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Investigation of frontal lobe subregions in first-episode schizophrenia.

The evidence for frontal lobe structural abnormalities in schizophrenia using magnetic resonance (MR) imaging has been mixed, but most studies used either single slice measures or total volumes of a single frontal region, neither of which is sensitive to potential volume differences in more specific subregions. This study employed reliable methods for parcellation of the frontal lobes from MR images based on the sulcal anatomy. Following a cytoarchitectonic theory that distinguishes dorsomedial (archicortically derived) from ventrolateral (paleocortically derived) frontal subregions, we measured the superior frontal gyrus, anterior cingulate gyrus, and orbital frontal region in 19 first-episode schizophrenia patients and 26 healthy comparison subjects. Results indicated that male patients had significantly larger right orbital frontal volume compared to their left orbital frontal volume and compared to healthy men. Among male patients larger right orbital frontal volume was significantly correlated with smaller right 'archicortical' (i.e. anterior cingulate and superior frontal gyri) volume. Furthermore, the ratio of right orbital frontal to right 'archicortical' volume was significantly and positively correlated with level of delusions among male patients. These findings suggest that there may be reciprocal controls on 'archicortical' and 'paleocortical' neurodevelopment among men with schizophrenia, and that larger paleocortical relative to archicortical volumes may be associated with increased delusions.

Brain↗

[Posterior fossa hemorrhage in newborns following vaccum extractor delivery].

AIM: To emphasize the risk of posterior fossa hemorrhage in newborns following vacuum extraction. PATIENTS AND METHODS: Over a period of 26 months (September 1996-December 1998), seven patients who underwent delivery with the vacuum extractor had symptoms of brain stem compression, related to posterior fossa hemorrhage. They were referred to the neonatal intensive care unit. Some parameters had been analyzed: gestational period, delivery circumstances, gestational age, parameters of newborn, indications of vacuum extraction and other paraclinical investigations (biological and radiological). RESULTS: Ultrasound scan revealed intracranial hemorrhage in five cases of seven; mean time of diagnosis was 10 hours of age. All patients presented symptoms of brain stem compression. Mean period of follow-up was 22 months: six of seven patients had a normal neurodevelopment. One patient had a cerebellar ataxia, another one a palsy of the IIIrd cranial nerve. CONCLUSION: Analyses of posterior fossa by ultrasound scan should be made for newborns delivered by vacuum extractor, especially if they had symptoms of brain stem compression.

Brain Stem↗

[A familial case with generalized resistance to thyroid hormones].

BACKGROUND: The syndrome of generalized resistance to thyroid hormones is more frequent than was thought. CASE REPORTS: A 13-year old girl was examined for her short stature. Evaluation of her thyroid function showed increased levels of IT3 and IT4 and normal value of TSH; she also had mosaic Turner's syndrome. Her cousin was rapidly diagnosed as suffering from the same syndrome because of moderately high thyrotropic levels found during neonatal screening; this syndrome was confirmed by molecular biology tests. Five generations of this family were identified as being affected with a pattern indicating autosomal dominant inheritance. CONCLUSION: The clinical manifestations of familial generalized resistance to thyroid hormones vary but this syndrome is easy to biologically confirm. The importance of diagnosing affected children as early as possible should be emphasized, as in such cases their development must be closely monitored particularly where their growth and neurodevelopment are concerned.

Adolescent↗

[Home management of bronchopulmonary dysplasia].

Bronchopulmonary dysplasia remains a significant clinical problem associated with the success on survival of neonatal intensive care and has become the common est cause of respiratory insufficiency in infants. The severity of the disease is highly variable from asymptomatic chronic lung disease to patients needing home care with continuous oxygenotherapy and artificial ventilation. Management must try to insure not only appropriate growth and neurodevelopment but also satisfactory well being of the patients. Current medications (aerosoltherapy, diuretics, steroids), rules for oxygenotherapy, follow-up and expected evolution are discussed according to the severity of the disease.

Bronchodilator Agents↗

[Vasoactive intestinal peptide: a novel neurotrophic factor].

Vasoactive intestinal peptide (VIP) is a 28-amino acid neuropeptide with potent growth-related actions on dissociated neural cells. In recent years its role in brain development has been elucidated: VIP has been shown to be a regulator of early neurodevelopment and embryonic growth, a stimulator of neocortical astrocytogenesis and a neuroprotective molecule against excitotoxic and other neurotoxic substances. Thus VIP appears as a fundamental regulator of brain growth and development, and a potent neuroprotective agent, possibly involved in pathological processes such as microcephalies and some neurological impairments observed in very premature babies. Similarly, VIP and VIP derivatives could represent a new avenue in the search of therapeutics for excitotoxic lesions of the developing brain.

Brain↗

The GDNF family ligands and receptors - implications for neural development.

The glial cell line derived neurotrophic factor (GDNF) family has recently been expanded to include four members, and the interactions between these neurotrophic factors and their unique receptor system is now beginning to be understood. Furthermore, analysis of mice lacking the genes for GDNF, neurturin, and their related receptors has confirmed the importance of these factors in neurodevelopment. The results of such analyses reveal numerous similarities and potential overlaps in the way the GDNF and the nerve growth factor (NGF) families regulate development of the peripheral nervous system.

Animals↗

Differential tissue distribution, developmental programming, estrogen regulation and promoter characteristics of cyp19 genes in teleost fish.

Teleost fish are characterized by exceptionally high levels of brain estrogen biosynthesis when compared to the brains of other vertebrates or to the ovaries of the same fish. Goldfish (Carassius auratus) and zebrafish (Danio rerio) have utility as complementary models for understanding the molecular basis and functional significance of exaggerated neural estrogen biosynthesis. Multiple cytochrome P450 aromatase (P450arom) cDNAs that derive from separate gene loci (cyp19a and cyp19b) are differentially expressed in brain (P450aromB>>A) and ovary (P450aromA>>B) and have a different developmental program (B>>A) and response to estrogen upregulation (B only). As measured by increased P450aromB mRNA, a functional estrogen response system is first detected 24-48 h post-fertilization (hpf), consistent with the onset of estrogen receptor (ER) expression (alpha, beta, and gamma). The 5'-flanking region of the cyp19b gene has a TATA box, two estrogen response elements (EREs), an ERE half-site (ERE1/2), a nerve growth factor inducible-B protein (NGFI-B)/Nur77 responsive element (NBRE) binding site, and a sequence identical to the zebrafish GATA-2 gene neural specific enhancer. The cyp19a promoter region has TATA and CAAT boxes, a steroidogenic factor-1 (SF-1) binding site, and two aryl hydrocarbon receptor (AhR)/AhR nuclear translocator factor (ARNT) binding motifs. Both genes have multiple potential SRY/SOX binding sites (16 and 8 in cyp19b and cyp19a, respectively). Luciferase reporters have basal promoter activity in GH3 cells, but differences (a>>b) are opposite to fish pituitary (b>>a). When microinjected into fertilized zebrafish eggs, a cyp19b promoter-driven green fluorescent protein (GFP) reporter (but not cyp19a) is expressed in neurons of 30-48 hpf embryos, most prominently in retinal ganglion cells (RGCs) and their projections to optic tectum. Further studies are required to identify functionally relevant cis-elements and cellular factors, and to determine the regulatory role of estrogen in neurodevelopment.

Animals↗

Season of birth: aetiological implications for epilepsy.

In most cases of epilepsy it is not possible to reach an aetiological diagnosis. Recent research points to a pre-perinatal disruption of the neurodevelopment as being the cause of at least some of these epilepsies of unknown aetiology. The object of this study was to corroborate this hypothesis from an epidemiological perspective and identify the most likely candidates for causes of this damage. The approach used was an analysis of the seasonal pattern of births in a large sample of epileptic patients discharged from NHS hospitals in England and Wales. The results illustrated that the seasonality of the births in the epileptic sample was significantly different from that of the general population, with an excess of patients born in December and January and a deficit of those born in September. This "seasonality' was present only in the patients born before the late 1950s. These results are suggestive of the existence of an aetiological factor for epilepsy with a seasonal presence in the environment and which is epileptogenic when acting in the pre-perinatal period. Prenatal infections, obstetric complications and nutrititional deficiencies are amongst the hypotheses developed on the nature of this agent(s).

Adolescent↗

Differential requirement for Malt1 in T and B cell antigen receptor signaling.

The translocation t(11;18)(q21;q21) involving MALT1 is the most common chromosomal abnormality in lymphomas of mucosa-associated lymphoid tissue. Although the paracaspase MALT1 can bind to BCL10, the physiological function of MALT1 is unknown. Using mouse models, we show that Malt1 is essential for T cell activation, proliferation, and IL-2 production in response to TCR ligation and strictly required for signal-specific NF-kappaB activation induced by the TCR but not TNF-alpha or IL-1 signaling. Malt1 operates downstream of Bcl10, controls the catalytic activity of the canonical IKK complex, and regulates the signaling of Jnk and p38 MAP kinases. In contrast to Bcl10 disruption, however, inactivation of Malt1 has only mild effects on B cell activation and does not cause defects during neurodevelopment. Thus, Malt1 is an essential regulator of Bcl10 signaling that is differentially required depending on cellular context.

Animals↗

Corticosteroids in the prevention and management of bronchopulmonary dysplasia.

Corticosteroids were first prescribed for preterm neonates to treat respiratory distress syndrome, but they were found to have no beneficial effect in this disorder. About 20 years ago, dexamethasone was first used to treat infants with bronchopulmonary dysplasia who were ventilator dependent after the age of 3 weeks. There were short-term benefits, with an improvement in lung function and a facilitation of endotracheal extubation. During the 1990s, corticosteroid treatment, mainly with dexamethasone in relatively high doses, became very common in neonatal intensive care units. Towards the end of the decade, however, follow-up studies provided evidence of abnormal neurodevelopment, especially in infants treated early (<4 days) with dexamethasone. The precise cause of these neurodevelopmental problems is unclear, but until further evidence has been obtained, the early use of dexamethasone cannot be recommended for preterm infants. This review attempts to provide evidence-based guidelines for postnatal steroid therapy in the management of chronic lung disease.

Adrenal Cortex Hormones↗

Weight-bearing patterns on the knees of preterm infants.

In this study we present a method of monitoring the forces under the knees of preterm infants lying in the prone position. Dual force sensing resistor transducers, connected to optically-isolated amplifiers, were used to monitor the forces. A thermistor airflow sensor was used for the parallel monitoring of the respiratory signal. The measurements were made on ten preterm infants. The average forces were 0.51 and 0.50 N for the left and right knees, respectively. In the frequency domain, the basic harmonic of the force traces was 1.27 Hz approximately, corresponding to the respiratory rhythm. Additional, smaller harmonics, were detected in the force traces at 2.54 and 3.81 Hz. A rather notable power signal could also be seen around 0.1 Hz. The results obtained indicate that the system developed is highly sensitive for providing data on the amplitudes, periods and sequences of oscillations and symmetry of load bearing in preterm infants. Knowledge of the normal and abnormal reaction force patterns may assist in the early diagnosis of abnormal neurodevelopment.

Humans↗

Cellular effects of dopamine--beyond oxidative mechanisms.

Cell cycle blockers inhibit growth in dividing cells, but promote survival of differentiated cells, including neurons. Low micromolar dopamine profoundly inhibited cell growth in dopamine transporter transfected SK-N-MC neuroblastoma cells by cell cycle arrest at G(1). This effect was independent of oxy radical formation, antagonized by transporter block, abolished by FeCl(3) and mimicked by the iron chelator deferoxamine. We propose that dopamine inhibits cell growth by its ability to chelate intracellular iron. This novel biological action unrelated to neurotransmitter receptors, second messengers or oxidative stress, observed in human neuroblastoma cells of striatal origin, may be important for cell differentiation during neurodevelopment and survival of differentiated dopamine (nigral) neurons.

Cell Count↗

Imprinted genes, cognition and behaviour.

The idea that genes can influence behavioural predispositions and their underlying psychological determinants is becoming increasingly tractable. In this article, recent findings are reviewed on a special type of inheritance, related to the transmission of traits via what have been termed 'imprinted' genes. In imprinted genes one allele is silenced according to its parental origin. This results in the inheritance of traits down the maternal or paternal line, in contrast to the more frequent mode of inheritance that is indifferent to the parental origin of the allele. Drawing on the advances made possible by combining the approaches of cognitive neuropsychology, behavioural neuroscience and contemporary molecular genetics, the detailed evidence for imprinted effects on behavioural and cognitive phenotypes is considered, focusing on findings from mental disorders, Turner's syndrome and experimental work in animal models. As prevailing evolutionary theories stress an essential antagonistic role of imprinted effects, these data might link such apparently diverse issues as neurodevelopment and the vulnerability to mental disease with the 'battle of the sexes', as joined at the level of cognitive and behavioural functioning.

Journal Article↗

Neonatal prefrontal cortex lesion using CO2 laser technique.

Prefrontal cortex (PFC) is a large area of the brain and its neonatal lesion with ibotenic or kainic acid is used to study the early abnormalities in neurodevelopment that lead to behavioral changes linked to schizophrenia. However, these exitotoxic drugs produce a large and asymmetric damage in the PFC. We produced the bilateral lesions of the dorsal part of the PFC of neonatal Sprague-Dawley rats (postnatal day 7, P7) at the anteroposterior +2.5 mm and mediolateral +/-0.4 coordinates by the new laser technique that employ the confined radiation of the CO(2) laser in the pulsed mode. The laser was used because its coherent radiation can be focused in a very small spot and as small as of several tens of micrometers in diameters. The CO(2) laser radiation is strongly absorbed by water that is present in any soft tissue. Thereafter, the configuration of the heated zone and, consequently, that of the lesion does not depend on the morphological non-homogeneity of particular structures. We obtained the symmetric, conical in shape and small-size bilateral lesions of the PFC. The size of the lesion depended on the beam spot-size and could be as small as several dozens of micrometers in diameter. Our data suggests that the laser technique will be used for the anatomical-functional studies of the PFC in the brain.

Animals↗

Functional brain maturation in neonates as measured by EEG-sleep analyses.

OBJECTIVE: Seven measures of neonatal EEG-sleep behavior were evaluated using multivariate analyses to ascertain if physiologic differences exist between healthy full- and preterm cohorts. METHODS: A total of 381 24-channel EEG-sleep studies were analyzed, including 125 recordings on 50 healthy fullterm and 256 recordings on 59 asymptomatic preterm infants between 28 and 70.6 weeks post-conceptional age. One EEG study for each subject was randomly assigned (109 studies) within the time window of 38-44 weeks post-conceptional age. A multivariate analytic procedure was applied to the data sets, by which a 'dysmaturity index' was assigned for each infant, based on 7 EEG-sleep measures. This index was defined in terms of the distance from the fullterm group's centroid (i.e. Mahalanobis distance). Receiver-operating characteristic curves (ROCs) were calculated for several different combinations of 7 EEG-sleep measures to describe differences between neonatal cohorts. RESULTS: The ROC curve corresponding to all 7 EEG-sleep measures covered the substantially largest area among the curves for the sets of variables considered, suggesting that all 7 measures of sleep behavior were required to best discriminate between cohorts. CONCLUSIONS: This methodology exemplifies how EEG-sleep analyses can be applied to the study of functional brain maturation of infants at risk for neurodevelopment problems. SIGNIFICANCE: Changes in EEG-sleep behavior in the preterm infant may represent altered activity-dependent development of neural circuitry, resulting in remodeling of the immature brain as a reflection of adaptation to conditions of prematurity.

Brain↗

Cortical correlates of neuromotor development in healthy children.

OBJECTIVE: To examine the relationship between acquisition of fine motor skills in childhood and development of the motor cortex. METHODS: We measured finger tapping speed and mirror movements in 43 healthy right-handed subjects (6-26 years of age). While recording surface electromyographic activity from right and left first dorsal interosseus, we delivered focal transcranial magnetic stimulation (TMS) over the hand areas of each motor cortex. We measured motor evoked potential (MEP) threshold, and ipsilateral (iSP) and contralateral (CSP) silent periods. RESULTS: As children got older, finger speeds got faster, MEP threshold decreased, iSP duration increased and latency decreased. Finger tapping speed got faster as motor thresholds and iSP latency decreased, but was unrelated to CSP duration. In all subjects right hemisphere MEP thresholds were higher than those on the left and duration of right hemisphere CSP was longer than that on the left. Children under 10 years of age had higher left hand mirror movement scores, and fewer left hemisphere iSPs which were of longer duration. CONCLUSIONS: Maturation of finger tapping skills is closely related to developmental changes in the motor threshold and iSP latency. Studies are warranted to explore the relationship between these measures and other neuromotor skills in children with motor disorders. SIGNIFICANCE: TMS can provide important insights into certain functional aspects of neurodevelopment in children.

Adolescent↗

Chemokines in the brain: neuroimmunology and beyond.

Chemokines in the brain have been recognised as essential elements in neurodegenerative diseases and related neuroinflammation. Recent studies suggest that in addition to the orchestration of chemotaxis of immune cells, chemokines are also involved in neurodevelopment and neurophysiological signalling.

Animals↗

The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial.

BACKGROUND: Infantile spasms is a severe infantile seizure disorder that is difficult to treat and has a high morbidity. Absence of spasms on days 13 and 14 after randomisation is more common in infants allocated hormone treatments than in those allocated vigabatrin. We sought to assess whether early control of spasms is associated with improved developmental or epilepsy outcomes. METHODS: Infants enrolled in the United Kingdom Infantile Spasms Study (UKISS) were randomly assigned hormone treatment (n=55) or vigabatrin (n=52) and were followed up until clinical assessment at 12-14 months of age. We assessed neurodevelopment with the Vineland adaptive behaviour scales (VABS) at 14 months of age on an intention to treat basis. FINDINGS: Of 107 infants enrolled, five died and 101 survivors reached both follow-up assessments. Absence of spasms at final clinical assessment (hormone 41/55 [75%] vs vigabatrin 39/51 [76%]) was similar in each treatment group (difference 1.9%, 95% CI -18.3% to 14.4%; chi(2)=0.05; p=0.82). Mean VABS score did not differ significantly (hormone 78.6 [SD 16.8] vs vigabatrin 77.5 [SD 12.7]; difference 1.0, 95% CI -4.9 to 7.0; t(99)=0.35, p=0.73). In infants with no identified underlying aetiology, the mean VABS score was higher in those allocated hormone treatment than in those allocated vigabatrin (88.2 [17.3] vs 78.9 [14.3]; difference 9.3, 95% CI 1.2 to 17.3; t(95)=2.28, p=0.025). INTERPRETATION: Hormone treatment controls spasms better than does vigabatrin initially, but not at 12-14 months of age. Better initial control of spasms by hormone treatment in those with no identified underlying aetiology may lead to improved developmental outcome.

Adaptation, Psychological↗