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Biomedical subjects

L E Becker

Publications and source records attributed to L E Becker.

At least 91 records · Page 5Linked to original sources
PubMed1994

Barth syndrome: clinical observations and genetic linkage studies.

Barth syndrome is an X-linked recessive condition characterized by skeletal myopathy, cardiomyopathy, proportionate short stature, and recurrent neutropenia, but with normal cognitive function. Some, but not all patients, exhibit carnitine deficiency and/or the presence of 3-methylglutaconic and ethylhydracylic acids in urine. Recently the mutation causing Barth syndrome was localised to the Xq28 region by linkage analysis. We report 6 cases of Barth syndrome from 4 families and highlight the fact that neuromuscular and cardiovascular symptoms and the severity of infections tend to improve with age, while short stature persists. Also previously unreported was myopathic facies and nasal quality to speech in our cases. The urinary organic acid abnormalities and plasma carnitine deficiency were inconsistent findings. We propose that they may be epiphenomena rather than indicators of the primary metabolic defect, and that the primary defect or defects in this disorder may lie in the mitochondrial electron transport chain.

Abnormalities, Multiple↗
PubMed1994

Pediatric malignant glioma with tubuloreticular inclusions and MYCN amplification. Report of a case with immunohistochemical, ultrastructural, flow cytometric, karyotypic, and Southern blot analysis.

BACKGROUND: The authors described unusual pathologic features in a left frontal lobe malignant glioma in a 31/2-year-old boy. The pathology was similar in the initial excision and two subsequent recurrences at 9 and 11 months and at autopsy, when extensive subarachnoid spread was noted. METHODS: The tumor was studied by conventional histology, immunohistochemistry, flow cytometry, transmission electron microscopy (TEM), immune electron microscopy (IEM), and cytogenetic and Southern blot analysis. RESULTS: The tumor revealed two different histologic patterns. One component showed large cells with eosinophilic cytoplasm, vesicular nuclei with prominent nucleoli, eosinophilic perinuclear inclusions, and immunoreactivity for glial fibrillary acidic protein (GFAP) and vimentin. The other component consisted of undifferentiated cells with hyperchromatic nuclei and scanty cytoplasm. By TEM, the perinuclear aggregates were composed of tubuloreticular inclusions, which were also observed in endothelial cells within the tumor vasculature. By IEM, the intermediate filaments in the tumor cell cytoplasm were decorated with GFAP. Flow cytometric results revealed a marked increase in the S-phase (48%), whereas cytogenetic analysis of short-term cultures showed an abnormal karyotype containing marker chromosomes and double minutes. In the second resection, additional karyotypic abnormalities were noted, including 1p- and several additional markers. The first and second resections showed MYCN amplification by Southern Blot analysis in the 60- to 80-fold range. CONCLUSIONS: This tumor presents unique histologic, ultrastructural, and cytogenetic findings as well as MYCN amplification that is notable for a pediatric malignant glioma. Tubuloreticular inclusions were a prominent feature in this tumor, which again is unique for a glioma.

Blotting, Southern↗
PubMed1994

Genotype-phenotype pitfalls in Gaucher disease.

Gaucher disease (GD), caused by inherited deficiency of beta-glucocerebrosidase (beta-Glc, EC 3.1.2.45), is classified type I if the CNS is not involved (non-neuronopathic), type II if CNS involvement is early and rapidly progressive (acute neuronopathic), and type III if CNS involvement occurs later and is slowly progressive (subacute neuronopathic). The clinical course is not predictable by measurement of residual beta-Glc activity. Patient classification by identification of specific mutations is more promising: homozygosity for the common A5841->G (N370S) mutation invariably predicts type I; homozygosity for the T6433->C (L444P) mutation usually indicates type III (Norbottnian). Type II disease patients often carry the T6433->C allele together with a complex allele derived in part from the downstream pseudogene by crossover or gene conversion, producing a T6433->C substitution, plus 2 or 3 additional single base substitutions (fusion gene). Employing selective PCR amplification of the structural gene, we detected homozygous T6433C (L444P) point mutations in a Caucasian boy, initially classified as having GD type I, who succumbed to severe visceral GD before age 3 years. A second novel PCR procedure for discriminating between the normal gene and the fusion gene confirmed the homozygous point mutation results. Post mortem neuropathological findings showed neuronal complex lipid accumulation consistent with late-onset type III disease. Although in Norbottnian patients it is generally accepted that onset of neurological findings is delayed, patients with the L444P/L444P genotype can only be initially classified as type III with this ancestry. Other patients described sporadically elsewhere are invariably considered type I until neurological findings arise.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1994

Cerebral and cerebellar gangliocytomas: a morphological study of nine cases.

Hypothalamic gangliocytomas have been shown to contain immunoreactivity for hypophysiotropic peptides and some have been associated with endocrine dysfunction. Extrahypothalamic gangliocytomas are usually not associated with endocrine abnormalities. We studied nine cerebral or cerebellar gangliocytomas from six men and three women; none of the patients had detectable alterations of endocrine homeostasis. On histological examination, the tumor cells resembled hypothalamic neurons. Electron microscopy disclosed the presence of dense-core vesicles in neuronal cytoplasm and processes resembling Herring bodies, and there were synaptic contacts between tumor cells. All but two tumors contained immunocytochemical positivity for at least one peptide hormone or amine; these included somatostatin, corticotropin-releasing hormone, beta-endorphin, galanin, vasoactive intestinal peptide, calcitonin, serotonin, catecholamines or met-enkephalin. These tumors have been thought to represent neoplasms arising in ectopic autonomic neural tissue. Their morphological features, their similarity to hypothalamic gangliocytomas and the multiple immunoreactivities shown here suggest that they can be regarded as tumors of peptidergic neurons that are widely distributed throughout the central nervous system.

Adolescent↗
PubMed1994

Cadmium encephalopathy: a report with elemental analysis and pathological findings.

We report a boy of East Indian origin, aged 2 years and 10 months, who died suddenly and unexpectedly. Autopsy findings showed marked cerebral swelling with herniation and histological evidence of marked cerebral edema with perivascular protein leakage, indicating blood-brain barrier disruption. Energy dispersive X-ray microprobe analysis of the brain demonstrated the presence of cadmium and a marked increase in sulfur, predominantly intracellular, both within neuroglial, and to a lesser degree endothelial, cells. Localization was predominantly in the nucleus. Analysis of the kidney showed cadmium deposition in renal tubules and in the basal lamina of podocytes within the glomerulus. Although the environmental source of cadmium remains unknown, we speculate that acute cadmium toxicity led to brain intracellular accumulation with resultant cellular dysfunction, blood-brain barrier disruption, and lethal cerebral edema.

Blood-Brain Barrier↗
PubMed1994

Benign cerebellar astrocytoma in childhood: experience at the Hospital for Sick Children 1980-1992.

Between 1 January 1980, and 31 December 1992, 66 patients with cerebellar astrocytoma were diagnosed and treated at The Hospital for Sick Children in Toronto. These patients ranged in age between 1 and 18 years, with a mean age of 7.3 years. Thirty-eight patients were male and 28 were female. Total removal was possible in 61 patients and no recurrence occurred in these 61 patients. In the 5 patients in whom an incomplete resection was carried out, regrowth occurred between 1 and 8 years following resection.

Adolescent↗
PubMed1994

Neuronal intranuclear hyaline inclusion disease with progressive cerebellar ataxia.

Neuronal intranuclear hyaline inclusion disease is a progressive, fatal neurologic condition characterized by eosinophilic inclusions in neurons of the central, autonomic, and peripheral nervous systems. The clinical and pathologic findings of a 4-year-old boy who presented with a rapidly progressive cerebellar ataxia and seizure disorder that had begun 2 years earlier are described. Although intraneuronal inclusions were identified in neurons of cortex, basal ganglia, brainstem, cerebellum, and spinal cord, clinical signs were restricted to cerebellar ataxia, internuclear ophthalmoplegia, and cognitive delay. Predominant cerebellar atrophy, early age of onset, and short clinical course distinguishes it from previously reported patients.

Atrophy↗
PubMed1994

Malignant rhabdoid tumour of the pineal region.

A 9-month-old male presented to hospital with signs and symptoms of raised intracranial pressure. A CT scan showed obstructive hydrocephalus from a large pineal region mass lesion into which an intratumoral hemorrhage had occurred. A posterior fossa craniectomy and subtotal excision of the mass lesion were performed. By histopathology, the lesion was a malignant rhabdoid tumour (MRT). Despite surgery and chemotherapy, the tumour grew inexorably, and the patient died four months after the initial diagnosis. MRT is a rare and highly invasive neoplasm which infrequently arises from the central nervous system. This is the first documented case of a MRT arising from the pineal region. The clinical, radiographic, and pathological features of the MRT in this patient are presented.

Brain Neoplasms↗
PubMed1994

The fate of Schwann cells in peripheral nerve allografts.

The phenotype of Schwann cells, whether of host or donor origin, in nerve allografts has been a source of debate. The origin of Schwann cells in peripheral nerve allografts under conditions of no, temporary or continuous immunosuppression was assessed by immunohistochemistry. We hypothesized that host-derived Schwann cells would replace rejected foreign donor Schwann cells after withdrawal of immunosuppression. A murine model of nerve transplantation to normal (wild-type) hosts from donor Shiverer mice, a mutant whose Schwann cells are deficient in myelin basic protein, was used and antibody reactivity against myelin basic protein was employed to ascertain the identity of Schwann cells in the nerve allograft. Without immunosuppression, donor Shiverer Schwann cells were rejected and the nerve graft morphology was restored by host-derived Schwann cells. With continuous immunosuppression, donor Shiverer Schwann cells persisted in the graft segment, associated with a chronic rejection phenomenon. The latter allowed migration of host-derived Schwann cells, over time, into the graft segment in approximately half the cases. After withdrawal of finite (6 weeks) immunosuppression, a rejection response eliminated donor Schwann cells. Replacement by host Schwann cells ensured as was hypothesized.

Animals↗
PubMed1994

Microglial aggregation in the dentate gyrus: a marker of mild hypoxic-ischaemic brain insult in human infants.

There are many reports in experimental animals indicating that microglia are activated in the dentate gyrus and hippocampus following hypoxic-ischaemic brain injury. The hippocampi of brains removed at autopsy from 178 children were studied retrospectively and the quantity of microglia in the polymorphous layer of the dentate gyrus was assessed. Up to the age of 8-9 months, patients with proven hypoxic or hypotensive episodes due to perinatal asphyxia, congenital heart defects, or chronic pulmonary dysfunction often had a dense infiltrate of microglial cells. A comparable microglial infiltrate was seen in most children dying under circumstances consistent with sudden infant death syndrome. Children under 9 months of age dying of other acute causes, for example trauma or sepsis either suddenly or with survival of less than 4 days in the intensive care unit, had significantly fewer microglia. After the age of 9 months a dense microglial infiltrate was never seen regardless of the cause of death. We conclude that the presence of abundant microglia in the polymorphous layer of the dentate gyrus of human infants is a marker of chronic illness or mild hypoxic-ischaemic brain injury which takes several days to develop.

Astrocytes↗
PubMed1994

Aberrant distribution of tyrosine hydroxylase and substance P in infants with brain-stem infarction.

The distribution of tyrosine hydroxylase (TH) and substance P (SP) was examined in the brain-stem of 4 infants with respiratory abnormalities associated with remote brain-stem or cerebellar infarction utilizing immunohistochemical methods. TH-immunoreactive cells and SP-immunoreactive fibers were found in and around the area of the infarction in the tegmentum, in amounts and sites different from that seen in controls. The aberrant localization of SP and TH may represent an altered repair process associated with resolution of the infarction and may be related to abnormal respiratory control or sudden death.

Brain Stem↗
PubMed1994

Neuropathology and immunohistochemistry of the brain-stem in neonates with congenital hydrocephalus: comparative studies between aqueductal stenosis and Arnold-Chiari malformation.

Neuropathological and immunohistochemical studies were done on the brain-stem of neonates who had congenital hydrocephalus with aqueductal stenosis or Arnold-Chiari malformation (ACM). The infants with aqueductal stenosis showed heterogeneity in their clinicopathological findings while the infants with ACM were relatively similar in neuropathological findings. There were prominent astrogliosis, decreased immunoreactivity with antisera to tyrosine hydroxylase and myelin basic protein in the periaqueductal area, and an increased reactivity with antiserum to substance P in the tegmentum of most patients with aqueductal stenosis and other malformations. In ACM, there was little gliosis in the tegmentum and periaqueductal area and minimal immunoreactivity of tyrosine hydroxylase, myelin basic protein and substance P. In both groups of cases, the cells in the periaqueductal region differ in neurotransmitter/neuromodulator immunoreactivity and degree of myelination reflecting a difference possibly in their maldevelopment.

Arnold-Chiari Malformation↗
PubMed1994

Fiber-type differentiation by myosin immunohistochemistry on paraffin-embedded skeletal muscle. A useful adjunct to fiber typing by the adenosine triphosphatase reaction.

The myofibrillar adenosine triphosphatase reaction has been traditionally used to delineate fiber types in skeletal muscle biopsy specimens. At a pH of 9.4, the type 2 fibers are stained and the type 1 fibers remain unstained, thus permitting a clear distinction between the two fiber types and allowing morphometric assessments of fiber size, fiber diameter, and fiber ratios. However, this histochemical reaction requires frozen muscle tissue and is not feasible in situations when only paraffin-embedded tissue is available. We describe a useful alternative to determine fiber types in skeletal muscle specimens by myosin histochemistry on formalin- or Bouin-fixed, paraffin-embedded tissue. Our experience with over 300 muscle samples from both surgical and autopsy specimens indicates that myosin immunohistochemistry also provides accurate assessments of fiber types, fiber sizes, and fiber ratios. The most significant advantage of this method is its applicability to nonfrozen material, thus permitting fiber-type distinction in situations when frozen tissue is unavailable and facilitating retrospective analysis on archival material.

Humans↗
PubMed1994

Neuroradiology of lysosomal disorders.

The role of neuroimaging in the lysosomal disorders has previously been limited to the initial evaluation and diagnosis of these disease processes and to the detection of treatable disease-related complications, such as hydrocephalus. Localization of changes to the gray or the white matter was useful in guiding the metabolic evaluation when clinical findings were indeterminate or unclear. Imaging features such as dilated VR spaces in MPS storage disease or focal calcifications in Krabbe's disease were occasionally pathognomonic for or highly suggestive of a specific disorder. Now that treatment options, including enzyme replacement therapy and bone marrow transplantation, are available for some of the neurometabolic disorders, staging before the initiation of therapy and evaluation throughout therapy are additional important roles. Even in those disease processes that are currently untreatable, imaging is useful in defining the radiographic appearance of the natural course of a given disorder, to aid in staging and treatment evaluation of future patients with that same disorder when treatment becomes available.

Brain↗
PubMed1994

Development of anaplastic changes in low-grade astrocytomas of childhood.

The authors present their experience with six children who developed anaplastic astrocytomas after receiving treatment for low-grade astrocytomas. Five children were from a series of 55 children with optic chiasmatic-hypothalamic gliomas who have been studied since 1976. The sixth child initially had a low-grade astrocytoma of the thalamus. The mean age of the children at initial presentation was 5.3 years. Five children were treated with surgery and radiation therapy; one child with a chiasmatic-hypothalamic glioma received radiation therapy alone. The amount of external radiation therapy used in all children was 50-52.5 Gy delivered in standard fractionations over approximately 6 weeks to include the volume of the original tumor plus a margin of 2 cm. The time to anaplastic transformation varied between 2 and 10 years (mean, 6.4 years). At tumor recurrence, the children had seizures or symptoms and signs of raised intracranial pressure. The location of the second tumor in all patients was either at the primary site or within the field of radiation therapy. Five of the six children underwent a second craniotomy and subtotal resection of their malignant gliomas. One child had positive cerebrospinal fluid cytology and multiple intraspinal metastatic tumor nodules detected by magnetic resonance imaging. On histopathological examination, four children had anaplastic astrocytoma, and two had glioblastoma multiforme. Four of the six children have died of their anaplastic astrocytomas (mean time from diagnosis of anaplastic astrocytoma to death, 10 months). Two children underwent chemotherapy and spinal irradiation for their anaplastic astrocytomas, and are currently alive and undergoing treatment. The possible mechanisms by which anaplastic tumors have developed in children treated previously for low-grade astrocytomas is discussed. The data suggest that radiation therapy may have played an integral role in the genesis of anaplastic astrocytomas in these children.

Astrocytoma↗
PubMed1994

Fetal nerve healing: an experimental study.

An experimental study was performed to assess fetal nerve repair and regeneration both qualitatively and quantitatively. The posterior tibial nerves in one hindlimb were transected in 16 midgestational fetal lambs and in their mothers. The nerves were then repaired with epineurial sutures and allowed to progress to 2, 4, 6, and 8 weeks postinjury. Qualitative assessment was performed through standard nerve histologic staining, including Luxol fast and toluidine blue for myelin and Bielschowsky stain for axons, and quantitative assessment through nerve conduction velocity studies and morphometry to determine mean myelinated fiber diameter, total fiber number, and density. A frequency histogram of the distribution of myelinated nerve fibers according to fiber diameter also was generated. In our model, the subsequent fetal nerve response to injury was characterized by earlier degeneration than in the adult counterparts. Repair and regeneration proceeded with dense collagenous scar formation in both groups. Electrophysiologic studies showed nerve impulse conduction across the repair site only at 6 and 8 weeks postinjury in both fetus and adult. Action potential amplitudes at 6 and 8 weeks were measured at 3 to 5 percent of control nerves in both nerve types. No electrophysiologic differences in the recovery of the injured fetal and adult nerves could be identified. Morphometry revealed that fetal nerve regeneration appeared to occur at a rate equivalent to that of the adult, although by 8 weeks the total percentage of remyelinated nerves appeared more complete in the fetus than in the adult (87 versus 59 percent), suggesting that fetal nerves may have a more favorable regenerative capacity than their adult counterparts.

Action Potentials↗
PubMed1993

Expression and distribution of peripherin protein in human neuroblastoma cell lines.

A series of human neuroblastoma (NB) cell lines was analyzed for expression of peripherin, a class-III intermediate filament protein expressed at high levels in ganglia of the peripheral nervous system. By Western blotting, peripherin protein was detected in all human NB cell lines examined. The highest level of peripherin was found in the NUB-7 cell line, previously characterized as homogeneously neuroblastic. By immunofluorescence labeling, peripherin was shown to be organized in a perinuclear filamentous pattern and, exemplified by IMR32 cells, was also shown to be localized to spontaneously formed neurites. Peripherin was expressed in neuroblastic but not substrate-adherent cells, and was found at low levels in I-type cells. There was a pronounced redistribution of peripherin to neurites formed in response to dibutyryl cyclic adenosine monophosphate (dbcAMP) and all-trans-retinoic acid (RA). In NUB-7 cells, which do not extend neurites in response to nerve growth factor, there was no change in the level of peripherin protein following treatment with this agent. Both dbcAMP and RA induced a redistribution of peripherin to neurite extensions, but only treatment with RA increased the level of the protein as demonstrated with NUB-6A4 and NUB-6C4 subclones. Peripherin was also variably expressed in peripheral neuroepithelioma (NE) cell lines tested, but was organized into a more basket-like filamentous pattern in these cells. The heterogeneous expression and distribution of peripherin in NB and NE cell lines indicate that this protein is associated with maturation of the neuronal phenotype and hence serves as a differentiation marker for tumors derived from the neural crest.

Blotting, Western↗