Wnt/ß-catenin pathway regulates bone morphogenetic protein (BMP2)-mediated differentiation of dental follicle cells.

BACKGROUND AND OBJECTIVE: Bone morphogenetic protein 2 (BMP2)-induced osteogenic differentiation has been shown to occur through the canonical Wnt/ßcatenin pathway, whereas factors promoting canonical Wnt signaling in cementoblasts inhibit cell differentiation and promote cell proliferation in vitro. The aim of this study was to investigate whether putative precursor cells of cementoblasts, dental follicle cells (murine SVF4 cells), when stimulated with BMP2, would exhibit changes in genes/proteins associated with the Wnt/ß-catenin pathway. MATERIAL AND METHODS: SVF4 cells were stimulated with BMP2, and the following assays were carried out: (i) Wnt/ß-catenin pathway activation assessed by western blotting, ß-catenin/transcription factor (TCF) reporter assays and expression of the lymphoid enhancer-binding factor-1 (Lef1), transcription factor 7 (Tcf7), Wnt inhibitor factor 1 (Wif1) and Axin2 (Axin2) genes; and (ii) cementoblast/osteoblast differentiation assessed by mineralization in vitro, and by the mRNA levels of runt-related transcription factor 2 (Runx2), osterix (Osx), alkaline phosphatase (Alp), osteocalcin (Ocn) and bone sialoprotein (Bsp), determined by quantitative PCR after treatment with wingless-type MMTV integration site family, member 3A (WNT3A) and knockdown of ß-catenin. RESULTS: WNT3A induced ß-catenin nuclear translocation and up-regulated the transcriptional activity of a canonical Wnt-responsive reporter, suggesting that the Wnt/ß-catenin pathway functions in SVF4 cells. Activation of Wnt signaling with WNT3A suppressed BMP2-mediated induction of cementoblast/osteoblast maturation of SVF4 cells. However, ß-catenin knockdown showed that the BMP2-induced expression of cementoblast/osteoblast differentiation markers requires endogenous ß-catenin. WNT3A down-regulated transcripts for Runx2, Alp and Ocn in SVF4 cells compared with untreated cells. In contrast, BMP2 induction of Bsp transcripts occurred independently of Wnt/ß-catenin signaling. CONCLUSION: These data suggest that stabilization of ß-catenin by WNT3A inhibits BMP2-mediated induction of cementoblast/osteoblast differentiation in SVF4 cells, although BMP2 requires endogenous Wnt/ß-catenin signaling to promote cell maturation.

Attention processes in children with shunted hydrocephalus versus attention deficit-hyperactivity disorder.

Children with congenital hydrocephalus, children with attention deficit-hyperactivity disorder, and normal controls were evaluated with measures of focused attention (Visual Orienting and Detection Task), sustained attention (continuous performance test), and attention shifting (Wisconsin Card Sorting Test). Components from these tasks have been linked to attention systems mediated by anterior or posterior brain networks. Children with congenital hydrocephalus showed an inability to focus and shift attention, which specifically implicated impairment of the disengage and move components of the posterior brain attention system. Children with attention deficit-hyperactivity disorder displayed the expected performance patterns on measures of focused attention once their difficulties with sustained attention were taken into account. However, they showed problems with shifting and sustaining attention, which are commonly associated with the anterior brain attention system.

Memory functions in children with early hydrocephalus.

Children with arrested, shunted, and no hydrocephalus were compared on verbal and nonverbal memory tasks assessing multiple components of memory. A gradient of severity was hypothesized, with the shunted hydrocephalus group expected to exhibit the most significant memory impairments and the arrested group expected to perform more poorly than children with no hydrocephalus. Etiologies of prematurity, spina bifida, and aqueductal stenosis were represented by 157 participants. Results supported the hypothesis; the shunted hydrocephalus group performed poorer on all memory measures. Differences for the arrested group were less frequently statistically significant relative to children with no hydrocephalus. Irrespective of etiology, the shunted hydrocephalus group exhibited a pattern of performance suggestive of encoding and retrieval deficits on both verbal and nonverbal tasks, showing a pervasive disturbance of memory processes.

Effects of intraventricular hemorrhage and hydrocephalus on the long-term neurobehavioral development of preterm very-low-birthweight infants.

Measures of intelligence, neuropsychological functions, academic skills, and behavioral adjustment were obtained at school-age from children born preterm with no hydrocephalus (N=29), arrested hydrocephalus (N=19), and shunted hydrocephalus (N=17), and a term comparison group (N=23). Most children also received concurrent neurological examinations and MRI brain scans. Results revealed significantly poorer neurobehavioral development in all four domains in preterm children with shunted hydrocephalus. Despite abnormal MRI findings in virtually all children with arrested hydrocephalus, significant differences between preterm children with arrested hydrocephalus and those with no hydrocephalus were largely in areas involving attentional and academic skills. Preterm children with no hydrocephalus tended to show poorer motor development relative to term children. Neurological abnormalities were restricted to children with spasticity in the arrested (N=2) and shunted (N=10) groups. These results highlight the importance of separating cases according to residual neurological and neuroimaging abnormalities in accounting for variations in the neurobehavioral development of preterm, low-birth-weight infants.

Magnetic resonance imaging in relation to functional outcome of pediatric closed head injury: a test of the Ommaya-Gennarelli model.

OBJECTIVE: To characterize late neuropathological findings of pediatric closed head injury (CHI), to assess depth of brain lesion in relation to acute severity, and to assess long-term outcome to test the Ommaya-Gennarelli model. METHODS: Magnetic resonance imaging (MRI) at least 3 months postinjury in a prospective sample (n 5 169) and at least 3 years after CHI in a retrospective sample (n 5 82) was studied. Lesion volume was measured by planimetry. Acute CHI severity was measured by the Glasgow Coma Scale. Patients were classified according to the depth of the deepest parenchymal lesion into no lesion, subcortical, and deep central gray/brain stem groups. The outcomes were assessed by the Glasgow Outcome Scale and the Vineland Adaptive Behavior Scale, which were performed at the time of the MRI in the retrospective sample and up to 3 years postinjury in the prospective sample. RESULTS: Focal brain lesions were present in 55.4% of the total sample. Depth of brain lesion was directly related to severity of acute impairment of consciousness and inversely related to outcome, as measured by both the Glasgow Outcome Scale and the Vineland Adaptive Behavior Scale. A rostrocaudal gradient of hemispheric lesion frequency was observed, whereas the posterior lesions of the corpus callosum were particularly common. Total lesion volume could not explain the depth of lesion effect. CONCLUSION: Our findings extend support for the Ommaya-Gennarelli model to pediatric CHI, indicating that depth of brain lesion is related to functional outcome. The relative frequency of focal brain lesions revealed by late MRI is higher than that of previous findings using acute computed tomography. Future investigations could explore whether depth of lesion observed using late MRI is sensitive to neuroprotective interventions.

Morphometric evaluation of the hydrocephalic brain: relationships with cognitive development.

The effects of early hydrocephalus and related brain anomalies on cognitive skills are not well understood. In this study, magnetic resonance scans were obtained from 99 children aged from 6 to 13 years with either shunted hydrocephalus (n = 42) or arrested (unshunted) hydrocephalus (n = 19), from patient controls with no hydrocephalus (n = 23), and from normal, nonpatient controls (n = 15). Lateral ventricle volumes and area measurements of the internal capsules and centra semiovale in both hemispheres were obtained from these scans, along with area measurements of the corpus callosum. Results revealed reductions in the size of the corpus callosum in the shunted hydrocephalus group. In addition, lateral ventricle volumes were larger and internal capsule areas were smaller in both hemispheres in children with shunted and arrested hydrocephalus. The centra semiovale measurements did not differentiate the groups. Correlating these measurements with concurrent assessments of verbal and nonverbal cognitive skills, motor abilities, and executive functions revealed robust relationships only between the area of the corpus callosum and nonverbal cognitive skills and motor abilities. These results support the theory of a prominent role for the corpus callosum defects characteristic of many children with shunted hydrocephalus in the spatial cognition deficits commonly observed in these children.

Reliability of brain structure morphometry in hydrocephalic children using MR images.

To assess the ability of human operators to make decisions about region boundaries in significantly malformed brains, we performed a study of the reliability of morphometric measurements of specific brain structures from MRI in children with hydrocephalus and controls. Cross-sectional area measures of the corpus callosum, internal capsules and centrum semiovale, and volumes of the lateral ventricles were made in 50 children. Independent measurements were made by two raters on T1 and T2-weighted MR images. Pearson's correlation coefficients (r) and intraclass correlation coefficients (ICC) between the two rater's sets of measures were computed for each structure across all subjects. ICCs ranged from a low of 0.7502 to a high of 0.9895. All ICCs were significant at the p < .0001 level and were generally less than or equal to the corresponding Pearson's r value in every case. Therefore, the Pearson's r may overestimate the reliability. The results of this study support the claim that the ICC should be used rather than the Pearson's r when assessing interater reliability in situations where large between-group differences are present. In addition, the results show that brains malformed by disorders, such as hydrocephalus, can be reliably assessed using morphometric measures of MR images.

Verbal and nonverbal skill discrepancies in children with hydrocephalus: a five-year longitudinal follow-up.

Compared verbal and nonverbal skills of 65 children ages 5 to 7 years, with a history of shunted hydrocephalus (n = 26), arrested hydrocephalus (n = 11), and no hydrocephalus (n = 28), over a 5-year period. Comparison of these skills in 4 assessments revealed poorer average nonverbal than verbal skills on measures from the McCarthy Scales of Children's Abilities, the Wechsler Intelligence Scales for Children-Revised (WISC-R), and composites of neuropsychological skills for the shunted hydrocephalus group in comparison to the arrested-hydrocephalus and no hydrocephalus groups. There were higher rates of significant discrepancies between WISC-R Verbal IQ (VIQ) and Performance IQ (PIQ), with PIQ < VIQ in the shunted group. However, relatively few children exhibited significant discrepancies on multiple test occasions. The poorer performance of the shunted hydrocephalus group could not be attributed to motor demands of the nonverbal tasks.

Behavioral adjustment of children with hydrocephalus: relationships with etiology, neurological, and family status.

Examined the relationship of hydrocephalus and behavioral adjustment in three groups of 5- to 7-year-old children (N = 84) with a history of early hydrocephalus (spina bifida, prematurity, aqueductal stenosis) and three non-hydrocephalic comparison groups (spina bifida, prematurity, normals). Results revealed no significant group differences on measures of behavioral adjustment and a variety of family and sociodemographic variables. Children with hydrocephalus were more likely to meet criteria for behavior problems, obtained lower scores on measures of adaptive behavior, and perceived themselves as less physically competent. Categorical modeling analyses showed that hydrocephalus and its treatment, gender, family variables, and motor skills were related to the presence of behavior problems.

Cerebral white matter and cognition in hydrocephalic children.

Although children with hydrocephalus frequently show poor development of nonverbal cognitive skills relative to verbal skills, little is known about the neuropathologic correlates of these discrepancies. In this study, cerebral white-matter structures and lateral ventricles were measured from the magnetic resonance images of age-matched children with meningomyelocele, meningocele, and aqueductal stenosis and normal subjects. The volume of each lateral ventricle and the cross-sectional area of the corpus callosum and internal capsules were correlated with concurrent measures of verbal and nonverbal cognitive skills. The corpus callosum in the meningomyelocele and aqueductal stenosis groups was smaller. The lateral ventricles were larger, and the internal capsules were smaller, in all patient groups than in normal subjects. There were no differences in the size of the centra semiovale. Although verbal and nonverbal measures correlated positively with the size of the corpus callosum, the correlation was higher for nonverbal measures. Nonverbal measures correlated with the right, but not the left, lateral ventricle and with the area of the right and left internal capsules. Verbal measures correlated with the left, but not right, lateral ventricle and with the left, but not right, internal capsule. These results show a relationship between the corpus callosum and cognitive skills that is also influenced by hydrocephalus-related changes in the lateral ventricles and other cerebral white-matter tracts.

Verbal and nonverbal skill discrepancies in hydrocephalic children.

This study evaluated a large sample (N = 90) of 5- to 7-year-old children with hydrocephalus caused by aqueductal stenosis or prematurity-intraventricular hemorrhage or associated with spina bifida. Comparison groups of normal controls, children with spina bifida and no shunt, and premature children with no hydrocephalus were also evaluated. Comparison of skill discrepancies at two occasions separated by 1 year revealed that hydrocephalic children, as a group, showed poorer nonverbal than verbal skills on measures from the McCarthy Scales of Children's Abilities, the WISC-R, and composites of neuropsychological skills. No discrepancies in verbal-nonverbal memory were found nor were any discrepancies attributable to etiology or motor demands of the tasks. Consistent with current hypotheses concerning the role of the cerebral white matter in cognitive development, these results show that hydrocephalic children in this age range generally have poorer development of nonverbal cognitive skills relative to their language development.

Analysis of change: modeling individual growth.

Research on change is complicated by problems of measurement and analysis stemming from a conceptualization of change as a series of accumulating increments and decrements. In contrast, individual growth curves depict change as a continuous process underlying individual performance. These two perspectives are reviewed, and some problems with the use of difference scores in the study of change are clarified. Traditional methods are contrasted with growth curve analysis for the purposes of measuring change and studying its correlates. An illustrative example of the use of growth curves is provided from research on recovery of cognitive function following pediatric closed head injury.

Comparisons of cutoff and regression-based definitions of reading disabilities.

This study addressed the issue of specificity in reading disability by comparing two approaches to defining and selecting children with reading disabilities. One approach defined reading disability according to cutoff scores representing appropriate levels of intelligence and reading deficiency, whereas the other approach adjusted these scores for their intercorrelation through regression procedures. Results revealed clear differences in which children were identified as reading disabled according to the two definitions. However, differences in neuropsychological performance between children whose reading scores were discrepant or not discrepant with IQ were small and nonspecific for both definitions. The results of this study show that children identified as reading disabled vary according to the definition employed; at this point, there is little evidence suggesting any specificity of reading disability according to definition.

Computerized tomography of prostatic and periurethral abscesses: 2 case reports.

We report 2 cases of lower urinary tract abscesses disclosed by contrast-enhanced computerized tomography scanning. In each case computerized tomography disclosed the diagnosis when conventional studies failed to reveal a cause, and treatment failed to relieve the signs and symptoms of urinary tract infection.

Primitive hypoglossal artery and carotid endarterectomy.

A patient with transient ischemic symptoms in the carotid and vertebrobasilar distribution is reported. His arteriogram demonstrated a persistent primitive hypoglossal artery which in part may explain the clinical picture. The embryology, radiology, clinical manifestations, and surgical considerations of this rare anomaly are discussed.

A semi-upright portable venographic table.

A 45 degrees semi-upright venographic table which incorporates superimposed variable-ratio water grids and variable speed screens in long cassettes for leg phlebographic recording is described. It is constructed from used x-ray table top material placed on a standard equipment moving truck, for convenient use and easy upright storage.