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Biomedical subjects

John H Gilmore

Publications and source records attributed to John H Gilmore.

15 recordsLinked to original sources
PubMed2006

Intracranial hemorrhage in asymptomatic neonates: prevalence on MR images and relationship to obstetric and neonatal risk factors.

PURPOSE: To retrospectively evaluate the prevalence of neonatal intracranial hemorrhage (ICH) and its relationship to obstetric and neonatal risk factors. MATERIALS AND METHODS: Pregnant women were recruited for a prospective study of neonatal brain development; the study was approved by the institutional review board and complied with HIPAA regulations. After informed consent was obtained from a parent, neonates were imaged with 3.0-T magnetic resonance (MR) imaging without sedation. The images were reviewed by a neuroradiologist with 12 years of experience for the presence of ICH. Medical records were prospectively and retrospectively reviewed for selected risk factors, which included method of delivery, duration of labor, and evidence of maternal or neonatal birth trauma. Risk factors were assessed for relationship to ICH by using Fisher exact test statistics. RESULTS: Ninety-seven neonates (mean age at MR imaging, 20.8 days +/- 6.9 [standard deviation]) underwent MR imaging between the ages of 1 and 5 weeks. Eighty-eight (44 male and 44 female) neonates (65 with vaginal delivery and 23 with cesarean delivery) completed the MR imaging evaluation. Seventeen neonates with ICHs (16 subdural, two subarachnoid, and six parenchymal hemorrhages) were identified. Seven infants had two or more types of hemorrhages. All neonates with ICH were delivered vaginally, with a prevalence of 26% in vaginal births. ICH was significantly associated with vaginal birth (P < .005) but not with prolonged duration of labor or with traumatic or assisted vaginal birth. CONCLUSION: Asymptomatic ICH following vaginal birth in full-term neonates appears to be common, with a prevalence of 26% in this study.

Birth Injuries↗
PubMed2006

Caspase-3 activation in rat frontal cortex following treatment with typical and atypical antipsychotics.

In schizophrenia, studies indicate that apoptotic susceptibility in cortex may be increased. A role for apoptosis in schizophrenia could potentially contribute to post-mortem evidence of reduced cortical neuropil and neuroimaging studies showing progressive cortical gray matter loss. Interestingly, antipsychotic treatment has been associated with higher cortical levels of anti-apoptotic Bcl-2 protein in rat cortex and preliminary data has suggested a similar association in schizophrenia and bipolar disorder. To better understand the effects of antipsychotics on apoptotic regulation, rats were administered haloperidol, clozapine, quetiapine, or saline daily for 4 weeks. Multiple apoptotic markers, including Bcl-2, pro-apoptotic Bax, anti-apoptotic XIAP, and the downstream protease caspase-3 were measured in frontal cortex using Western blot. Caspase-3 activity, activated caspase-3-positive cell number, and DNA/histone fragmentation levels were also determined. Western blot showed that immunoreactivity of Bax and Bcl-2 bands were unchanged with treatment. However, mean density of the 19 kD activated caspase-3 band was 55% higher with haloperidol (p<0.001), 40% higher with clozapine (p<0.05), and 48% higher with quetiapine (p<0.01) compared to saline control. Specific activity of caspase-3 was also increased across all treatments (p<0.0001), while DNA fragmentation rates remained unchanged. These data suggest that sub-chronic antipsychotic treatment is associated with non-lethal caspase-3 activity. The findings do not support a prominent Bcl-2-mediated neuroprotective role for antipsychotics. Although the association between antipsychotic treatment and increased pro-apoptotic caspase-3 is intriguing, further study is needed to understand its potential effects.

Analysis of Variance↗
PubMed2005

Apoptotic mechanisms and the synaptic pathology of schizophrenia.

The cortical neuropathology of schizophrenia includes neuronal atrophy, decreased neuropil, and alterations in neuronal density. Taken together with evidence of decreased synaptic markers and dendritic spines, the data suggest that synaptic circuitry is altered. Recent neuroimaging studies also indicate that a progressive loss of cortical gray matter occurs early in the course of schizophrenia. Although the mechanisms underlying these deficits are largely unknown, recent postmortem data implicate a role for altered neuronal apoptosis. Apoptosis, a form of programmed cell death, is regulated by a complex cascade of pro- and anti-apoptotic proteins. Apoptotic activation can lead to rapid neuronal death. However, emerging data also indicate that sub-lethal apoptotic activity can lead to a limited form of apoptosis in terminal neurites and individual synapses to cause synaptic elimination without cell death. For example, in Alzheimer's disease, a localized apoptotic mechanism is thought to contribute to early neurite and synapse loss leading to the initial cognitive decline. Recent studies indicate that apoptotic regulatory proteins and DNA fragmentation patterns are altered in several cortical regions in schizophrenia. This paper will review converging lines of data that implicate synaptic deficits in the pathophysiology of schizophrenia and propose an underlying role for apoptotic dysregulation.

Apoptosis↗
PubMed2005

Fiber tract-oriented statistics for quantitative diffusion tensor MRI analysis.

Diffusion tensor imaging (DTI) has become the major modality to study properties of white matter and the geometry of fiber tracts of the human brain. Clinical studies mostly focus on regional statistics of fractional anisotropy (FA) and mean diffusivity (MD) derived from tensors. Existing analysis techniques do not sufficiently take into account that the measurements are tensors, and thus require proper interpolation and statistics based on tensors, and that regions of interest are fiber tracts with complex spatial geometry. We propose a new framework for quantitative tract-oriented DTI analysis that includes tensor interpolation and averaging, using nonlinear Riemannian symmetric space. As a result, tracts of interest are represented by the geometry of the medial spine attributed with tensor statistics calculated within cross-sections. Examples from a clinical neuroimaging study of the early developing brain illustrate the potential of this new method to assess white matter fiber maturation and integrity.

Algorithms↗
PubMed2005

Automatic segmentation of MR images of the developing newborn brain.

This paper describes an automatic tissue segmentation method for newborn brains from magnetic resonance images (MRI). The analysis and study of newborn brain MRI is of great interest due to its potential for studying early growth patterns and morphological changes in neurodevelopmental disorders. Automatic segmentation of newborn MRI is a challenging task mainly due to the low intensity contrast and the growth process of the white matter tissue. Newborn white matter tissue undergoes a rapid myelination process, where the nerves are covered in myelin sheathes. It is necessary to identify the white matter tissue as myelinated or non-myelinated regions. The degree of myelination is a fractional voxel property that represents regional changes of white matter as a function of age. Our method makes use of a registered probabilistic brain atlas. The method first uses robust graph clustering and parameter estimation to find the initial intensity distributions. The distribution estimates are then used together with the spatial priors to perform bias correction. Finally, the method refines the segmentation using training sample pruning and non-parametric kernel density estimation. Our results demonstrate that the method is able to segment the brain tissue and identify myelinated and non-myelinated white matter regions.

Aging↗
PubMed2005

Apoptotic mechanisms in the pathophysiology of schizophrenia.

While schizophrenia is generally considered a neurodevelopmental disorder, evidence for progressive clinical deterioration and subtle neurostructural changes following the onset of psychosis has led to the hypothesis that apoptosis may contribute to the pathophysiology of schizophrenia. Apoptosis (a.k.a. programmed cell death) is a mechanism of cell death that operates in normal neurodevelopment and is increasingly recognized for its role in diverse neuropathological conditions. Activation of apoptosis can lead to rapid and complete elimination of neurons and glia in the central nervous system. Studies also show that in certain settings, pro-apoptotic triggers can lead to non-lethal and localized apoptotic activity that produces neuritic and synaptic loss without causing cell death. Given that the neuropathology of schizophrenia is subtle and includes reduced neuropil (especially synaptic elements), limited and often layer-specific reductions of neurons, as well as neuroimaging data suggesting progressive loss of cortical gray matter in first-episode psychosis, a role for apoptosis in schizophrenia appears plausible. Studies that have examined markers of apoptosis and levels of apoptotic regulatory proteins in postmortem schizophrenia brain tissue will be reviewed in context of this hypothesis. Overall, the data seem to indicate a dysregulation of apoptosis in several cortical regions in schizophrenia, including evidence that the apoptotic vulnerability is increased. Although the exact role of apoptosis in schizophrenia remains uncertain, the potential involvement of non-lethal localized apoptosis is intriguing, especially in earlier stages of the illness.

Apoptosis↗
PubMed2004

Maternal poly I:C exposure during pregnancy regulates TNF alpha, BDNF, and NGF expression in neonatal brain and the maternal-fetal unit of the rat.

Maternal infection during pregnancy is associated with increased risk for neurodevelopmental disorders. Polyriboinosinic-polyribocytidilic acid (poly I:C) or saline was administered to rats to model maternal infection; levels of TNFalpha, brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) were determined by ELISA. TNFalpha was significantly increased in maternal plasma, placenta, and amniotic fluid, while it was significantly decreased in fetal liver/spleen and neonatal brain. NGF and BDNF were significantly decreased in the placenta and fetal liver/spleen. There was no change in BDNF or NGF in the fetal or neonatal brain. Changes in TNFalpha, BDNF, and NGF after maternal exposure to poly I:C represent a potential mechanism through which maternal infection increases risk for neurodevelopmental disorders.

Amniotic Fluid↗
PubMed2004

3 Tesla magnetic resonance imaging of the brain in newborns.

While it has been hypothesized that brain development is abnormal in schizophrenia and other neurodevelopmental disorders, there have been few attempts to study very early brain development in children. Twenty unsedated healthy newborns underwent 3 Tesla magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI). The left ventricle was significantly larger than the right; females had significantly larger ventricles than males. Fractional anisotropy (FA) increased significantly with gestational age in the genu and splenium of the corpus callosum. It is feasible to study brain development in unsedated newborns using 3 T MRI.

Brain↗
PubMed2004

Prenatal infection and risk for schizophrenia: IL-1beta, IL-6, and TNFalpha inhibit cortical neuron dendrite development.

Prenatal exposure to infection increases risk for schizophrenia, and we have hypothesized that inflammatory cytokines, generated in response to maternal infection, alter neuron development and increase risk for schizophrenia. We sought to study the effect of cytokines generated in response to infection-interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNFalpha), and interleukin-6 (IL-6)-on the dendritic development of cortical neurons. Primary mixed neuronal cultures were obtained from E18 rats and exposed to 0, 100, or 1000 units (U)/ml of IL-1beta, TNFalpha, IL-6, or IL-1beta+TNFalpha for 44 h. MAP-2-positive neurons were randomly identified for each condition and the number of primary dendrites, nodes, and total dendrite length was determined. We found that 100 U of TNFalpha significantly reduced the number of nodes (27%, p=0.02) and total dendritic length (14%, p=0.04), but did not affect overall neuron survival. A measure of 100 U IL-1beta+TNFalpha significantly reduced the number of primary dendrites (17%, p=0.006), nodes (32%, p=0.001), and total dendritic length (30%, p<0.0001), although it did not affect overall neuron survival. At 1000 U, each cytokine significantly reduced the number of primary dendrites (14-24%), nodes (28-37%), as well as total dendritic length (25-30%); neuron survival was reduced by 14-21%. These results indicate that inflammatory cytokines can significantly reduce dendrite development and complexity of developing cortical neurons, consistent with the neuropathology of schizophrenia. These findings also support the hypothesis that cytokines play a key mechanistic role in the link between prenatal exposure to infection and risk for schizophrenia.

Animals↗
PubMed2004

Apoptotic proteins in the temporal cortex in schizophrenia: high Bax/Bcl-2 ratio without caspase-3 activation.

OBJECTIVE: Neuroimaging findings have identified lower cortical gray matter volume in schizophrenia. Apoptosis (programmed cell death) has been proposed as a contributing pathophysiological mechanism. Levels of antiapoptotic Bcl-2 protein are low in the temporal cortex of schizophrenia patients. Bcl-2 interacts with the proapoptotic Bax protein at an upstream checkpoint to regulate the activation of apoptosis by caspase-3 and other proteolytic caspase proteins. A high Bax/Bcl-2 ratio is associated with greater vulnerability to apoptotic activation, while a high caspase-3 level is often associated with apoptotic activity. It was hypothesized that the Bax/Bcl-2 ratio, but not caspase-3, would be high in the temporal cortex of patients with chronic schizophrenia. METHOD: Bax, Bcl-2, and caspase-3 proteins were measured by semiquantitative Western blot in Brodmann's area 21 (middle temporal gyrus) of postmortem tissue from patients with schizophrenia (N=15), bipolar disorder (N=15), or major depression (N=15) and nonpsychiatric comparison subjects (N=15). RESULTS: The Bax/Bcl-2 ratio was 50% higher in the schizophrenia patients than the nonpsychiatric comparison subjects. The level of caspase-3 (inactive zymogen and activated subunits) was not significantly different. CONCLUSIONS: The higher Bax/Bcl-2 ratio suggests that cortical cells are vulnerable to apoptosis in chronic schizophrenia. However, the normal caspase-3 level suggests that apoptosis is not active in this illness phase. Furthermore, the results appear to distinguish the pathophysiology of schizophrenia from most classic neurodegenerative disorders, in which postmortem caspase-3 levels are high. Further studies are needed to investigate the implications of abnormal apoptotic proteins in schizophrenia.

Aged↗
PubMed2003

Maternal infection regulates BDNF and NGF expression in fetal and neonatal brain and maternal-fetal unit of the rat.

Maternal infection during pregnancy is associated with increased risk for neurodevelopmental disorders. Lipopolysaccharide (LPS) or saline was administered to rats to model maternal infection, and levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in maternal plasma, placenta, amniotic fluid, fetal liver/spleen, fetal brain, and cerebral cortex after birth were determined by ELISA or semiquantitative Western blot analysis. BDNF expression was significantly increased in the fetal brain (p=0.039); NGF expression was significantly increased in neonatal cortex (p=0.0009). Neurotrophic factor expression was also altered in other tissues of the maternal-fetal unit. Abnormal expression of neurotrophic factors represents a potential mechanism through which maternal infection increases risk for neurodevelopmental disorders.

Animals↗
PubMed2003

Recent advances in the neurobiology of schizophrenia.

Despite great progress in basic schizophrenia research, the conclusive identification of specific etiological factors or pathogenic processes in the illness has remained elusive. The convergence of modern neuroscientific studies in molecular genetics, molecular neuropathology, neurophysiology, in vivo brain imaging, and psychopharmacology, however, indicates that we may be coming much closer to understanding the molecular basis of schizophrenia. Schizophrenia may be a neurodevelopmental and progressive disorder with multiple biochemical abnormalities involving the dopaminergic, serotonin, glutamate, and gamma -aminobutyric acidergic systems. In the near future, biological markers for the illness may come from the combination of diverse assessment techniques. An understanding of the pathophysiology of schizophrenia will be essential to the discovery of preventive measures and therapeutic intervention. Rapidly advancing research into schizophrenia includes diverse etiological hypotheses, and offers directions for future research and treatments.

Antipsychotic Agents↗
PubMed2003

Comparisons of regional white matter diffusion in healthy neonates and adults performed with a 3.0-T head-only MR imaging unit.

PURPOSE: To evaluate the normal brains of adults and neonates for regional and age-related differences in apparent diffusion coefficient (ADC) and fractional anisotropy (FA). MATERIALS AND METHODS: Eight healthy adults and 20 healthy neonates were examined with a 3.0-T head-only magnetic resonance (MR) imaging unit by using a single-shot diffusion-tensor sequence. Trace ADC maps, FA maps, directional maps of the putative directions of white matter (WM) tracts, and fiber-tracking maps were obtained. Regions of interest-eight in WM and one in gray matter (GM)-were predefined for the ADC and FA measurements. The Student t test was used to compare FA and ADC between adults and neonates, whereas the Tukey multiple-comparison test was used to compare FA and ADC in different brain regions in the adult and neonate groups. RESULTS: A global elevation in ADC (P <.001) in both GM and WM and a reduction in FA (P <.001) in WM were observed in neonates as compared with these values in adults. In addition, significant regional variations in FA and ADC were observed in both groups. Regional variations in FA and ADC were less remarkable in adults, whereas neonates had consistently higher FA values and lower ADC values in the central WM as compared with these values in the peripheral WM. Fiber tracking revealed only major WM tracts in the neonates but fibers extending to the peripheral WM in the adults. CONCLUSION: There were regional differences in FA and ADC values in the neonates; such variations were less remarkable in the adults.

Adult↗
PubMed2002

Analysis of ependymal abnormalities in subjects with schizophrenia, bipolar disorder, and depression.

Abnormalities of the ependyma can serve as a marker of early brain insults. The presence of ependymal abnormalities was determined in sections containing ependyma of the temporal horn obtained from the Stanley Neuropathology Consortium: 15 subjects with schizophrenia, 15 with bipolar illness, 15 with major depression and 15 normal controls. There were no significant differences in numbers of subjects with ependymal discontinuities or subventricular rosettes. Subjects with schizophrenia had significantly less nodular gliosis than normal subjects (p=0.02); there was a trend for subjects with depression to have less nodular gliosis than normal subjects (p=0.06). Control subjects had unexpectedly high rates of ependymal abnormalities, indicating that ependymal abnormalities may not be a useful marker of pre- or perinatal events associated with schizophrenia and other psychiatric disorders in adult postmortem tissue.

Adult↗