Do the early development of gestures and receptive and expressive language predict language skills at 5;0 in prematurely born very-low-birth-weight children?

UNLABELLED: It is unclear what the predictive value of very early development of gestures and language is on later language ability in prematurely born very-low-birth-weight (VLBW; birth weight ≤1500g) children. The aim of the present study was to analyse the predictive value of early gestures and a receptive lexicon measured between the ages of 0;9 and 1;3, as well as the predictive value of receptive and expressive language ability at 2;0 for language skills at 5;0 in VLBW children. The subjects were 29 VLBW children and 28 full-term children whose language development has been followed intensively between the ages of 0;9 and 2;0 using the Finnish version of the MacArthur Developmental Inventory and the Reynell Developmental Language Scales (RDLS III). At 5;0, five selected verbal subtests of the Nepsy II test and the Boston Naming Test (BNT) were used to assess children's language skills. For the first time in VLBW children, the development of gestures measured between the ages of 0;9 and 1;3 was shown to correlate significantly and positively with language skills at 5;0. In addition, both receptive and expressive language ability measured at 2;0 correlated significantly and positively with later language skills in both groups. Moreover, according to the hierarchical regression analysis, the receptive language score of the RDLS III at 2;0 was a clear and significant predictor for language skills at 5;0 in both groups. The findings particularly underline the role of early receptive language as a significant predictor for later language ability in VLBW children. The results provide evidence for a continuity between early language development and later language skills. LEARNING OUTCOMES: After reading this article, readers will understand the associations between the very early (≤2 years of age) development of gestures and language (i.e. early receptive lexicon, expressive lexicon at 2;0, receptive and expressive language ability at 2;0) and the language skills at 5;0 in prematurely born very-low-birth-weight (VLBW) children. In addition, readers will understand the heterogeneity of the group of VLBW children. The information presented in this article is informative for those who work in a clinical context and who want to be able to identify those VLBW children who need support for their language development at an early age.

Early relations between language development and the quality of mother-child interaction in very-low-birth-weight children.

BACKGROUND: It is not clearly understood how the quality of early mother-child interaction influences language development in very-low-birth-weight children (VLBW). AIMS: We aim to analyze associations between early language and the quality of mother-child interaction, and, the predictive value of the features of early mother-child interaction on language development at 24 months of corrected age in VLBW children. STUDY DESIGN: A longitudinal prospective follow-up study design was used. METHODS: The participants were 28 VLBW children and 34 full-term controls. Language development was measured using different methods at 6, 12 and at 24 months of age. The quality of mother-child interaction was assessed using PC-ERA method at 6 and at 12 months of age. RESULTS: Associations between the features of early interaction and language development were different in the groups of VLBW and full-term children. There were no significant correlations between the features of mother-child interaction and language skills when measured at the same age in the VLBW group. Significant longitudinal correlations were detected in the VLBW group especially if the quality of early interactions was measured at six months and language skills at 2 years of age. However, when the predictive value of the features of early interactions for later poor language performance was analyzed separately, the features of early interaction predicted language skills in the VLBW group only weakly. CONCLUSIONS: The biological factors may influence on the language development more in the VLBW children than in the full-term children. The results also underline the role of maternal and dyadic factors in early interactions.

Apolipoprotein E, brain injury and neurodevelopmental outcome of children.

Apolipoprotein E plays an important role in neurodegenerative processes in adulthood, whereas its neurodevelopmental role is uncertain. We aimed to study the effect of apolipoprotein E on neurodevelopment in a cohort liable to neurodevelopmental changes. The cohort consisted of very preterm (<32 gestational weeks) and/or very low birth weight (<1500 g) children, and the longitudinal follow-up protocol included sequential cranial ultrasounds during infancy, brain magnetic resonance imaging at term-equivalent age, neurological and cognitive assessment (Mental Developmental Index) at the corrected age of 2 years and cognitive and neuropsychological assessments (Wechsler Preschool and Primary Scale of Intelligence and Developmental NEuroPSYchological Assessment) at the chronological age of 5 years. Apolipoprotein E genotypes were determined from 322 children. Ultrasound and magnetic resonance imaging data were available for 321 (99.7%) and 151 (46.9%) children, respectively. Neurodevelopmental assessment data were available for 138 (42.9%) to 171 (53.1%) children. Abnormal findings in ultrasounds and magnetic resonance imaging were found in 163 (50.8%) and 64 (42.4%) children, respectively. Mild cognitive delay at the corrected age of 2 years and the chronological age of 5 years was suspected in 21 (12.3%) of 171 and 19 (13.8%) of 138 children, respectively. In the Developmental NEuroPSYchological Assessment, 47 (32.6%) of 144 children had significantly impaired performances in more than one study subtest. No associations between the apolipoprotein E genotypes and imaging findings or measured neurodevelopmental variables were found. Apolipoprotein E genotypes do not appear to have major impact on brain vulnerability or neurodevelopment in children.

Effect of antenatal growth and prematurity on brain white matter: diffusion tensor study.

BACKGROUND: White matter maturation is characterised by increasing fractional anisotropy (FA) and decreasing mean diffusivity (MD). Contradictory results have been published on the effect of premature birth on white matter maturation at term-equivalent age. OBJECTIVE: To assess the association of gestational age and low birth-weight-for-gestational-age (z-score) with white matter maturation. MATERIALS AND METHODS: Infants (n = 76, 53 males) born at different gestational ages were imaged at term-equivalent age. Gestational age and birth weight z-score were used as continuous variables and the effect on diffusion parameters was assessed. Brain maturation was studied using regions-of-interest analysis in several white matter areas. RESULTS: Gestational age showed no significant effect on white matter maturation at term-equivalent age. Children with low birth weight z-score had lower FA in the genu and splenium of the corpus callosum (regression, P = 0.012 and P = 0.032; correlation, P = 0.009 and P = 0.006, respectively), and higher MD in the splenium of the corpus callosum (regression, P = 0.002; correlation, P = 0.0004) compared to children whose birth weight was appropriate for gestational age. CONCLUSION: Children with low birth weight relative to gestational age show delay and/or anomaly in white matter maturation at term-equivalent age.

Abnormal antenatal Doppler velocimetry and cognitive outcome in very-low-birth-weight infants at 2 years of age.

OBJECTIVE: To study neurodevelopmental outcome at 2 years of corrected age in very-low-birth-weight (VLBW) (< or = 1500 g) preterm infants with abnormal fetoplacental flow. METHODS: A total of 258 VLBW infants were born at Turku University Hospital between 2001 and 2006. Of these, 99 had undergone, within 1 week of delivery, antenatal Doppler assessment of blood flow in the umbilical artery (UA), fetal middle cerebral artery (MCA), descending aorta (DAo), aortic isthmus and ductus venosus and were eligible for inclusion in the study. Postnatally brain pathology was assessed by serial ultrasound and magnetic resonance imaging in 86 of the neonates and brain volume was measured in 80. Cognitive development was evaluated at 2 years of corrected age in 83 infants using the Bayley Scales of Infant Development-II. Motor development was assessed using the Hammersmith Infant Neurological Examination. RESULTS: On univariate analysis, abnormal pulsatility index (PI) in the UA and an abnormal UA-PI/MCA-PI ratio (P = 0.04 and P = 0.003, respectively) as well as increases in both the DAo-PI and in the DAo-PI/MCA-PI ratio (P = 0.03 and P = 0.02, respectively), were associated with adverse cognitive outcome at 2 years of age. However, when controlling for cerebral volume using multivariate analysis, the association between abnormal antenatal Doppler characteristics and cognitive outcome became statistically non-significant, which indicated the determinant role of the volume reduction. Motor development was not associated with antenatal Doppler indices. CONCLUSION: Abnormal antenatal Doppler indices are associated with adverse cognitive outcome at 2 years in VLBW infants. Our findings suggest that this association may be mediated through brain volume.

Cognitive outcome at 2 years of age in Finnish infants with very low birth weight born between 2001 and 2006.

AIM: To study cognitive outcome of premature, very low birth weight (VLBW) infants in relation to parental education and neonatal data. METHODS: A regional cohort of 182 VLBW infants born between 2001 and 2006 was followed up. Brain ultrasounds (US) were examined serially until term age and brain magnetic resonance imaging at term age. Neurological status was examined systematically. Cognitive development was assessed using the Mental Developmental Index (MDI) of Bayley Scales at 2 years of corrected age. A total of 192 healthy full-term (FT) controls were assessed with the MDI at 2 years of age. RESULTS: The mean MDI in VLBW infants was 101.7 (SD 15.4), which was lower compared with FT controls (109.8, SD 11.7, p < 0.001). In regression analysis of the demographic and medical data of VLBW infants, postnatal corticosteroids (p = 0.04), intestinal perforation (p = 0.03) and major brain pathology (p = 0.02) were negatively associated with the MDI. In VLBW infants, the prevalence of neurodevelopmental impairment was 9.9% (3.3% MDI below 70, 7.1% cerebral palsy, 2.2% hearing aid, no blind infants). CONCLUSION: Cognitive development of VLBW infants seemed to have improved in comparison with earlier publications, but it differed from the FT controls. Neonatal factors affected cognitive development. Therefore, updated regional follow-up data are important for clinicians.

Five-year follow-up of prematurely born children with postnatally developing caudothalamic cysts.

AIM: To assess the long-term developmental outcome of very low birth weight children with postnatally developing caudothalamic cysts. METHODS: Five very low birth weight children with postnatal caudothalamic cysts were examined using cranial ultrasound and brain Magnetic Resonance Imaging as neonates, the Bayley Scales of Infant Development, 2nd edition, and the Hammersmith Infant Neurological Examination at 2 years of corrected age, and with the Wechsler Preschool and Primary Scale of Intelligence-Revised and the standardization version of NEPSY II at 5 years of age. The Magnetic Resonance Imaging of the brain was repeated at 5 years of age. The developmental outcome at 5 years of age was compared with that of 23 very low birth weight children with normal brain structure. RESULTS: A cognitive level below normal and/or neuropsychological impairments was seen in all the children with caudothalamic cysts as well as in those with normal brain structure. CONCLUSION: Very low birth weight children with postnatally developing caudothalamic cysts had cognitive and neuropsychological impairments similar to very low birth weight children without such cysts.

Neurological examination at 6 to 9 months in infants with cystic periventricular leukomalacia.

The Hammersmith Infant Neurological Examination was performed in 24 infants with cystic periventricular leukomalacia whose gestational age ranged between 26-38 weeks. The infants were examined between 6 and 9.5 months corrected age. The aim of the study was to establish the different patterns of neurological abnormality as well as the optimality scores that predict the severity of motor sequelae at 2 years. Increased neck and trunk extensor tone, and a posture of flexed arms and extended legs between 6 and 9 months were always associated with the inability to sit unsupported at 2 years, whilst truncal hypotonia and extended arms and legs were associated with unsupported sitting but not walking. Optimality scores between 41 and 60 were generally associated with sitting but not walking at 2 years whilst scores below 40 were always associated with the inability to sit independently at 2 years. All infants who did not develop cerebral palsy at 2 years had scores > 60. Our results suggest that the pattern of findings on neurological examination performed between 6 and 9 months as well as the calculated optimality score helps to predict motor impairment in infants with PVL.

Sequential neurological examinations in infants with neonatal encephalopathy and low apgar scores: relationship with brain MRI.

OBJECTIVE: The aims of this study were to (a) describe the evolution of neurological signs after the neonatal period in infants with neonatal encephalopathy and abnormal outcome and (b) to establish the relationship between the evolution of neurological signs and patterns of lesions on brain MRI. PATIENTS: Fifteen children with low Apgar scores, abnormal neurological signs at the end of the neonatal period, and abnormal outcome were examined at 1 - 2 weeks, 5 - 7 weeks, and 6 months. All the infants had at least one MRI scan performed in the neonatal period. RESULTS: All infants had persistent abnormalities on all examinations performed but the severity of neurological impairment was variable and was related to the pattern of brain lesions. Infants with severe basal ganglia and white matter lesions showed abnormal axial and limb tone, movements, and visual function on all the examinations and none achieved independent sitting. In infants with moderate basal ganglia lesions and/or severe white matter changes, visual function and feeding improved by 5 - 7 weeks and were still normal at 6 months while limb tone, which was reduced in the first weeks, appeared to be normal at 5 - 6 weeks but was found to be increased at 6 months; all were able to sit unsupported at 2 years and most of them achieved the ability to walk with support. CONCLUSIONS: Our results suggest that the evolution of the neurological patterns after the neonatal period in infants with persisting neonatal abnormalities depends on their pattern of brain lesions.

Can the Griffiths scales predict neuromotor and perceptual-motor impairment in term infants with neonatal encephalopathy?

AIMS: To examine the predictive value of early developmental testing for identifying neuromotor and perceptual-motor impairment at school age in children with neonatal encephalopathy (NE). METHODS: Eighty full term infants with NE were followed longitudinally. Where possible, children were tested on the Griffiths scales at 1 and 2 years and at 5-6 years, on the Touwen Examination, Movement ABC, and WPPSI. The relation between the Griffiths scores and later outcome measures was examined using correlation coefficients and sensitivity and specificity values. RESULTS: By 2 years, 25 children with cerebral palsy were too severely impaired to be formally assessed and remained so at 5-6 years. Abnormal Griffiths scores were obtained by 12% and 7% of the children at 1 and 2 years respectively. At 5-6 years, 33% had poor Movement ABC scores and 15% poor WPPSI scores. The highest correlation between Griffiths scores and the outcome measures was for the Movement ABC (0.72), although this accounted for only 50% of the variance. Sensitivity scores for the Movement ABC were below 70% but specificity was 100%. CONCLUSIONS: A poor score on the Griffiths scales at 1 and/or 2 years is a good predictor of impairment at school age. However, a normal score in the early years cannot preclude later neurological, perceptual-motor, or cognitive abnormalities.

Visual function at school age in children with neonatal encephalopathy and low Apgar scores.

OBJECTIVE: To assess different aspects of visual function at school age in children who suffered from neonatal encephalopathy. METHOD: Thirty nine full term infants with neonatal encephalopathy, low Apgar scores, and early neonatal imaging were studied using a battery of tests assessing different aspects of visual function (crowding acuity, stereopsis, visual fields) at school age. The results were compared with brain magnetic resonance imaging (MRI) findings and, when possible, with the results of the assessment of visual function performed at 5 and 12 months, available in 24 of the 39 children examined at school age. RESULTS: Sixteen of the 39 children (41%) had abnormal results at school age in at least one of the visual tests used. Seven of these 16 were untestable on all tests. The remaining 23 children (59%) had normal results. CONCLUSIONS: The presence and severity of visual impairment was related to the severity of brain lesions. Moderate or severe basal ganglia lesions and severe white matter changes were always associated with abnormal visual function. Infants with normal MRI, minimal basal ganglia lesions, and minimal or moderate white matter involvement tended to have normal vision. It was also found that the assessment of visual function performed in the first year was a reliable indicator of visual function at school age. With two exceptions, the results on the 5 month visual assessment were predictive of visual outcome at school age. In the remaining two cases, a normal visual outcome at 5 years was associated with visual abnormalities at 5 months but these had already normalised by the age of 1 year.

Neonatal cerebral infarction and visual function at school age.

OBJECTIVE: To assess various aspects of visual function at school age in children with neonatal cerebral infarction. PATIENTS AND METHODS: Sixteen children born at term, who had cerebral infarction of perinatal onset on neonatal magnetic resonance imaging (MRI) were assessed using a battery of visual tests. This included measures of crowding acuity (Cambridge Crowding Cards), stereopsis (TNO test), and visual fields. The results of the visual assessment were compared with the type and the extent of the lesion observed on neonatal MRI. RESULTS: Only six of the 16 children (28%) had some abnormalities of visual function on these tests. Visual abnormalities were more common in children with more extensive lesions involving the main branch of the middle cerebral artery and were less often associated with lesions in the territory of one of the cortical branches of the middle cerebral artery. The presence of visual abnormalities was not always associated with the involvement of optic radiations or occipital primary visual cortex. Abnormal visual fields were only found in children who also developed hemiplegia. CONCLUSIONS: Abnormality of visual function is not common in children who had neonatal infarction and, when present, tends to be associated with hemiplegia and more extensive lesions.

MRI lesions and infants with neonatal encephalopathy. Is the Apgar score predictive?

OBJECTIVE: The aim of this study was to establish whether, in full-term infants presenting with neonatal encephalopathy, the 1 minute Apgar score gives an indication of the presence, site or type of lesions observed on brain MRI in the neonatal period. PARTICIPANTS AND METHODS: The study cohort included 157 full-term infants who had neurological abnormalities during the first 48 hours after delivery. Infants with developmental, genetic, infective or metabolic diagnoses were excluded from the study. The infants were subdivided according to their 1 minute Apgar score into three groups as follows: Apgar score 0 - 3 (n = 108/157, 69 %), 4 - 7 (n = 29, 19 %), 8 - 10 (n = 21, 12 %). Results. Severe and moderate basal ganglia and thalamic (BGT) lesions, with one exception, were only observed in the group with an Apgar score of 3 or below. Minimal BGT lesions were, with one exception, associated with scores below 7 and mainly below 3. However, not all the infants with low Apgar scores had BGT lesions and 28 % of the patients with Apgar scores below 3 had normal scans or only minimal white matter changes. White matter lesions without BGT involvement were equally distributed in the cohort, irrespective of the Apgar scores. Cerebral infarction and scattered white matter haemorrhages were the most common findings in infants with Apgar scores of 4 and above. The Apgar scores were not always predictive of motor outcome at 2 years but the presence and severity of the sequelae mainly reflected the site and severity of MRI findings. CONCLUSIONS: These findings stress the importance of subdividing neonatal encephalopathy into diagnostic categories according to brain lesions if one wishes to study either causative factors or outcome.

Neurological and perceptual-motor outcome at 5 - 6 years of age in children with neonatal encephalopathy: relationship with neonatal brain MRI.

OBJECTIVE: The aims of this study were 1) to determine the incidence of minor neurological dysfunction and perceptual-motor difficulties in children aged 5-1/2 -- 6-1/2, who had been born full-term but presented with neonatal encephalopathy (NE) and low Apgar scores and 2) to examine the relationships between the presence/absence of these difficulties with neonatal brain MRI. PARTICIPANTS AND METHODS: Sixty-eight full-term infants with one minute Apgar scores less than or equal to 5 and neurological abnormalities during the first 48 hours after birth were included in the study. All children had a neonatal MRI brain scan. Surviving infants were assessed between the age of 5 and 6 years using the Touwen Examination, the Movement ABC and the WPPSI-R. RESULTS: Fifteen of the 68 infants (22 %) died in the neonatal period. Of the 53 surviving infants, 19 (36 %) had cerebral palsy. The remaining 34 were considered normal at 2 years of age but, when assessed at school age, 8 (15 %) had minor neurological dysfunction and/or perceptual-motor difficulties, 1 (2 %) had only cognitive impairment and 25 (47 %) were normal. The outcome largely reflected the pattern of lesions on brain imaging. While 83 % of those with a normal outcome had normal scans or minimal white matter lesions, 80 % of those with minor neurological dysfunction and/or perceptual-motor difficulties had mild or moderate basal ganglia or more marked white matter lesions. CONCLUSION: Continued surveillance is recommended for children with apparently normal outcome at two years of age after NE, particularly when abnormalities are detected on brain MRI.

Abnormal function of astroglia lacking Abr and Bcr RacGAPs.

Experiments in cultured cells have implicated the molecular switch Rac in a wide variety of cellular functions. Here we demonstrate that the simultaneous disruption of two negative regulators of Rac, Abr and Bcr, in mice leads to specific abnormalities in postnatal cerebellar development. Mutants exhibit granule cell ectopia concomitant with foliation defects. We provide evidence that this phenotype is causally related to functional and structural abnormalities of glial cells. Bergmann glial processes are abnormal and GFAP-positive astroglia were aberrantly present on the pial surface. Older Abr;Bcr-deficient mice show spontaneous mid-brain glial hypertrophy, which can further be markedly enhanced by kainic acid. Double null mutant astroglia are hyper-responsive to stimulation with epidermal growth factor and lipopolysaccharide and exhibit constitutively increased phosphorylation of p38 mitogen-activated protein kinase, which is regulated by Rac. These combined data demonstrate a prominent role for Abr and Bcr in the regulation of glial cell morphology and reactivity, and consequently in granule cell migration during postnatal cerebellar development in mammals.

The small GTPase Rac interacts with ubiquitination complex proteins Cullin-1 and CDC23.

Racs are involved in the regulation of important cellular processes including mitogenesis. We found that the E3 ubiquitination ligase subunit Cullin-1 interacts with constitutively active Rac3 but not with wild-type Rac3 in yeast. In mammalian cell lysates, Cullin-1 bound to V12Rac3, effector domain mutants V12L37Rac3 and V12H40Rac3, and insert domain deletion mutant V12Rac3DeltaIns(124-135). Cullin-1 also formed a clearly detectable complex with other activated Rac3-related proteins including Rac1, Rac2, Cdc42 and RhoA but not with the distantly related small GTPase Rap1. Since the proteasome is involved in cell cycle control through the programmed degradation of cell cycle proteins, the possible regulation of Rac levels during the cell cycle was examined. However, Rac was expressed at constant levels throughout the cell cycle, and a specific proteasome inhibitor had no effect on Rac protein levels. These combined results indicate that the binding of activated Rac to Cullin-1 does not affect Rac protein levels, nor does it mediate the regulation of mitogenesis by Rac. However, Rac-Cullin-1 interactions may serve to regulate other E3 ligase functions such as subcellular localization. Indeed, activated Rac3 and Cullin-1 co-localized to the perinuclear region of the cell. We also detected complex formation between Rac and the APC component CDC23. These results indicate that Rac may regulate specific proteolytic processes through directed subcellular localization of SCF or APC complexes.

Neurologic examination in infants with hypoxic-ischemic encephalopathy at age 9 to 14 months: use of optimality scores and correlation with magnetic resonance imaging findings.

OBJECTIVES: To evaluate whether a structured and scorable neurologic examination (The Hammersmith Infant Neurological Examination) correlates with early magnetic resonance imaging findings in a group of infants with hypoxic-ischemic encephalopathy (HIE) and whether the scores of this assessment can predict the locomotor function in these children. STUDY DESIGN: A total of 53 term infants fulfilling the criteria for HIE underwent scanning within 4 weeks from delivery with a 1 Tesla HPQ magnet. The scores from the neurologic examination performed between 9 to 14 months were correlated to the neonatal magnetic resonance imaging findings and to the maximal locomotor function defined at the ages of 2 and 4 years. RESULTS: The scores were always optimal in the infants with normal or minor neonatal magnetic resonance imaging findings. The lowest scores were associated with severe basal ganglia and white matter lesions. All the infants who had a global score between 67 and 78 at 1 year were able to walk independently at 2 years and without restrictions at 4 years. Scores between 40 and 67 were associated with restricted mobility and scores <40 with severely limited self-mobility at 2 and 4 years. CONCLUSIONS: The use of a standardized neurologic optimality scoring system gives additional prognostic information, easily available in the clinic, on the severity of the functional motor outcome in infants with HIE.

Reduced oncogenicity of p190 Bcr/Abl F-actin-binding domain mutants.

The deregulated Bcr/Abl tyrosine kinase is responsible for the development of Philadelphia (Ph)-positive leukemia in humans. To investigate the significance of the C-terminal Abl actin-binding domain within Bcr/Abl p190 in the development of leukemia/lymphoma in vivo, mutant p190 DNA constructs were used to generate transgenic mice. Eight founder and progeny mice of 5 different lines were monitored for leukemogenesis. Latency was markedly increased and occurrence decreased in the p190 del C lines as compared with nonmutated p190 BCR/ABL transgenics. Western blot analysis of involved hematologic tissues of the p190 del C transgenics with end-stage disease showed high-level expression of the transgene and tyrosine phosphorylation of Cbl and Hef1/Cas, proteins previously shown to be affected by Bcr/Abl. These results show that the actin-binding domain of Abl enhances leukemia development but does not appear to be an absolute requirement for leukemogenesis.

Head growth in infants with hypoxic-ischemic encephalopathy: correlation with neonatal magnetic resonance imaging.

OBJECTIVES: The aims of the study were to establish the relationship between head growth in the first year of life with the pattern on injury on neonatal magnetic resonance imaging (MRI) in infants with hypoxic-ischemic encephalopathy (HIE) and to relate these to the neurodevelopmental outcome. METHODS: Fifty-two term infants who presented at birth with a neonatal encephalopathy consistent with HIE and who had neonatal brain MRI were entered into the study. Head circumference charts were evaluated retrospectively and the head growth over the first year of life compared with the pattern of brain lesions on MRI and with the neurodevelopmental outcome at 1 year of age. Suboptimal head growth was classified as a drop of >2 standard deviations across the percentiles with or without the development of microcephaly, which was classified as a head circumference below the third percentile. RESULTS: There was no statistical difference between the neonatal head circumferences of the infants presenting with HIE and control infants. At 12 months, microcephaly was present in 48% of the infants with HIE, compared with 3% of the controls. Suboptimal head growth was documented in 53% of the infants with HIE, compared with 3% of the controls. Suboptimal head growth was significantly associated with the pattern of brain lesions, in particular to involvement of severe white matter and to severe basal ganglia and thalamic lesions. Suboptimal head growth predicted abnormal neurodevelopmental outcome with a sensitivity of 79% and a specificity of 78%, compared with the presence of microcephaly at 1 year of age, which had a sensitivity of only 65% and a specificity of 73%. The exceptions were explained by infants with only moderate white matter abnormalities who had suboptimal head growth but normal outcome at 1 year of age and by infants with moderate basal ganglia and thalamic lesions only who had normal head growth but significant motor abnormality.

The small GTPase RAC3 gene is located within chromosome band 17q25.3 outside and telomeric of a region commonly deleted in breast and ovarian tumours.

The closely related small GTP-binding proteins Rac1, Rac2, and Rac3 are part of a larger Rho subfamily of Ras proteins. Because disruption of Ras signaling pathways is relevant to the pathogenesis of a wide variety of cancers, it is important to clearly define the structural and functional characteristics of the participating proteins and their encoding genes. Rho subfamily members are involved in a range of signal transduction pathways relevant to cell growth, differentiation, motility, and stress, and Rac proteins are now recognised as a necessary component of Ras-mediated cellular transformation. We previously mapped RAC3 to chromosome band 17q23--> q25, a region that contains a number of candidate tumour suppressor genes. Because of its oncogenic potential, we have now further refined the location of this gene. Here we confirm that RAC3 maps to chromosome band 17q25.3 and further show that it maps some distance telomeric of a well-characterised minimal breast and ovarian candidate tumour suppressor gene region, BROV. The genomic structure of RAC3, including exon and intron boundaries, is also presented.