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James T. Rutka, Jackson Hall, Jane R. Giblin, Dolores V. Dougherty, Michael S. B. Edwards, Robert Stern and Mark L. Rosenblum

✓ To determine how medulloblastoma cells might influence the proliferation and phenotype of normal stromal cells, normal human leptomeningeal cells were treated in culture with medulloblastoma-conditioned medium; their ability to incorporate tritiated thymidine and synthesize collagen was measured. The treated leptomeningeal cells had a significantly greater uptake of tritiated thymidine and grew faster than control leptomeningeal cells. Immunofluorescence studies demonstrated a greater intensity of staining for procollagen type III in the cell layer of the treated cultures than in control cultures; diethylaminoethyl (DEAE)-cellulose chromatography of the medium showed that the treated cells synthesized predominantly type III collagen, whereas control cells synthesized type I collagen. Analysis of the medulloblastoma-conditioned medium revealed that the soluble factor responsible for these effects is an acid- and heat-stable protein. The increased proliferation and altered collagen synthesis induced in leptomeningeal cell cultures by a soluble factor from a medulloblastoma are examples of how tumor and stromal elements interact, and may be related to the process of desmoplasia often observed in medulloblastomas in vivo.

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James T. Rutka, Gerard Apodaca, Robert Stern and Mark Rosenblum

✓ The extracellular matrix (ECM) is the naturally occurring substrate upon which cells migrate, proliferate, and differentiate. The ECM functions as a biological adhesive that maintains the normal cytoarchitecture of different tissues and defines the key spatial relationships among dissimilar cell types. A loss of coordination and an alteration in the interactions between mesenchymal cells and epithelial cells separated by an ECM are thought to be fundamental steps in the development and progression of cancer. Although a substantial body of knowledge has been accumulated concerning the role of the ECM in most other tissues, much less is known of the structure and function of the ECM in the nervous system. Recent experiments in mammalian systems have shown that an increased knowledge of the ECM in the nervous system can lead to a better understanding of complex neurobiological processes under developmental, normal, and pathological conditions. This review focuses on the structure and function of the ECM in the peripheral and central nervous systems and on the importance of ECM macromolecules in axonal regeneration, cerebral edema, and cerebral neoplasia.

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James T. Rutka, Mark L. Rosenblum, Robert Stern, Henry J. Ralston III, Dolores Dougherty, Jane Giblin and Steve DeArmond

✓ The effect of concentrated conditioned medium from each of eight human malignant glioma cell lines on the growth of indicator cells (normal rat kidney fibroblasts (NRK), clone 14) was determined in monolayer and in soft agar assay systems. The conditioned medium from all cell lines was mitogenic in the monolayer assay, but only SF-210, U-343 MG-A, and U-251 MG produced soluble factors that caused NRK cells to grow in soft agar. The soluble growth-promoting factors from these three cell lines were acid- and heat-stable (60°C for 30 minutes) but were inactivated by trypsin (100 µm/ml) and dithiothreitol (50 µM). The growth factors from SF-210 and U-343 MG-A were further purified by molecular-sieve chromatography. The partially purified growth factor from U-343 MG-A retained transforming growth factor (TGF)-like activity, had a molecular weight of 9 kD, was potentiated by TGF-β in the soft agar assay, competed effectively with 125I-epidermal growth factor (EGF) radiolabeled for the EGF receptor on A 431 epidermoid carcinoma cells, and was completely inhibited by monoclonal antibodies to TGF-α. The partially purified growth factor from SF-210 had a molecular weight of 17 kD, was not inhibited by monoclonal antibodies to platelet-derived growth factor (PDGF) or TGF-α, and did not bind to a heparin-Sepharose column. These results imply that U-343 MG-A secretes a growth factor with TGF-α-like activity, and SF-210 secretes a TGF with neither TGF-α nor TGF-β activity.

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Fred S. C. Kim, James T. Rutka, Mark Bernstein, Lothar Resch, Ellen Warner and Dominic Pantalony

✓ Granulocytic sarcoma usually occurs in the setting of leukemia and myeloproliferative disorders. Rarely, it can occur in isolation at various anatomical sites without hematological evidence of leukemia. The unique case of an elderly man presenting with right L2–3 radiculopathy is described. Intradural granulocytic sarcoma of the L-2 and L-3 nerve roots with extradural extension was found at surgery and he was treated with incomplete resection and antileukemic chemotherapy. Local recurrence at 3 months was treated with irradiation. Granulocytic sarcoma is frequently misdiagnosed and invariably progresses to acute leukemia. The chloroacetic acid esterase, granulocytic immunohistochemical markers, and electron microscopy appearance can aid in diagnosis. The prognosis is improved with initial aggressive antileukemic chemotherapy and local irradiation.

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William P. Vandertop, Akio Asai, Harold J. Hoffman, James M. Drake, Robin P. Humphreys, James T. Rutka and Laurence E. Becker

✓ Between January, 1981, and July, 1991, 17 infants under 1 month of age were admitted to The Hospital for Sick Children with the signs and symptoms of a Chiari II malformation. These patients' presentation included swallowing difficulty (71%), stridor (59%), apneic spells (29%), aspiration (12%), weakness of cry (18%), and arm weakness (53%). Decompression of the Chiari II malformation was performed in all patients, with a time interval between onset of symptoms and surgery ranging from 1 to 121 days. Fifteen patients (88%) remain alive, all of whom have shown a complete recovery. The mean follow-up period in this group of patients was 65 months. Two patients died, one due to respiratory arrest 8 months after decompression and the other because of shunt infection and peritonitis 7 years after decompression. These results support the concept that compressive forces, rather than a primary intrinsic disorder of the brain-stem nuclei, play a crucial etiological role in the development of a symptomatic Chiari II malformation. Early recognition of the symptoms of Chiari II malformation should be followed by immediate decompressive laminectomy in order to promote a prompt and full neurological recovery.

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Paul D. Chumas, Derek C. Armstrong, James M. Drake, Abhaya V. Kulkarni, Harold J. Hoffman, Robin P. Humphreys, James T. Rutka and E. Bruce Hendrick

✓ Although the development of tonsillar herniation (acquired Chiari malformation) in association with lumboperitoneal (LP) shunting is well recognized, it has previously been considered rare. In order to ascertain the incidence of this complication after LP shunting, the authors undertook a retrospective study of all patients in whom this form of shunt had been inserted between 1974 and 1991 at The Hospital for Sick Children, Toronto. In the 143 patients, the mean age at insertion was 3.3 years and the indications for shunt placement were hydrocephalus (81%), pseudotumor cerebri (7%), cerebrospinal fluid fistula (6%), and posterior fossa pseudomeningocele (6%). The mean follow-up period was 5.7 years, during which time there was one shunt-related death due to unsuspected tonsillar herniation. Five other patients developed symptomatic tonsillar herniation treated by suboccipital decompression.

Review of all computerized tomography (CT) scans not degraded by artifact showed evidence of excess soft tissue at the level of the foramen magnum in 38 (70%) of 54 patients so studied. In order to confirm that this CT finding represented hindbrain herniation, sagittal and axial magnetic resonance (MR) images were obtained for 17 asymptomatic patients and revealed tonsillar herniation (range 2 to 21 mm) in 12 (70.6%). In addition, some of these asymptomatic patients had evidence of uncal herniation and mesencephalic distortion. Similarities and distinctions are drawn between the morphological changes occurring after LP shunting and those seen in association with the Chiari I and II malformations. Although less than 5% of this study population required treatment for tonsillar herniation, the incidence of this complication was high in asymptomatic patients; MR imaging surveillance for patients with LP shunts is therefore recommended.

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James T. Rutka, Masaji Murakami, Peter B. Dirks, Sherri Lynn Hubbard, Laurence E. Becker, Kozo Fukuyama, Shin Jung and Kazuhito Matsuzawa

In the adult human brain, normal astrocytes constitute nearly 40% of the total central nervous system (CNS) cell population and may assume a star-shaped configuration resembling epithelial cells insofar as the astrocytes remain intimately associated, through their cytoplasmic extensions, with the basement membrane of the capillary endothelial cells and the basal lamina of the glial limitans externa. Although their exact function remains unknown, in the past, astrocytes were thought to subserve an important supportive role for neurons, providing a favorable ionic environment, modulating extracellular levels of neurotransmitters, and serving as spacers that organize neurons. In immunohistochemical preparations, normal, reactive, and neoplastic astrocytes may be positively identified and distinguished from other CNS cell types by the expression of the astrocyte-specific intermediate filament glial fibrillary acidic protein (GFAP). This GFAP is a 50-kD intracytoplasmic filamentous protein that constitutes a portion of, and is specific for, the cytoskeleton of the astrocyte. This protein has proved to be the most specific marker for cells of astrocytic origin under normal and pathological conditions. Interestingly, with increasing astrocytic malignancy, there is progressive loss of GFAP production. As the human gene for GFAP has now been cloned and sequenced, this review begins with a summary of the molecular biology of GFAP including the proven utility of the GFAP promoter in targeting genes of interest to the CNS in transgenic animals. Based on the data provided the authors argue cogently for an expanded role of GFAP in complex cellular events such as cytoskeletal reorganization, maintenance of myelination, cell adhesion, and signaling pathways. As such, GFAP may not represent a mere mechanical integrator of cellular space, as has been previously thought. Rather, GFAP may provide docking sites for important kinases that recognize key cellular substrates that enable GFAP to form a dynamic continuum with microfilaments, integrin receptors, and the extracellular matrix.

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James T. Rutka, Masaji Murakami, Peter B. Dirks, Sherri Lynn Hubbard, Laurence E. Becker, Kozo Fukuyama, Shin Jung, Atsushi Tsugu and Kazuhito Matsuzawa

✓ In the adult human brain, normal astrocytes constitute nearly 40% of the total central nervous system (CNS) cell population and may assume a star-shaped configuration resembling epithelial cells insofar as the astrocytes remain intimately associated, through their cytoplasmic extensions, with the basement membrane of the capillary endothelial cells and the basal lamina of the glial limitans externa. Although their exact function remains unknown, in the past, astrocytes were thought to subserve an important supportive role for neurons, providing a favorable ionic environment, modulating extracellular levels of neurotransmitters, and serving as spacers that organize neurons. In immunohistochemical preparations, normal, reactive, and neoplastic astrocytes may be positively identified and distinguished from other CNS cell types by the expression of the astrocyte-specific intermediate filament glial fibrillary acidic protein (GFAP). Glial fibrillary acidic protein is a 50-kD intracytoplasmic filamentous protein that constitutes a portion of, and is specific for, the cytoskeleton of the astrocyte. This protein has proved to be the most specific marker for cells of astrocytic origin under normal and pathological conditions. Interestingly, with increasing astrocytic malignancy, there is progressive loss of GFAP production. As the human gene for GFAP has now been cloned and sequenced, this review begins with a summary of the molecular biology of GFAP including the proven utility of the GFAP promoter in targeting genes of interest to the CNS in transgenic animals. Based on the data provided the authors argue cogently for an expanded role of GFAP in complex cellular events such as cytoskeletal reorganization, maintenance of myelination, cell adhesion, and signaling pathways. As such, GFAP may not represent a mere mechanical integrator of cellular space, as has been previously thought. Rather, GFAP may provide docking sites for important kinases that recognize key cellular substrates that enable GFAP to form a dynamic continuum with microfilaments, integrin receptors, and the extracellular matrix.

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Eelco Hoving, Susan Blaser, Edmond Kelly and James T. Rutka

✓ The case of a neonate with a large vertex cephalocele is presented. The anatomical features of this anomaly were evaluated by means of magnetic resonance imaging and magnetic resonance angiography. Fusion of the thalami, dysgenesis of the corpus callosum, and failure of adequate formation of the interhemispheric fissure were characteristics of the major cerebral anomalies associated with the cephalocele. The absence of a falx in the midline, a split configuration of the superior sagittal sinus, and a dysgenetic tentorium with a concomitant abnormal venous drainage pattern were found in association with a large dorsal cyst. Repair of the anomaly was undertaken on the 3rd postnatal day. A cerebrospinal fluid shunt was required to treat hydrocephalus on Day 30. The child is well at age 3 years, but with significant developmental delay. The pathogenesis of this vertex cephalocele relates to semilobar holoprosencephaly and dorsal cyst formation. In addition, a disturbance in the separation of the diencephalic portion of the neural tube from the surface ectoderm or skin during the final phases of neurulation had occurred to help create the large cephalocele. Detailed preoperative imaging studies and awareness of the embryology and anatomy of this lesion facilitated the repair of the cephalocele. The prognosis of the child is determined not only by the presence of hydrocephalus, but also by the number of associated major cerebral anomalies. Options for treatment are discussed.

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Lynn M. Myles, Nalin Gupta, Derek Armstrong and James T. Rutka

✓ Symptomatic arachnoid cysts of the spine are uncommon in children and have only rarely been reported to occur extradurally. The authors report a case of multiple extradural spinal arachnoid cysts in a 9-year-old child who presented with signs of spinal cord compression. The extent of the disease, which affected the thoracic, lumbar, and sacral spine, and the number of independent cysts make this case unique and suggest an underlying defect in the dura of the spinal canal that is predisposed to the formation of cysts. The investigations of choice, surgical planning, and surgical technique are considered. The literature is reviewed and mechanisms of cyst formation discussed.