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Biomedical subjects

J R Leonard

Publications and source records attributed to J R Leonard.

At least 19 recordsLinked to original sources
PubMed2001

Neural precursor cell apoptosis and glial tumorigenesis following transplacental ethyl-nitrosourea exposure.

Neural precursor cells (NPCs) populate the embryonic ventricular zone and persist in the subependymal zone of the adult brain. We hypothesized that hereditary and/or acquired mutations in apoptosis-associated genes, such as p53 and caspases, may protect NPCs from DNA damage-induced death and predispose them to subsequent neoplastic transformation. To test this hypothesis, we exposed NPCs from wild-type and targeted gene-disrupted mouse embryos (p53, caspase-9, caspase-3, and bax mutants) to ethyl-nitrosourea (ENU), a known DNA mutagen and neural carcinogen, and measured NPC viability. We found that ENU produced caspase-3 activation and apoptotic NPC death 6-24 h after administration both in vivo and in vitro. This effect was critically dependent on p53 and caspase-9 expression. The long-term effect of intrauterine ENU exposure was examined in control and p53-deficient mice. High grade glial tumors were found in 60% of p53(-/-) young adult mice exposed to ENU on gestational day 12.5 but not in p53(+/-) or p53(+/+) littermates or in untreated p53-deficient mice. All the tumors were located supratentorially and possessed strong immunoreactivity for glial fibrillary acidic protein and the anti-apoptotic molecule Bcl-X(L). These results suggest that intrauterine exposure of NPCs to certain DNA damaging agents may synergistically interact with specific genetic abnormalities (e.g. p53 deficiency) to produce glial neoplasms in the adult brain.

Animals↗
PubMed2001

Bid regulation of neuronal apoptosis.

Bid is a BH3 domain only pro-apoptotic member of the Bcl-2 family which interacts with Bax to regulate apoptosis. Bax-deficient embryos show decreased neuronal programmed cell death in vivo and resistance to cytosine arabinoside (AraC)-induced neuronal apoptosis in vitro. In this report, we demonstrate that Bid-deficient embryos show no neurodevelopmental abnormalities, and Bid-deficiency has no effect on the in vitro apoptotic response of either telencephalic neural precursor cells or neurons to AraC-induced death. We conclude that bid does not play an essential role in either naturally occurring or genotoxin-induced neuronal cell death.

Animals↗
PubMed2001

DNA damage-induced neural precursor cell apoptosis requires p53 and caspase 9 but neither Bax nor caspase 3.

Programmed cell death (apoptosis) is critical for normal brain morphogenesis and may be triggered by neurotrophic factor deprivation or irreparable DNA damage. Members of the Bcl2 and caspase families regulate neuronal responsiveness to trophic factor withdrawal; however, their involvement in DNA damage-induced neuronal apoptosis is less clear. To define the molecular pathway regulating DNA damage-induced neural precursor cell apoptosis, we have examined the effects of drug and gamma-irradiation-induced DNA damage on telencephalic neural precursor cells derived from wild-type embryos and mice with targeted disruptions of apoptosis-associated genes. We found that DNA damage-induced neural precursor cell apoptosis, both in vitro and in vivo, was critically dependent on p53 and caspase 9, but neither Bax nor caspase 3 expression. Neural precursor cell apoptosis was also unaffected by targeted disruptions of Bclx and Bcl2, and unlike neurotrophic factor-deprivation-induced neuronal apoptosis, was not associated with a detectable loss of cytochrome c from mitochondria. The apoptotic pathway regulating DNA damage-induced neural precursor cell death is different from that required for normal brain morphogenesis, which involves both caspase 9 and caspase 3 but not p53, indicating that additional apoptotic stimuli regulate neural precursor cell numbers during telencephalic development.

Animals↗
PubMed2001

Large cell/anaplastic medulloblastomas and medullomyoblastomas: clinicopathological and genetic features.

OBJECT: Medulloblastoma is the most common malignant central nervous system neoplasm found in children. A distinct variant designated large cell/anaplastic (LC/A) medulloblastoma is characterized by frequent dissemination of cerebrospinal fluid (CSF) at presentation and a more aggressive clinical course. The authors report on their examination of the clinicopathological and genetic features of seven such cases encountered at their institution. METHODS: Eighty cases of medulloblastomas were reviewed and seven (8.8%) of these were believed to fit the histological and immunohistochemical criteria for LC/A medulloblastoma. In three cases (43%) either desmoplastic or classic medulloblastoma was the underlying subtype, and in two cases (28%) the LC/A tumor was found within the setting of medullomyoblastoma. Fluorescence in situ hybridization was used in six of the seven cases to characterize the presence of isochromosome 17q, deletion of chromosome 22q (a deletion characteristically found in atypical teratoid/rhabdoid tumors), and c-myc amplification. The patients' clinical histories revealed CSF dissemination in all cases and lymph node metastasis in one case. Isochromosome 17q was found in five (83%) of six cases. Evidence of chromosomal gains indicated aneuploidy in three tumors (50%), and amplification of c-myc was found in three tumors (50%). No 22q deletions were encountered. CONCLUSIONS: A high percentage of LC/A medulloblastomas arise within a background of typical medulloblastomas or medullomyoblastomas. As is the case in conventional medulloblastomas, the presence of 17q is a common early tumorigenic event; however, in a significant percentage of specimens there is also evidence of aneuploidy and/or amplification of c-myc. These findings indicate that LC/A morphological characteristics reflect a more advanced tumor stage than that found in pure medulloblastomas or in typical medullomyoblastomas.

Adolescent↗
PubMed2000

MR imaging of herpes simplex type 1 encephalitis in infants and young children: a separate pattern of findings.

OBJECTIVE: We sought to identify the initial MR findings of herpes simplex encephalitis in infants and young children. CONCLUSION: MR imaging findings of herpes encephalitis in infants and young children appear to differ from those seen in neonates, older children, and adults. Appreciation of this MR imaging pattern coupled with a strong clinical suspicion of herpes helps to ensure the correct diagnosis is made.

Brain↗
PubMed1997

Fluid percussion injury causes disruption of the septohippocampal pathway in the rat.

Fluid percussion injury (FPI) causes memory deficits, loss of hippocampal neurons, and basal forebrain cholinergic immunoreactivity in rats. Basal forebrain septohippocampal projections terminate in specific hippocampal regions. The purpose of this study was to examine the effects of FPI on the septohippocampal pathway (SHP). Halothane-anesthetized rats received either a sham injury or a parasagittal FPI. To characterize the anatomical effects of FPI on the SHP, silver stains were performed on brains of animals at 1, 5, and 10 days following FPI and were compared to sham-injured preparations. To characterize the effects of FPI on retrograde transport in the SHP, a separate group of FPI and sham-injured animals with survival times of 2, 5, and 10 days received bilateral WGA-HRP injections into the hippocampal formation 24 h prior to sacrifice. Argyrophilic CA3 neurons were present 1 day following FPI. Five days following FPI, terminal degeneration was present in the inner third of the molecular layer of the dentate gyrus bilaterally that was not present 1 day after injury. Fiber and terminal degeneration was not observed in the basal forebrain until 10 days after FPI. WGA-HRP-labeled septal neurons decreased significantly (P < 0.05) ipsilateral to injury in animals sacrificed 5 and 10 days following FPI but not 2 days after injury. This investigation demonstrated that FPI produces focal injury in the hippocampal formation. In addition, the appearance of terminal degeneration in the dentate molecular layer correlated with the significant reduction in axonal transport 5 days following injury. This correlation illustrates the secondary processes that structurally damage the SHP up to 10 days after injury.

Animals↗
PubMed1995

Olfactory bulb transplants establish afferent and efferent connections with host forebrain in rat.

We are using wheat germ agglutinin-conjugated horseradish peroxidase (WHRP) to study reconnectivity in the transplanted (TX) olfactory bulb (OB) in Sprague-Dawley rats. Tritium-labeled OBs from fetal rat donors of Embryonic Days 14-15 were immediately grafted into neonatal rats in the site from which the host OB had been removed. Following survival times of 7 weeks and longer, WHRP solution was injected into the TX OB, and subjects were perfused after 24 h. The WHRP transport is seen in fibers from the TX OB into layer I of the host olfactory peduncle (OP) and olfactory cortex (OC) and in cell bodies in layers II and III of the OP and OC, the lateral hypothalamus, and the contralateral anterior olfactory nucleus (AON). These findings reaffirm that the axons from a TX OB make connections with some appropriate areas of the host brain and also indicate that axons from cells in the target areas of the host brain, including contralateral AON, reinnervate the TX OB.

Afferent Pathways↗
PubMed1994

Fluid percussion injury causes loss of forebrain choline acetyltransferase and nerve growth factor receptor immunoreactive cells in the rat.

Memory dysfunction is a common sequela of human traumatic brain injury (TBI). Cholinergic forebrain neurons are recognized for their role in memory. We tested the hypothesis that forebrain cholinergic neurons are vulnerable to fluid percussion injury (FPI), a model of human TBI. Rodents were subjected to a moderate parasagittal FPI, sham injury, or fimbria/fornix axotomy and then killed 10 days after the procedure. Additional animals underwent FPI or sham injury and were killed 7, 14, and 28 days after the procedure. Neurons in the medial septal nucleus and vertical limb of the nucleus of the diagonal band of Broca were identified and quantitated using choline acetyltransferase (ChAT) and low affinity nerve growth factor receptor (NGF-R) immunohistochemistry. Our results showed a significant decrease in ChAT (17% +/- 5%) and NGF-R (24% +/- 8%) immunoreactive cells in FPI animals killed after 10 days when compared to sham-injured animals. Animals undergoing fimbria/fornix axotomy showed a greater reduction in ChAT (53% +/- 13%) and NGF-R (55% +/- 5%) immunoreactive cells 10 days postaxotomy. The number of ChAT and NGF-R immunoreactive neurons was reduced at all time points. However, statistical significance was present 10 and 14 days postinjury for ChAT immunoreactive neurons and 10 days only for NGF-R immunoreactive neurons. These studies have shown that FPI produces transient loss of ChAT and NGF-R immunoreactive neurons.

Animals↗
PubMed1987

Multiple subdural hematomas associated with breakdancing.

A 17-year-old, previously healthy, male breakdancer presented with a three-month history of crescendo headache and newly identified papilledema. The patient was found to have four separate, unilateral extracranial collections. At surgery, three were subdural hematomas, and one was a probable arachnoid cyst containing a hematoma. These were removed, and the patient made an uneventful recovery with no neurosurgical sequelae. The possibility of serious head injury must be considered when evaluating headache in youngsters who engage in this new and apparently popular dance form.

Adolescent↗
PubMed1986

Cytologic results of fine-needle aspiration biopsies of the central nervous system.

The cytologic results of 34 fine-needle aspiration (FNA) biopsies of the central nervous system (CNS) are reported. There were 31 intraoperative biopsies performed at the time of craniotomy. All the cases were diagnosed using direct smear preparations stained with Papanicolaou and Diff-Quik (Harleco, NJ) stains. The sensitivity of the procedure was 90.7%, specificity 100%, positive predictive value 100%, and efficiency of the test of 91%. There were no false-positive diagnoses and three false-negative diagnoses. This study attests to the diagnostic accuracy of FNA cytologic examination of the central nervous system. Statistical analysis of the few previous FNA biopsy series of the CNS are presented. Review of the indications, advantages and complications of CNS needle biopsy are discussed. This report supports the role of fine-needle aspiration cytology in the evaluation of CNS lesions. With recent developments in radiologic imaging, especially ultrasound and computed tomography (CT) using stereotactic guidance, specimens can be obtained for cytologic diagnosis using thinner needles. Excellent diagnostic accuracy can be obtained, as pathologists gain greater familiarity with interpreting FNA biopsy material. Other advantages of FNA biopsy of the central nervous system include the low morbidity and mortality of the procedure and the ability to perform the biopsy through a burr hole under local anesthesia and thereby decrease hospitalization time and cost.

Adult↗
PubMed1975

Value of sequential postoperative brain scans in patients with anaplastic gliomas.

The authors analyze the postoperative course of 30 patients with anaplastic supratentorial gliomas to evaluate the usefulness of sequential brain scanning as an adjunct to clinical neurological examinations in the early detection of tumor recurrence. The correlation between sequential scanning and clinical evaluation was excellent; no examples of divergent resu;ts were seen. With the exception of scans made very early in the postoperative period or when postoperative scalp flap infections were present, initial postoperative scans were easily interpreted in terms of both the superficial (postcraniotomy) and parenchymal changes. The specific type of postoperative therapy (radiation therapy, chemotherapy, or both) could not be correlated with whether scan or examination ultimately changed first. However, analysis of original tumor location revealed that while sequential postoperative scanning offered no advantage over repetitive neurological examinations in the detection of recurrent tumor in the neurologically dominant left hemisphere, scan changes preceded examination changes in eight of 17 cases involving tumors of the neurologically nondominant right hemisphere.

Brain Neoplasms↗