIVE: Cytogenetic abnormalities are increased in schizophrenia, suggesting a possible etiologic contribution. However, their clinical and pathophysiologic roles in the disorder are unknown. To investigate this, a group of children and adolescents participating in a comprehensive study of childhood-onset schizophrenia were screened for chromosomal abnormalities, and their clinical and neurobiological correlates were examined. METHOD: Cytogenetic screening with the use of high-resolution banding, fluorescent in situ hybridization for chromosome 22q11 deletions, and molecular fragile X testing was undertaken in a group of 47 children and adolescents with very early onset of schizophrenia. Clinical, neurobiological (including brain morphometry), and risk factor measures of the subjects with cytogenetic abnormalities were compared with those of the remaining patients without cytogenetic anomalies. RESULTS: Five patients had previously undiagnosed cytogenetic abnormalities. Lower performance IQ and more pronounced premorbid developmental impairments were seen in this subgroup. Rates of obstetric complications, familial schizophrenia spectrum disorders, and familial eye tracking dysfunction were similar for the patients with and without cytogenetic abnormalities. CONCLUSIONS: Cytogenetic abnormalities appear to be increased in childhood-onset schizophrenia, suggesting an association with a very early age at onset. The data from the subgroup of patients with cytogenetic anomalies are consistent with a model in which a childhood onset of schizophrenia is due to a greater impairment of neurodevelopment secondary to the interaction of a number of factors, particularly genetic ones.

Adolescent↗