p140trk mRNA marks NGF-responsive forebrain neurons: evidence that trk gene expression is induced by NGF.

Nerve growth factor (NGF) appears to act as a neurotrophic factor for basal forebrain and caudate-putamen cholinergic neurons. The mechanism by which NGF transduces its signal in these neurons is yet to be defined. Recent data indicate that the product of the trk gene, p140trk, is a critical component of the NGF receptor. Herein, we show that p140trk mRNA is highly restricted in its distribution in the adult rat forebrain, that it is present in cholinergic neurons, and that most if not all cholinergic neurons contain p140trk mRNA. Furthermore, induction of trk expression by NGF suggests that neurotrophin-mediated up-regulation of their receptor tyrosine kinases is an important feature of their actions and that neurotrophins may regulate the activity of responsive neurons through increasing the level of their receptors.

MRI shows abnormal white matter maturation in classical holoprosencephaly.

In an attempt to assess white matter maturation in holoprosencephaly (HPE), MRI scans of 47 patients with HPE were retrospectively reviewed. White matter maturation was delayed in 25/47 patients, including 24/29 patients with classic HPE who were

Neuroanatomy of holoprosencephaly as predictor of function: beyond the face predicting the brain.

BACKGROUND: Despite advances in neuroimaging and molecular genetics of holoprosencephaly (HPE), the clinical spectrum of HPE has remained inadequately described. OBJECTIVE: To better characterize the clinical features of HPE and identify specific neuroanatomic abnormalities that may be useful predictors of neurodevelopmental function. METHODS: The authors evaluated 68 children with HPE in a multicenter, prospective study. Neuroimaging studies were assessed for the grade of HPE (lobar, semilobar, and alobar), the degree of nonseparation of the deep gray nuclei, and presence of dorsal cyst or cortical malformation. RESULTS: In general, the severity of clinical problems and neurologic dysfunctions correlated with the degree of hemispheric nonseparation (grade of HPE). Nearly three-quarters of the patients had endocrinopathies, with all having at least diabetes insipidus. The severity of endocrine abnormalities correlated with the degree of hypothalamic nonseparation (p = 0.029). Seizures occurred in approximately half of the children with HPE. The presence of cortical malformations was associated with difficult-to-control seizures. The presence and degree of dystonia correlated with the degree of nonseparation of the caudate and lentiform nuclei and the grade of HPE (p < 0.05). Hypotonia correlated with the grade of HPE (p < 0.05). Mobility, upper extremity function, and language correlated with the degree of nonseparation of the caudate, lentiform and thalamic nuclei, and grade of HPE (p < 0.01). CONCLUSIONS: Patients with HPE manifest a wide spectrum of clinical problems and neurologic dysfunction. The nature and severity of many of these problems can be predicted by specific neuroanatomic abnormalities found in HPE.

Disturbance and Predictability of Flowering Patterns in Bird-Pollinated Cloud Forest Plants.

The distribution and flowering patterns of hummingbird-pollinated plants were compared from July 1981 to June 1983 in three patch types in cloud forest at Monteverde, Costa Rica. Study plots were: (1) four recent, large (1100-2500 m2 ) disturbances ("cutovers") produced by cutting vegetation, (2) six recent, smaller (200-600 m2 ) disturbances caused by treefalls, and (3) four plots (1600-1800 m2 ) of canopied forest. Based on published literature dealing with communities that characterize different regimes of disturbance, we tested one assumption and two hypotheses. Assumption: Plant species composition differs among the three patch types. Hypothesis 1: Phenotypic specialization by plants for co-evolved interactions with hummingbirds will be lowest in large gaps, highest in forest, and intermediate in treefalls. Hypothesis 2: Predictability of flowering phenologies and nectar production will be lowest in large gaps, highest in forest, intermediate in treefalls. Neither the assumption nor the hypotheses were supported by the results. The patch mosaic in this cloud forest was not associated with major differences in species composition of bird-pollinated plants. Most species studied were self-compatible. Most abundant in cutovers were species with long corollas, relatively specialized for attracting long-billed hummingbirds. Species with short corollas, which can be visited by many hummingbird species and some insects, were most abundant in treefalls and forest. Variation in phenological patterns showed no consistent trends among patch types. Predictability of flower and nectar production tended to be greatest in treefalls, which are foci of concentrated flowering activity by all species. Discrepancies between our results and previous studies can be ascribed to two facts. (1) Much of the literature dealing with ecological consequences of disturbance has dealt with large-scale anthropogenic disturbances such as old fields of the eastern USA, whereas we studied small, natural, or quasi-natural disturbances. (2) Studies of forest disturbance have focused on the tree layer, whereas we studied the understory herbs, shrubs, and epiphytes. Natural disturbance usually involves death and replacement of one or more trees, whereas individuals of other life forms may persist through the disturbance.

RNA editing of a human glutamate receptor subunit.

AMPA receptors are comprised of individual subunits, and the divalent cation permeability of assembled AMPA receptors is determined by a single amino acid residue in the second transmembrane region of the GluR-B subunit. At this site, GluR-B subunits contain an arginine while other AMPA receptor subunits contain glutamine. Interestingly, the murine gene for GluR-B actually specifies a glutamine at the divalent cation permeability site. The appearance of arginine and not glutamine in the mature GluR-B protein is thought to be a result of RNA editing of the GluR-B messenger RNA. In that AMPA receptors are thought to mediate the bulk of fast excitatory signalling within the mammalian central nervous system, this process of RNA editing may play a pivotal role in normal neural function by mediating divalent cation permeability of AMPA receptors. Disruptions of RNA editing could lead to phenotypically altered AMPA receptors, with implications for pathogenic brain processes. We report that the human GluR-B gene sequence is also edited such that there is a difference between the human GluR-B gene and the complementary DNA (cDNA), as demonstrated both with allele-specific polymerase chain reaction (PCR) and restriction enzyme digestion of PCR products. Thus, as in the rodent brain, RNA editing of an AMPA receptor subunit appears to be an important process in the human brain. Disruptions of RNA editing may have neuropathological consequences.

A reverse transcription-polymerase chain reaction study of p75 nerve growth factor receptor gene expression in developing rat cerebellum.

The actions of the neurotrophins are mediated through specific receptors. Nerve growth factor (NGF), the prototypic neurotrophin, binds to receptors of both high and low affinity. A protein 75 kDa in size (p75NGFR) binds NGF, as well as brain-derived neurotrophic factor and neurotrophin 3, with low affinity. Recent investigations suggest that this protein may also be a component of the high affinity NGF receptor complex. To study gene expression of the p75NGFR molecule, we used a sensitive reverse transcription-polymerase chain reaction (RT-PCR) assay to measure levels of its messenger RNA (mRNA) in small samples of total RNA. The assay is based on using a shortened p75NGFR cRNA as an internal RNA standard to control for variability in reverse transcription and polymerase chain amplification. We measured p75NGFR mRNA levels in the rat cerebellum during ontogeny to further study the transient developmental increase in receptor gene expression known to occur in this brain region during the early postnatal period. We found that p75NGFR mRNA levels were most abundant at postnatal day 2, and then declined to lower levels throughout postnatal development and in the adult. Northern blot analysis of the same total RNA samples used in our RT-PCR assay verified that p75NGFR expression is highest in the early postnatal period. These results confirm those of previous studies accomplished with much larger amounts of RNA using ribonuclease protection or northern blot assays. The use of an RT-PCR assay that utilized an internal standard also controls against changes in RNA complexity which can affect the measurement of message abundance across developmental stages.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of NMDA receptor subunit mRNA after MK-801 treatment in neonatal rats.

Although NMDA receptor antagonists are neuroprotective when delivered in conjunction with NMDA, supersensitivity to NMDA-mediated injury follows dizocilpine (MK-801) administration in neonatal rats. An increase in NMDA-sensitive [3H]-glutamate binding accompanies the increase in vulnerability to excitotoxic injury. The present study tests the hypothesis that MK-801 may alter gene expression for the NMDA receptor subunits. Quantitative in situ hybridization histochemistry was used to evaluate the expression of NMDA receptor subunits NR1 and NR2A-D in neonatal rats, 2 to 4 h after treatment with MK-801. Increased mRNA for multiple NMDA receptor subunits was observed in cerebral cortex, striatum and hippocampus. The percent increase in NR2A mRNA was larger than the percent change in NR1, NR2B or NR2D. A small increase in mRNA for the metabotropic glutamate receptor mGluR5 was also observed after MK-801 treatment. These results indicate that gene expression for NMDA receptor subunits in the developing brain is rapidly altered after antagonist exposure. Increased expression of excitatory amino acid receptor subunit mRNA may contribute to the enhanced vulnerability to excitotoxic injury that has been observed after MK-801 treatment.

Mauthner axon diameter and impulse conduction velocity decrease with growth of goldfish.

Conduction velocities of antidromically evoked impulses along the goldfish Mauthner axon were found to be inversely correlated with body length. To test the hypothesis that such a relation is accompanied by a reduction in axonal diameter with increasing fish size, Mauthner axon diameters were measured. A parabolic relationship with respect to body length was obtained, axonal diameter being maximal in 9.5 cm fish. To our knowledge, this is the first report of a decrease in conduction velocity and axonal size during growth of an organism were functioning of the cell is maintained.

Assessment of the deep gray nuclei in holoprosencephaly.

BACKGROUND AND PURPOSE: Although holoprosencephaly has been known for many years, few detailed analyses have been performed in a large series of patients to outline the range of morphology in this disorder, particularly regarding the deep gray nuclear structures. We reviewed a large patient cohort to elucidate the combinations of morphologic aberrations of the deep gray nuclei and to correlate those findings with recent discoveries in embryology and developmental neurogenetics. METHODS: A retrospective review of the imaging records of 57 patients (43 MR studies and 14 high-quality CT studies) to categorize the spectrum of deep gray nuclear malformations. The hypothalami, caudate nuclei, lentiform nuclei, thalami, and mesencephalon were graded as to their degree of noncleavage. Spatial orientation was also evaluated, as was the relationship of the basal ganglia to the diencephalic structures and mesencephalon. The extent of noncleavage of the various nuclei was then assessed for statistical association. RESULTS: In every study on which it could be accurately assessed, we found some degree of hypothalamic noncleavage. Noncleavage was also common in the caudate nuclei (96%), lentiform nuclei (85%), and thalami (67%). Complete and partial noncleavage were more common in the caudate nuclei than in the lentiform nuclei. The degree of thalamic noncleavage was uniformly less than that in the caudate and lentiform nuclei. Abnormalities in alignment of the long axis of the thalamus were seen in 71% of cases, and were associated with degree of thalamic noncleavage; 27% of patients had some degree of mesencephalic noncleavage. CONCLUSION: The hypothalamus and caudate nuclei are the most severely affected structures in holoprosencephaly, and the mesencephalic structures are more commonly involved than previously thought in this "prosencephalic disorder." These findings suggest the lack of induction of the most rostral aspects of the embryonic floor plate as the cause of this disorder.

Maternal shunt dependency: implications for obstetric care, neurosurgical management, and pregnancy outcomes and a review of selected literature.

OBJECTIVE: Because more women with cerebrospinal fluid shunts are surviving to child-bearing age, neurosurgeons, obstetricians, and other health care professionals require information about the care of these patients, especially during pregnancy and delivery. The purpose of this study was to gather comprehensive data from women with shunts regarding their clinical histories during and immediately after pregnancy. The following questions were addressed. 1) How does maternal shunt dependency influence the course of pregnancies and pregnancy outcomes? 2) What neurosurgical complications characterize this population of patients? 3) What complications of shunt dependency influence obstetric management, including prenatal testing and delivery? METHODS: A total of 37 respondents (age, 18-41 yr), accounting for 77 pregnancies, completed a questionnaire providing information on maternal background and medical history, shunt performance during pregnancy, management of delivery, pregnancy outcomes, and unusual complications. RESULTS: Fifty-six pregnancies resulted in live births; of these, 47 occurred in women with ventriculoperitoneal shunts. Three women underwent therapeutic abortions, 1 experienced preterm delivery, and 8 experienced 17 miscarriages. Four women experienced seizures during pregnancy, five reported third-trimester headaches, and eight described abdominal pains during the first and third trimesters. Four babies were diagnosed as having congenital defects. Shunt malfunctions and revisions occurred 10 times in 7 women, either during pregnancy or within 6 months after delivery. No acute malfunctions occurred during delivery. Forty-seven cases, representing 84% of all pregnancies, exhibited no shunt malfunctions or revisions. CONCLUSION: This study extends previous observations to a larger population of shunt-dependent mothers. The results suggest that maternal shunt dependency entails a relatively high incidence of complications but that proper care of these patients can lead to normal pregnancies and deliveries.

Barriers to adolescent prenatal care.

It is estimated that over one-half of all adolescent mothers receive inadequate prenatal care. Our objectives were to explore the barriers to care as perceived by adolescents and to develop a model to identify adolescents at risk for inadequate care. Structured interviews were conducted with 101 adolescents less than 17 years of age who delivered infants at an urban university hospital between September 1988 and January 1989. All the interviews were conducted within 48 hr of delivery by a single investigator. The Maternal Health Services Index was used to divide subjects into those who received inadequate care (Group 1, n = 37) and those who received intermediate or adequate care (Group 2, n = 64). Both groups were predominantly black (99%), poor (mean Hollingshead score = 2), and unmarried (99%). Groups 1 and 2 differed (p less than 0.05) in 12 variables pertaining to beliefs about prenatal care and course during the pregnancy. Of the 12 variables, 7 comprised a stepwise logistic regression model designed to maximally differentiate Groups 1 and 2--negative attitudes towards physicians (20% vs 6%), perceived importance of first trimester care (78% vs 94%), confusion about available prenatal services (24% vs 5%), lack of health insurance (41% vs 16%), exposure to pregnant friends (76% vs 95%), mean gestational age at recognition of pregnancy (15 wks vs 11 wks), and desire for an adolescent-only prenatal clinic (78% vs 58%). The adjusted odds ratios of the variables ranged in declining order from 15.4 to 4.7. The attributable risks, or etiologic fractions, of the variables ranged in increasing order from 0.19 to 0.49. Receiver-operating characteristic curve analysis of the model demonstrated a curve area of 0.89 +/- 0.04, significantly better than chance. We conclude that the model clarifies the barriers to care and helps identify pregnant adolescents who are likely to receive inadequate prenatal care.

Pregnancy among American Indian adolescents: reactions and prenatal care.

PURPOSE: Adolescent childbearing is twice as common among Native Americans as among all US races combined. Despite this, little is written about the psychosocial context or prenatal care of pregnant Native American adolescents. The objective of this study was to explore the reactions and prenatal care of Navajo and Apache adolescents delivering infants at Shiprock Indian Hospital, New Mexico, between January and March 1991, and Whiteriver Indian Hospital, Arizona, between May and June 1991. METHODS: Of the 25 eligible adolescents aged 19 years and younger, 15 Navajo and 5 Apache participants were interviewed within 24 hours of delivery. The interview consisted of 121 questions divided into 5 areas: sociodemographics, personal and family reactions to the pregnancy, knowledge and attitudes toward prenatal care, barriers to care, and ways to improve access to care. RESULTS: The mean age was 17.4 +/- 1.1, 6 were married, and 13 were primiparous. According to the Maternal Health Services Index, 5 adolescents received adequate, 13 intermediate, and 2 inadequate prenatal care. During the pregnancy, 3 adolescents used tobacco, 3 used alcohol, and none admitted to other drugs. Although only 1 adolescent planned the pregnancy, 15 were not using contraception when they became pregnant. In exploring reactions to the pregnancy, 13 adolescents were afraid to tell their families and 4 concealed the pregnancy until confronted. During the pregnancy, 7 adolescents described loneliness and 6 expressed suicidal ideation. Although over half reported no barriers to obtaining prenatal care, barriers that were noted by the remainder included transportation, family problems, and missing school. CONCLUSION: We conclude that pregnancy among many American Indian adolescents is unplanned and characterized by uncertainty and fear of disclosure, resembling the reactions to pregnancy of other adolescent populations. Furthermore, despite universal access to health services, many American Indian adolescents continue to experience barriers to care and receive intermediate or inadequate prenatal care. These preliminary findings suggest further research may help clarify how adolescent reactions to pregnancy and knowledge of prenatal care affect health care utilization.

Young women with physical disabilities: risk factors for symptoms of eating disorders.

Women with disabilities are at risk for poor psychological adjustment and unhealthy weight-control practices. This study was conducted to determine the prevalence of symptoms of eating disorders in a clinic-based sample of women who had two disabling conditions and to identify condition-related risk factors that were linked to these symptoms. A cross-sectional survey of 71 women (mean age = 23 yr) with spina bifida or rheumatologically related illnesses was conducted to assess the symptoms of eating disorders, condition-related characteristics, and weight-control practices. Symptoms of eating disorders were measured by the Eating Disorders Inventory (EDI). Eight percent of the respondents reported a sufficient number of symptoms of eating disorders to indicate a possible clinical disorder. More than 20% of the respondents scored at or above the clinical cut-point on at least one of the eight EDI subscales. Selected condition-related characteristics (multiple conditions, condition-affected driving, and uncertainty of illness course) were associated with EDI scores after adjusting for demographic variables, family factors, and weight-control practices.

The cost of preventable conditions in adults with spina bifida.

Adults with spina bifida are at risk of developing secondary health conditions that are causally related to the primary condition and are to some degree preventable. By investigating preventable secondary conditions in adults with spina bifida, we can determine the burden of care that might be reduced if preventive strategies were developed. We audited hospitalizations of adults with spina bifida to gain insight into serious secondary conditions in this population. We reviewed all admissions of adults with spina bifida to a large American tertiary care center (Johns Hopkins Hospital; Baltimore, Maryland) over 11 years. We determined the discharge diagnoses for each admission and the hospital costs associated with admission. We defined preventable secondary conditions in this adult population and calculated the percentage of total admissions and of total costs for these secondary conditions. The patient population consisted of spina bifida patients 18 years and over admitted from January 1982 to December 1992, including 59 females and 39 males. 77 of our patients were identified as white, 20 as black, and 1 as "other". Patient age ranged from 18 to 61 years with an average age of 25.8 years. There were 353 admissions and admissions per patient ranged from 1 to 25 over the 11-year period. The average number of admissions per patient was 3.6 and the average length of stay for all admissions was 11.2 days. Of the 353 total admissions, 166 (47.0%) were due to potentially preventable secondary conditions such as serious urologic infections, renal calculi, pressure ulcers, and osteomyelitis. For admissions due to these secondary conditions, the average length of stay was 12.5 days. The total hospital costs, excluding professional fees, were $175,885, $247,355, and $437,262 for 1990, 1991, and 1992 respectively. Permanent loss of function resulting from secondary conditions, not investigated in this study, can also be a source of long-term financial and psychological cost to the patient. This study found a high number of patients with multiple admissions and that many admissions qualified as potentially preventable. More information is needed if we are to understand the factors associated with secondary health conditions in adults with spina bifida. We need to investigate the roles played by physician and patient knowledge, attitudes, and behaviors in contributing to patient outcome.

Chiari-II malformation: a biometric analysis.

INTRODUCTION: Chiari-II malformation is a complex set of anatomic abnormalities of the posterior fossa, brainstem, and cerebellum seen in myelomeningocele. Previous studies have tried to understand this condition and its clinical consequences by studying a few fixed anatomic landmarks as dependent variables and clinical symptoms as outcome variables. These studies have led to conflicting and limited results. As a first step towards a more comprehensive study of the structural-functional relationships in Chiari-II malformation, we undertook a biometric case-series analysis of a group of individuals with MMC, using both traditional methods to study size, and thin-plate spline methodology to study shape. MATERIALS AND METHODS: The traditional analysis was a retrospective, randomly obtained case-series of 25 individuals with myelomeningocele and Chiari-II malformation. MRIs were digitized for biometric analysis of the component structures and compared to 25 controls. Landmarks on the digitized images were measured using Scion Image. Data were statistically analyzed using SPSS. The thin-plate spline analysis used a subset of these individuals (n = 14). Landmarks on digitized MRIs were identified and marked with TPSDig software. Landmark data was then imported into Splus to generate a series of shape variables. Statistical analysis using Splus was then undertaken. RESULTS: Traditional analysis revealed relationships between vermian herniation and pontomedullary junction position (p < 0.05) as well as between the height (and overall size) of the posterior fossa and degree of vermian herniation (p < 0.05). The degree of brainstem herniation/elongation did not correlate with the degree of vermian herniation. The shape analysis revealed that there is as much shape variability within the group of Chiari-II patients as there is between this group and unaffected controls. Thin-plate spline analysis shows that the position of the caudal-most aspect of the vermis is the point of greatest brain rearrangement; likewise, the opisthion is the point of greatest bony rearrangement. Partial least-squares analysis shows that in Chiari-II patients, a strong correlation (r = 0.821) exists between the extent to which the brain is warped (specifically, in regard to vermian descent) and the extent to which the bone is warped (specifically, in regard to the displacement of the opisthion) (p < 0.05). CONCLUSION: Traditional biometric analysis of size confirms that the degree of vermian herniation and cervicomedullary junction herniation are independent variables in Chiari-II malformation. Posterior fossa size is an important factor in explaining the variability of vermian herniation. The relationship between IPN position and vermian herniation suggests the possibility of a common etiology. The phenomenon of cervicomedullary junction descent appears to be independent, suggesting a different etiology. Analysis of shape indicated that shape changes in bone and brain are related, and that the Chiari-II-associated abnormalities vary greatly in their degree of abnormality. The extreme morphological variability argues against the use of mean differences as a statistical technique in analyzing morphological abnormalities in the structures we investigated.

Beyond multidisciplinary care: a new conceptual model for spina bifida services.

Medical care for people who are born with spina bifida (myelodysplasia) is complex and challenging, but the goal of such care is to optimize health and function for people with this condition. Despite years of expert agreement that multidisciplinary care is the medical standard for individuals with spina bifida, this model does not seem to go far enough towards accomplishing the goal of improved function as well as health for all people with spina bifida. Advances in the medical and surgical management of people with spina bifida and society's increased desire to include those with disabilities in family and community life has heightened our expectations for functional/participatory improvement for people with this condition. Some large spina bifida programs have added a separate rehabilitation component to the comprehensive package of services offered to people with spina bifida. The problem with adding further services to the traditional multidisciplinary spina bifida program is the increased complexity and potential for fragmentation that it presents, particularly for the patient and family. We performed a MEDLINE literature search to find information on integrating these services. Although several articles address the importance of either the multidisciplinary spina bifida clinic or a rehabilitation approach, there is little information about integration of medical and rehabilitation services. We propose a new model for spina bifida services throughout the lifespan that integrates the medical and functional/rehabilitative perspectives. Our model for conceptualizing spina bifida services builds on the WHO framework for coding disability (ICIDH-2). This framework includes not only health and functional perspectives, but a participation dimension as well. Furthermore, our new model emphasizes the importance of anticipatory guidance and transitional planning as an integrating dimension applicable across the lifespan. The model is based on three main conceptual dimensions--comprehensiveness, coordination and longitudinality. We are using the model to create standards of care, integrate services and improve their efficiency, and to develop policies regarding spina bifida services. Through this effort we hope to provide better medical and rehabilitation services to those with spina bifida and meet the complex challenge the condition presents throughout the lifespan.