Herbert H. Engelhard

Developing a clinical algorithm for early management of cervical spine injury in child trauma victims

To define a subset of injured children for whom emergency cervical spine radiography may be unnecessary, we performed a retrospective chart and radiologic review. Two entry methods were used: All injured children, from birth through 16 years, who had received cervical spine radiographs at The Childrens Memorial Hospital from September 1983, to September 1984, were included. All patients from birth to 16 years with proven or suspected cases of cervical spine injury who had received cervical spine radiographs and who had been treated at either the Childrens Memorial Hospital or the Northwestern University Spine Trauma Unit during period 1974 to 1984 also were included. Each childs chart was reviewed, and 84 clinical variables were recorded. All radiographs were reviewed by a pediatric neuroradiologist. Of 206 children studied, 59 had cervical spine injuries. A clinical algorithm was derived using the following eight variables: neck pain; neck tenderness; limitation of neck mobility; history of trauma to the neck; and abnormalities of reflexes, strength, sensation, or mental status. The following decision rule was selected: Positive findings in any of these eight variables mandates cervical spine radiography. This algorithm correctly identified 58 of 59 children with cervical spine injury, yielding a sensitivity of 98% and specificity of 54%. Cervical spine radiographs could have been avoided in 79 children (38% of the entire sample). This algorithm performed better than did models derived from logistic regression analysis of the same data. Validation trials are required prior to the implementation of this or other clinical decision algorithms in practice.

Abdominal CSF pseudocyst: Clinical features and surgical management

Twenty-six cases of abdominal cerebrospinal fluid (CSF) pseudocyst have been reviewed and the clinical features identified. Typical presentation includes abdominal pain and/or distention, with nausea or vomiting. Manifest shunt malfunction is not a prominent feature. Diagnosis can usually be confirmed by abdominal ultrasound and/or CT scan. No clear predisposing factors were identified, although a prior shunt infection was found in 62% of the patients. The number of previous shunt revisions ranged from 0 to 51 (average 11.2). This revision rate is significantly higher than in other groups of patients. CSF obtained at the time of surgery was infected 36% of the time. CSF appearance and laboratory value did not reliably indicate infection as a cause of the pseudocyst. Suggested surgical management consists of a contralateral ventriculoperitoneal shunt or a ventriculoatrial shunt.

suramin inhibits glioma cell proliferation in vitro and in the brain

SummarySuramin is a novel anticancer agent that blocks the binding of growth factors, including basic fibroblast growth factor (bFGF), to their receptors. Prior studies showed human and experimental gliomas to upregulate and respond to autocrine stimulation by bFGF, the antiproliferative effects of suramin were therefore studied on glioma cell turnoverin vitro and in the brain. Suramin inhibited the growth of rat (C6,9L) and human (U-118, U-138, A-172, T98G) glioma cell lines in a dose-dependent manner. Suramin significantly reduced the bromodeoxyuridine (BUdR) labeling index of cultured glioma cells at 250 µg/ml, P < 0.0001. DNA flow cytometry revealed a significant decrease in the percentage of suramin-treated glioma cells in S-phase, P < 0.01. Using intracerebral rat C6 glioma modelin vivo, suramin, 10–60 mg/kg, i.p., produced a dose-dependent reduction of BUdR labeling in both the glioma and endothelial cell subpopulations. Suramin, 200 mg/kg i.V., however, led to intratumoral hemorrhages that reduced survival. Electron microscopy revealed membranous inclusion bodies in the cytoplasm of C6 glioma and endothelial cells, an indication of excess glycosaminoglycans. Moreover, 46% of endothelial cells within the C6 glioma tumor treated with suramin, 60 mg/kg, i.p., developed membrane blebs. Suramin, in clinically relevant doses, significantly inhibits glioma cell growth and cytokinetics. The risk of intratumoral hemorrhage, possibly related to injury of endothelial cells or the accumulation of anticoagulant glycosaminoglycans, constitutes a major side effect and caution should be exercised in consideration of clinical application for intracerebral tumors.

Inhibitory effects of phenylbutyrate on the proliferation, morphology, migration and invasiveness of malignant glioma cells

The purpose of this study was to characterize the effects of sodium 4-phenylbutyrate (phenylbutyrate) on the proliferation, morphology, migration and invasiveness of malignant glioma cells in vitro. Phenylbutyrate is a novel differentiating and cytotoxic compound used clinically with low toxicity in the treatment of β-thalassemia, sickle cell anemia and urea cycle disorders. Preliminary clinical trials testing phenylbutyrate as an anti-cancer agent have included patients with malignant glioma. However, little information is available regarding the effects of phenylbutyrate on glioma cells, particularly with respect to the expression of genes important in the pathogenesis of glial malignancy. In experiments reported here, glioma cell lines and explant cells from a tumor patient were exposed to 2, 4 and 8 mM phenylbutyrate and compared to untreated control cells. The effect on cellular proliferation was assessed using cell counts and DNA flow cytometry. Changes in morphology were evaluated using vimentin staining. Scratch and Matrigel assays were performed to assess changes in cellular migration and invasiveness. Finally, Northern blot analysis was used to study c-myc and urokinase expression. Phenylbutyrate was found to have dose-dependent inhibitory effects on glioma cell proliferation, morphology, migration, invasiveness and c-myc and urokinase expression. Mean growth-inhibitory (IC50) phenylbutyrate concentrations ranged from 0.5 mM for T98G cells to 5.0 mM for explant cells. Phenylbutyrate treatment reduced % S phase cells, increased % G0/G1 cells, and produced morphologic changes consistent with induction of differentiation. 24 hours of treatment with 4 mM phenylbutyrate resulted in a 50% reduction in migration and invasiveness. Northern blots showed a decrease in urokinase and c-myc expression at non-cytotoxic doses. We conclude that phenylbutyrate is a promising candidate compound for treating patients with malignant glioma.

Adult-onset presentation of Dandy-Walker variant in siblings

BACKGROUND The Dandy-Walker syndrome and Dandy-Walker variant usually present as isolated cases of hydrocephalus in pediatric patients. METHODS AND RESULTS THis paper consists of a case report of the adult onset of symptoms in two sisters having Dandy-Walker variant. Such an occurrence has never before been reported in the medical literature. Both patients presented with headaches and progressive neurologic deficit. On computed tomography (CT scan) of the head, both were found to have hydrocephalus, with hypoplasia of the inferior vermis. Both patients were treated successfully with ventriculoperitoneal shunting. A third sister, with a similar history, elected not to undergo CT scanning or surgical treatment. CONCLUSIONS Variants of the Dandy-Walker syndrome may occasionally present clinically in the adult age group. Such an occurrence in siblings is consistent with an underlying genetic etiology.

Paraplegia resulting from thoracolumbar stenosis in a seven-month-old achondroplastic dwarf

In young achondroplastic children, neurological manifestations have been found to include macrocephaly, hydrocephalus or ventriculomegaly and cervicomedullary compression. Occasionally in the second decade, lumbar radiculopathy or paraparesis resulting from severe thoracolumbar kyphosis develops. In this paper, we report the unique case of an achondroplastic dwarf who developed paraplegia due to thoracolumbar spinal cord compression at the age of 7 months. Compromise of the spinal canal was found to be due not to bony stenosis, but to a second layer of fibrous tissue, histologically identical to the dura. Treatment consisting of decompressive laminectomy and resection of the constricting tissue allowed the child to recover completely. Clinical, radiographic and pathological findings are discussed.

Analysis of CerbB2 protein content of human glioma cells and tumor tissue

SummaryThis study was designed to determine whether or not overexpression of the cerbB2 protein plays a role in the etiology of human gliomas. The cerbB2 gene codes for a 185 kDa cell membrane glycoprotein (gpl85cerbB2), which is similar to the receptor for epidermal growth factor. In initial studies, four human glioma cell lines (A-172, U118MG, U138MG and SW608) were used to develop techniques for detecting and quantifying gpl85cerbB2, using immunofluorescence microscopy, immunoblot analysis and flow cytometry. A-172 cells were found to have the highest content of gpl85cerbB2. More detailed studies utilizing A-172 cells indicated that cellular gpl85cerbB2 content changed little in response to conditions affecting cellular proliferative status, including serum deprivation, growth in low glucose medium and treatment with dimethyl sulfoxide. Ten human glioma specimens were then analyzed for cellular gpl85cerbB2 fluorescence and DNA content, using A-172 cells as a biological standard. Results indicated that gpl85cerbB2 was expressed at levels comparable to that of A-172 cells in many specimens, and at a very high level in one specimen. These data reiterate the problem of themolecular heterogeneity of human gliomas and indicate that gpl85cerbB2 may have a role in at least asubset of malignant glial tumors.

Angiosuppressive and Antiproliferative Actions of Suramin: A Growth Factor Antagonist

Suramin is a novel anticancer agent1 that appears to be effective against advanced adrenocortical carcinoma2,3, prostatic cancer4,5, ovarian cancer6, renal cell carcinome and certain refractory lymphomas8. The antiproliferative action is possibly related to the ability of suramin to block the binding of autocrine growth factors to their receptors9-18, to inhibit a variety of cytoplasmic and intranuclear enzymes critical for cell maintenance and proliferation19,20, and to disrupt cellular respiration and energy balance21. Cell migration and adhesion of B16 melanoma cells to the extracellular matrix is inhibited following suramin exposure 22,23 suggesting a mechanism for suramin to inhibit tumor invasion.