Biomedical subjects

Laura R Ment

Publications and source records attributed to Laura R Ment.

At least 19 recordsLinked to original sources

PubMed2006

Functional analysis of a novel potassium channel (KCNA1) mutation in hereditary myokymia.

Myokymia is characterized by spontaneous, involuntary muscle fiber group contraction visible as vermiform movement of the overlying skin. Myokymia with episodic ataxia is a rare, autosomal dominant trait caused by mutations in KCNA1, encoding a voltage-gated potassium channel. In the present study, we report a family with four members affected with myokymia. Additional clinical features included motor delay initially diagnosed as cerebral palsy, worsening with febrile illness, persistent extensor plantar reflex, and absence of epilepsy or episodic ataxia. Mutation analysis revealed a novel c.676C>A substitution in the potassium channel gene KCNA1, resulting in a T226K nonconservative missense mutation in the Kv1.1 subunit in all affected individuals. Electrophysiological studies of the mutant channel expressed in Xenopus oocytes indicated a loss of function. Co-expression of WT and mutant cRNAs significantly reduced whole-oocyte current compared to expression of WT Kv1.1 alone.

Amino Acid Sequence↗

PubMed2006

Early postnatal astroglial cells produce multilineage precursors and neural stem cells in vivo.

To identify the fates that astroglial cells can attain in the postnatal brain, we generated mice carrying an inducible Cre recombinase (Cre-ER(T2)) controlled by the human GFAP promoter (hGFAP). In mice carrying the GCE (hGFAP-Cre-ER(T2)) transgene, OHT (4-hydroxy-tamoxifen) injections induced Cre recombination in astroglial cells at postnatal day 5 and allowed us to permanently tag these cells with reporter genes. Three days after recombination, reporter-tagged cells were quiescent astroglial cells that expressed the stem cell marker LeX in the subventricular zone (SVZ) and dentate gyrus (DG). After 2-4 weeks, the tagged GFAP lineage included proliferating progenitors expressing the neuronal marker Dcx (Doublecortin) in the SVZ and the DG. After 4 weeks, the GFAP lineage generated mature neurons in the olfactory bulb (OB), DG, and, strikingly, also in the cerebral cortex. A major portion of all neurons in the DG and OB born at the end of the first postnatal week were generated from GFAP+ cells. In addition to neurons, mature oligodendrocytes and astrocytes populating the cerebral cortex and white matter were also the progeny of GFAP+ astroglial ancestors. Thus, genetic fate mapping of postnatal GFAP+ cells reveals that they seed the postnatal brain with neural progenitors/stem cells that in turn give rise to neural precursors and their mature neuronal and oligodendrocytic progeny in many CNS regions, including the cerebral cortex.

Animals↗

PubMed2006

Cortical neurogenesis enhanced by chronic perinatal hypoxia.

Most regions of the mature mammalian brain, including the cerebral cortex, appear to be unable to support the genesis of new neurons. Here, we report that a low level of neurogenesis occurs in the cerebral cortex of the infant mouse brain and is enhanced by chronic perinatal hypoxia. When mice were reared in a low-oxygen environment from postnatal days 3 to 11, approximately 30% of the cortical neurons were lost after the insult; yet this damage was transient. The loss of cortical neuron number, cortical volume, and brain weight were all reversed during the recovery period. At P18, 7 days after the cessation of hypoxia, there was a marked increase in astroglial cell proliferation within the SVZ, as assessed by 5-bromodeoxyuridine (BrdU) incorporation in S-phase cells. One month after BrdU incorporation, 40% more BrdU-positive cells were found in the cerebral cortex of hypoxic-reared as compared to normoxic control mice. Among these newly generated cortical cells, approximately 45% were oligodendrocytes, 35% were astrocytes, and 10% were neurons in both hypoxic and normoxic mice. However, twice as many BrdU-labeled cells expressed neuronal markers in the neocortex in mice recovering from hypoxia as compared to controls. In both hypoxic-reared and normoxic infant/juvenile mice, putative neuroblasts could be seen detaching from the forebrain subventricular zone, migrating through the subcortical white matter and entering the lower cortical layers, 5 to 11 days after their last mitotic division. We suggest that cortical neurogenesis may play a significant role in repairing neuronal losses after neonatal injury.

Age Factors↗

PubMed2006

Cortical recruitment patterns in children born prematurely compared with control subjects during a passive listening functional magnetic resonance imaging task.

OBJECTIVES: To use functional magnetic resonance imaging (fMRI) to test the hypothesis that subjects who were born prematurely develop alternative systems for processing language. STUDY DESIGN: Subjects who were born prematurely (n = 14; 600-1250 g birthweight) without neonatal brain injury and 10 matched term control subjects were examined with a fMRI passive listening task of language, the Clinical Evaluation of Language Fundamentals (CELF) and portions of the Comprehensive Test of Phonological Processing (CTOPP). The fMRI task was evaluated for both phonologic and semantic processing. RESULTS: Although there were differences in CELF scores between the subjects born prematurely and control subjects, there were no significant differences in the CTOPP measures in the 2 groups. fMRI studies demonstrated that the groups differentially engaged neural systems known to process language. Children born at term were significantly more likely to activate systems for the semantic processing of language, whereas subjects born prematurely preferentially engaged regions that subserve phonology. CONCLUSIONS: At 12 years of age, children born prematurely and children born at term activate neural systems for the auditory processing of language differently. Subjects born prematurely engage different networks for phonologic processing; this strategy is associated with phonologic language scores that are similar to those of control subjects. These biologically based developmental strategies may provide the substrate for the improving language skills noted in children who are born prematurely.

Auditory Perception↗

PubMed2006

Familial and genetic susceptibility to major neonatal morbidities in preterm twins.

BACKGROUND: Intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia remain significant causes of morbidity and mortality in preterm newborns. OBJECTIVES: Our goal was to assess the familial and genetic susceptibility to intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia. METHODS: Mixed-effects logistic-regression and latent variable probit model analysis were used to assess the contribution of several covariates in a multicenter retrospective study of 450 twin pairs born at < or =32 weeks of gestation. To determine the genetic contribution, concordance rates in a subset of 252 monozygotic and dizygotic twin pairs were compared. RESULTS: The study population had a mean gestational age of 29 weeks and birth weight of 1286 g. After controlling for effects of covariates, the twin data showed that 41.3%, 51.9%, and 65.2%, respectively, of the variances in liability for intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia could be accounted for by genetic and shared environmental factors. Among the 63 monozygotic twin pairs, the observed concordance for bronchopulmonary dysplasia was significantly higher than the expected concordance; 12 of 18 monozygotic twin pairs with > or =1 affected member had both members affected versus 3.69 expected. After controlling for covariates, genetic factors accounted for 53% of the variance in liability for bronchopulmonary dysplasia. CONCLUSIONS: Twin analyses show that intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia are familial in origin. These data demonstrate, for the first time, the significant genetic susceptibility for bronchopulmonary dysplasia in preterm infants.

Bronchopulmonary Dysplasia↗

PubMed2006

A functional magnetic resonance imaging study of the long-term influences of early indomethacin exposure on language processing in the brains of prematurely born children.

BACKGROUND: Previous studies have demonstrated that indomethacin lowers the incidence and decreases the severity of intraventricular hemorrhage, as well as improves the cognitive outcome, in prematurely born male infants. OBJECTIVE: The purpose of this work was to use functional magnetic resonance imaging to test the hypothesis that neonatal indomethacin treatment would differentially affect brain activation across genders in school-aged, prematurely born children during performance of a language task. METHODS: Forty-seven prematurely born children (600-1250-g birth weight) and 24 matched term control subjects were evaluated using a functional magnetic resonance imaging passive language task and neurodevelopmental assessments that included the Wechsler Intelligence Scale for Children-III and the Peabody Picture Vocabulary Test-Revised. Neural activity was assessed during both phonologic and semantic processing in the functional magnetic resonance imaging protocol. RESULTS: Neurodevelopmental assessments demonstrated significant differences in full-scale, verbal, and performance intelligence quotient, as well as Peabody Picture Vocabulary Test scores, between the preterm and term control subjects. Rates of perinatal complications did not differ significantly across preterm treatment groups, but male preterm subjects randomly assigned to saline tended to have lower Peabody Picture Vocabulary Test-Revised scores than did all of the other preterm groups. During phonological processing, a significant treatment-by-gender effect was demonstrated in 3 brain regions: the left inferior parietal lobule, the left inferior frontal gyrus (Broca's area), and the right dorsolateral prefrontal cortex. CONCLUSIONS: These data demonstrate a differential effect of indomethacin administration early in postnatal life on the subsequent development of neural systems that subserve language functioning in these male and female preterm infants.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2006

Genetic susceptibility to retinopathy of prematurity.

OBJECTIVES: The goals were to isolate and to estimate the genetic susceptibility to retinopathy of prematurity. METHODS: A retrospective study (1994-2004) from 3 centers was performed with zygosity data for premature twins who were born at a gestational age of < or = 32 weeks and survived beyond a postmenstrual age of 36 weeks. Retinopathy of prematurity was diagnosed and staged by pediatric ophthalmologists at each center. Data analyses were performed with mixed-effects logistic regression analysis and latent variable probit modeling. RESULTS: A total of 63 monozygotic and 137 dizygotic twin pairs were identified and analyzed. Data on gestational age, birth weight, gender, respiratory distress syndrome, retinopathy of prematurity, bronchopulmonary dysplasia, duration of ventilation and supplemental oxygen use, and length of stay were comparable between monozygotic and dizygotic twins. In the mixed-effects logistic regression analysis for retinopathy of prematurity, gestational age and duration of supplemental oxygen use were significant covariates. After controlling for known and unknown nongenetic factors, genetic factors accounted for 70.1% of the variance in liability for retinopathy of prematurity. CONCLUSION: In addition to prematurity and environmental factors, there is a strong genetic predisposition to retinopathy of prematurity.

Female↗

PubMed2005

Increased temporal lobe gyrification in preterm children.

Preterm birth often results in significant learning disability, and previous magnetic resonance imaging (MRI) studies of preterm children have demonstrated reduction in overall cortical tissue with particular vulnerability in the temporal lobe. We measured cortical gyrification in 73 preterm and 33 term control children at 8 years of age and correlated these findings with tests of language ability to determine the associations among preterm birth, neurodevelopment and functional outcome. Preterm children demonstrated significantly increased bilateral temporal lobe gyrification index compared to term controls. Left temporal gyrification index was significantly negatively correlated with left temporal lobe gray matter volume as well as reading recognition scores in the preterm group. Cortical development in the temporal lobe appears to be differentially vulnerable to preterm birth.

Cerebral Cortex↗

PubMed2005

Grade 3 to 4 intraventricular hemorrhage and Bayley scores predict outcome.

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Cerebral Hemorrhage↗

PubMed2004

Sex differences in cerebral volumes of 8-year-olds born preterm.

We investigate sex-associated effects of preterm birth on cerebral gray matter (GM) and white matter (WM) volumes. Preterm children (n=65) and 31 healthy, term control children had usable magnetic resonance imaging (MRI) data acquired at 8 years of age. Both GM and WM volumes were significantly reduced in the preterm group compared with controls. However, only males with preterm birth had significantly reduced WM compared with term males (P=.021), whereas WM volumes were equivalent in the female groups. Lower birth weight was associated with reduced WM in both boys and girls with preterm birth, whereas intraventricular hemorrhage (IVH) was associated with reduced GM in girls only. Positive correlations between GM and cognitive outcome were observed in girls with preterm birth but not boys. We conclude that preterm birth has a significant impact on brain development with increased risk for smaller GM and WM cerebral volumes. Males appear particularly vulnerable to adverse effects of preterm birth on WM development. However, girls with preterm birth show stronger correlations between neuro-anatomical variables and both neonatal risk factors and cognitive outcome, compared with boys. These findings indicate that the sex of the very preterm newborn influences the mechanisms by which the developing brain is affected.

Brain↗

PubMed2004

Prevention of intraventricular hemorrhage by indomethacin in male preterm infants.

Our multicenter Indomethacin Intraventricular Hemorrhage (IVH) Prevention Trial demonstrated a reduction of IVH in preterm infants. Analysis of our cohort by sex showed indomethacin halved the incidence of IVH, eliminated parenchymal hemorrhage, and was associated with higher verbal scores at 3 to 8 years in boys.

Cardiovascular Agents↗

PubMed2004

Fetal stroke.

Fetal stroke, or that which occurs between 14 weeks of gestation and the onset of labor resulting in delivery, has been associated with postnatal epilepsy, mental retardation, and cerebral palsy. The entity is caused by antenatal ischemic, thrombotic, or hemorrhagic injury. We present seven new cases of fetal stroke diagnosed in utero and review the 47 cases reported in the literature. Although risk factors could not be assigned to 50% of the fetuses with stroke, the most common maternal conditions associated with fetal stroke were alloimmune thrombocytopenia and trauma. Magnetic resonance imaging was optimal for identifying fetal stroke, and prenatal imaging revealed hemorrhagic lesions in over 90% of studies; porencephalies were identified in just 13%. Seventy-eight percent of cases with reported outcome resulted in either death or adverse neurodevelopmental outcome at ages 3 months to 6 years. Fetal stroke appears to have different risk factors, clinical characteristics, and outcomes than other perinatal or childhood stroke syndromes. A better understanding of those risk factors predisposing a fetus to cerebral infarction may provide a basis for future therapeutic intervention trials. Ozduman K, Pober BR, Barnes P, Copel JA, Ogle EA, Duncan CC, Ment LR. Fetal stroke.

Brain↗

PubMed2004

Volumetric analysis of regional cerebral development in preterm children.

Preterm birth is frequently associated with both neuropathologic and cognitive sequelae. This study examined cortical lobe, subcortical, and lateral ventricle development in association with perinatal variables and cognitive outcome. High-resolution volumetric magnetic resonance imaging scans were acquired and quantified using advanced image processing techniques. Seventy-three preterm and 33 term control children ages 7.3-11.4 years were included in the study. Results indicated disproportionately enlarged parietal and frontal gray matter, occipital horn, and ventricular body, as well as reduced temporal and subcortical gray volumes in preterm children compared with control subjects. Birth weight was negatively correlated with parietal and frontal gray, as well as occipital horn volumes. Intraventricular hemorrhage was associated with reduced subcortical gray matter. Ventricular cerebrospinal fluid was negatively correlated with subcortical gray matter volumes but not with white matter volumes. Maternal education was the strongest predictor of cognitive function in the preterm group. Preterm birth appears to be associated with disorganized cortical development, possibly involving disrupted synaptic pruning and neural migration. Lower birth weight and the presence of intraventricular hemorrhage may increase the risk for neuroanatomic abnormality.

Cerebral Cortex↗

PubMed2004

Preterm birth: a cost benefit analysis.

Advances in prenatal and perinatal treatment of preterm and VLBW infants have dramatically increased the survival rate of these infants. Some interventions decrease long term sequelae associated with preterm birth, making them more cost-effective than other treatments. This paper reviews the cost-effectiveness of therapies targeted to protect the preterm brain. Birth in a center with a NICU improves survival and decreases the rate of severe neurologic disability. Administration of antenatal steroids increases survival and decreases rates of periventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, respiratory distress syndrome, and severe disability. Administration of antenatal steroids decreases costs per additional survivor. Addition of surfactant to the treatment of PT infants has also decreased treatment costs. Administration of surfactant is beneficial for symptomatic RDS but recognizes a greater benefit when given to infants younger than 30 weeks gestation prophylactically. Treatment with prophylactic indomethacin decreases the rate of intraventricular hemorrhage and results in cost savings in survivors. Postnatal administration of dexamethasone can lead to severe disability when administered before 7 to 10 days of life. Postnatal dexamethasone does not increase survival or decrease rates of chronic lung disease.

Adrenal Cortex Hormones↗

PubMed2004

Chronic neonatal hypoxia leads to long term decreases in the volume and cell number of the rat cerebral cortex.

Preterm birth results in significant neurodevelopmental disability. The neonatal rodent model of chronic sublethal hypoxia faithfully mimics the effect of preterm birth on the developing brain. We employed this model to test the hypothesis that the hypoxia that accompanies preterm birth results in inappropriate signaling of apoptotic mechanisms in developing brain. We performed cortical cell counts, determinations of neuronal size and Western analyses of the apoptosis related proteins, Bcl-2 and Bax, in rat pups who were raised in chronic hypoxia (FiO2 9.5%) beginning on postnatal day 3 (P3) and extending for either 10 (P13) or 30 (P33) days. A third group of animals was exposed to 30 days of hypoxia followed by an additional 30 days in a normoxic environment (P63) to assess the potential for recovery from the initial effects of hypoxia. Age matched control pups were raised in room air throughout the experimental time period. Assessment of cortical cell number revealed a 25% reduction (P < 0.01) in total cell number following 30 days of hypoxic rearing. Glia were significantly reduced by 34% and 41% after 10 and 30 days of hypoxia, respectively, while neuron numbers were only significantly reduced (14%) after 30 days of hypoxia. Animals exposed to a hypoxic environment for 30 days followed by 30 days in a normoxic environment revealed some recovery of glial cell numbers, but no significant recovery of neuronal cell numbers. Measurement of cell size at both P13 and P33 revealed that neurons of layer III were significantly smaller in cross-sectional area in hypoxic compared with control rats (P < 0.01). However, no significant difference was noted in neuronal size following 30 days of normoxic recovery. Western blot analyses of Bcl-2 and Bax protein levels demonstrated a ratio favorable to Bax at multiple time points during the period of hypoxic exposure. These data suggest that chronic exposure to hypoxia during the perinatal period alters the production and maintenance of glial and neuronal cells and that glia and neurons demonstrate differential patterns of vulnerability and recovery following subsequent periods of normoxic exposure. It is hypothesized that the mechanisms responsible for these alterations in cortical cell number may depend on the state of differentiation of the different cell types at the time of hypoxic exposure.

Animals↗

PubMed2004

An evidence-based approach to predicting low IQ in very preterm infants from the neurological examination: outcome data from the indomethacin Indomethacin Intraventricular Hemorrhage Prevention Trial.

We evaluated whether the degree of cerebral palsy (CP) at age 3 in very preterm children is predictive of full-scale intelligence quotient (FSIQ) <70 at age 8 by calculating likelihood ratios (LRs) for findings on the neurologic examination. Data from the follow-up phase of the Indomethacin Intraventricular Hemorrhage Prevention Trial, which includes periodic neurologic examination and neuropsychometric testing, were used. Information was available on 366 of 440 (83%) children with birth weight of 600 to 1250 g who survived. Neurologic examination at age 3 was grouped by presence and type of CP, and the Weschler Intelligence Scale for Children-Third Edition FSIQ at age 8 was grouped dichotomously (<70 or > or =70). CP was identified in 35 of 366 3-year-olds (9.5%). An FSIQ <70 was identified in 47 of 366 children at 8 years old (12.8%). FSIQ <70 occurred in 14 of 17 children with tri- or quadriplegia (82%), 8 of 18 children with di- or hemiplegia (44%), and 25 of 331 children without CP (7.5%). Useful LRs were calculated for tri- or quadriplegia (30), di- or hemiplegia (5.7), and children without CP (0.55). These LRs have greater impact on posttest odds for FSIQ <70 than those for birth weight <1000 g, history of bronchopulmonary dysplasia, and Stanford-Binet Intelligence Score <70 at age 3. We conclude that the neurologic examination at 3 years old predicts FSIQ <70 at age 8 with LRs that allow evidence-based parental counseling and intervention planning.

Cerebral Palsy↗

PubMed2003

Change in cognitive function over time in very low-birth-weight infants.

CONTEXT: Preterm very low-birth-weight (VLBW) infants have a high prevalence of neurodevelopmental disability when evaluated during the first several years of life. However, recent experimental data suggest that the developing brain may recover from or compensate for injury. OBJECTIVE: To determine if there is cognitive improvement throughout early and middle childhood following VLBW birth. DESIGN, SETTING, AND PARTICIPANTS: Follow-up data of 296 infants born weighing 600 to 1250 g who participated in a prospective, randomized, placebo-controlled intraventricular hemorrhage (IVH) prevention study performed at 3 northeastern US hospitals between September 1989 and August 1992 and who were serially evaluated at 36, 54, 72, and 96 months of corrected age (CA). MAIN OUTCOME MEASURES: The age-normed Peabody Picture Vocabulary Test-Revised (PPVT-R) score and measures of intelligence. RESULTS: Overall, the median PPVT-R score increased from 88 at 36 months of CA to 99 at 96 months of CA; when data from 36 and 96 months of CA were compared, 45% of children gained 10 points or more and 12.5% showed a 5- to 9-point increase in test scores. Similar findings were noted for full-scale and verbal IQ scores. Multivariate analyses demonstrated that increasing age, residence in a 2-parent household, and higher levels of maternal education were all significantly associated with higher PPVT-R scores (for each, P<.001). In addition, early intervention led to greater increases over time in PPVT-R scores among children whose mothers had less than a high school education compared with those with a high school education level or greater (P =.03 by test for interaction). Although most children showed improvement in PPVT-R scores with increasing CA, children with early-onset IVH and subsequent significant central nervous system injury had the lowest PPVT-R scores initially and the scores declined over time (P =.009 by test for interaction). CONCLUSIONS: The majority of VLBW children had improvement in verbal and IQ test scores over time. Only children with early-onset IVH followed by significant central nervous system injury had low PPVT-R scores that declined over time.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2003

School-age outcomes of very low birth weight infants in the indomethacin intraventricular hemorrhage prevention trial.

OBJECTIVE: The cohort consisted of 328 very low birth weight infants (600-1250 g birth weight) who were enrolled in the low-dose prophylactic indomethacin prevention trial and were intraventricular hemorrhage (IVH) negative at 6 postnatal hours. The objective was to determine the effects of both IVH and indomethacin on cognitive, language, and achievement performance at 8 years of age. METHODS: The cohort was divided into 4 subgroups for analysis: indomethacin plus IVH, indomethacin no IVH, saline plus IVH, and saline with no IVH. The children were evaluated prospectively at 8 years of age with a neurologic assessment, history of school performance, and a battery of cognitive, academic, behavioral, and functional assessments. RESULTS: Children in both IVH groups had more cerebral palsy; more hearing impairment; lower daily living skills scores; lower IQ, vocabulary, and reading and mathematics achievement test scores; and greater educational resource needs. With logistic regression analyses grade 3 to 4 IVH, periventricular leukomalacia and/or ventriculomegaly, male gender, maternal education, and language spoken in the home contributed to outcomes. No effects of indomethacin or gestational age were identified. CONCLUSIONS: Although biological factors including IVH, ventriculomegaly, and periventricular leukomalacia contribute significantly to school age outcomes among very low birth weight survivors at 8 years of age, social and environmental factors including maternal level of education and primary language spoken in the home are also important contributors to outcome.

Cerebral Hemorrhage↗