Biomedical subjects
Publications and source records attributed to A W Bollen.
Explore the source record for details and available documents.
We analyzed 72 primary and 25 recurrent glioblastoma multiforme (GBM) samples for DNA sequence copy number abnormalities (CNAs) by comparative genomic hybridization (CGH). The number of aberrations per tumor ranged from 2 to 23 in primary GBM and 5 to 25 in recurrent GBM. There were 26 chromosome regions with CNAs in more than 20% of tumors. 7q22-36 was the most common gain and 10q25-26 was the most common loss; each occurred in more than 70% of tumors. Of 27 amplification sites, epidermal growth factor receptor (EGFR) was the most common; it was observed in 25% of primary GBMs. Statistical analysis based on pairwise correlation of CNAs indicated that there is more than one class of primary GBM.
The stroke-prone spontaneously hypertensive rat (SHRSP) is a genetically determined model of "salt-sensitive" stroke and hypertension whose full phenotypic expression is said to require a diet high in Na+ and low in K+. We tested the hypothesis that dietary Cl- determines the phenotypic expression of the SHRSP. In the SHRSP fed a normal NaCl diet, supplementing dietary K+ with KCl exacerbated hypertension, whereas supplementing either KHCO3 or potassium citrate (KB/C) attenuated hypertension, when blood pressure (BP) was measured radiotelemetrically, directly and continually. Supplemental KCl, but not KB/C, induced strokes, which occurred in all and only those rats in the highest quartiles of both BP and plasma renin activity (PRA). PRA was higher with KCl than with KB/C. These observations demonstrate that with respect to both severity of hypertension and frequency of stroke the phenotypic expression of the SHRSP is (i) either increased or decreased, depending on whether the anionic component of the potassium salt supplemented is, or is not, Cl-; (ii) increased by supplementing Cl- without supplementing Na+, and despite supplementing K+; and hence (iii) both selectively Cl--sensitive and Cl--determined. The observations suggest that in the SHRSP selectively supplemented with Cl- the likelihood of stroke depends on the extent to which both BP and PRA increase.
Apoptosis is thought to be important in the pathogenesis of cerebral ischemia. The mechanism of apoptosis induction remains unclear but several studies suggest that it is preferentially triggered by mild/moderate microcirculatory disturbances. We examined in cats whether induction of apoptosis after 2.5 h of unilateral middle cerebral artery occlusion plus 10 h of reperfusion is influenced by the degree of cerebral microcirculatory disturbance. Quantitative monitoring over time of the disturbances of cerebral microcirculation in ischemic brain areas and evaluation of cytotoxic edema associated with perfusion deficits was achieved by using two noninvasive magnetic resonance imaging techniques: (a) high-speed echo planar imaging combined with a bolus of magnetic susceptibility contrast agent; and (b) diffusion-weighted imaging. Apoptosis-positive cells were counted in anatomic areas with different severity of ischemic injury characterized by magnetic resonance imaging, triphenyltetrazolium chloride, and hemotoxylin and eosin staining. The number of apoptosis-positive cells was significantly higher in anatomic areas with severe perfusion deficits during occlusion and detectable histologic changes 10 h after reperfusion. In contrast, in areas where perfusion was reduced but maintained during occlusion there were no detectable histological changes and significantly fewer apoptosis-positive cells. A similar number of cells that undergo apoptosis were shown in regions with transient or prolonged subtotal perfusion deficits. These results suggest that the apoptotic process is induced in the ischemic core and contributes significantly in the degeneration of neurons associated with transient ischemia.
We report 18 patients who presented prior to age 20 years with epilepsy or fixed neurologic deficits. MRI showed signal abnormality extending from the cortex to the superolateral wall of the lateral ventricle. Histology showed cortical disorganization, neuronal cytomegaly, balloon cells, indistinct cortical gray matter-white matter junctions, and variable accompanying astrogliosis. We propose that this transmantle dysplasia is a specific anomaly resulting from abnormal stem cell development.
BACKGROUND: The authors previously described an in vivo model suitable for investigation of functional impairment induced by intrathecally injected local anesthetic. However, meaningful histologic analysis could not be performed because catheterization, per se, induced morphologic changes in control animals. In the current experiments, the authors sought to identify an alternative, less reactive, catheterization technique for intrathecal drug administration. METHODS: Twenty-five rats received an intrathecal infusion of normal saline through a catheter composed of either 28-gauge polyurethane, 32-gauge polyimide, 32-gauge polyurethane, PE-10 polyethylene, or PE-10 polyethylene that had been stretched to twice its original length. Seven days after infusion, sensory function was assessed using the tail-flick test, and the spinal cord and nerve roots were prepared for neuropathologic evaluation. RESULTS: There was no significant difference in sensory function among groups. Animals in which 28-gauge polyurethane, 32-gauge polyimide, PE-10, and double-stretched PE-10 had been implanted had moderate to severe nerve injury in 11%, 14%, 23%, and 8% of fascicles, respectively, whereas none of the animals in which 32-gauge polyurethane was implanted had any evidence of moderate or severe damage. CONCLUSIONS: Morphologic changes induced by intrathecal catheterization in the rat can be minimized by the use of 32-gauge polyurethane tubing.
To investigate whether local anesthetic neurotoxicity results from sodium channel blockade, we compared the effects of intrathecally administered lidocaine, bupivacaine, and tetrodotoxin (TTX), the latter a highly selective sodium channel blocker, on sensory function and spinal cord morphology in a rat model. First, to determine relative anesthetic potency, 25 rats implanted with intrathecal catheters were subjected to infusions of lidocaine (n = 8), bupivacaine (n = 8), or TTX (n = 9). The three drugs produced parallel dose-effect curves that differed significantly from one another: the EC50 values for lidocaine, bupivacaine, and TTX were 28.2 mM (0.66%), 6.6 mM (0.19%), and 462 nM, respectively. Twenty-five additional rats were then given intrathecal lidocaine (n = 8), bupivacaine (n = 8), or TTX (n = 9) at concentrations 10 times the calculated EC50 for sensory block. Lidocaine and bupivacaine induced persistent sensory impairment, whereas TTX did not. Finally, 28 rats were given either intrathecal bupivacaine (n = 10) or TTX (n = 9) at 10 times the EC50, or normal saline (n = 9). Significant sensory impairment again occurred after infusion of bupivacaine, but not after infusion of TTX or saline. Neuropathologic evaluation revealed moderate to severe nerve root injury in bupivacaine-treated animals; histologic changes in TTX- and saline-treated animals were minimal, similar, and restricted to the area adjacent to the catheter. These results indicate that local anesthetic neurotoxicity does not result from blockade of the sodium channel, and suggest that development of a safer anesthetic is a realistic goal.
The development of sarcoma subsequent to cranial irradiation is a rare but serious and potentially fatal event. We describe seven patients who had undergone cranial irradiation (range, 1600-6000 cGy) to treat their primary disease and who developed sarcomas within the irradiated field. The median time from radiation therapy to the development of a sarcoma was 8 years (range, 4 to 15 yr). Fibrosarcomas developed in four patients, and malignant fibrous histiocytomas developed in three. Despite aggressive treatment, the prognosis was poor; the median survival from the diagnosis of sarcoma was 19 months. Sarcoma should be considered in the differential diagnosis of a new lesion or a lesion that progresses several years after radiation therapy.
This is the first report of a series of adults (> 16 years of age) with pineoblastomas who had their entire neuraxis staged at the time of diagnosis. Between 1975 and 1992, seven men and four women with histologically proven pineoblastomas were evaluated at the University of California, San Francisco. The median age at diagnosis was 36 years (range, 17-59 yr). All patients presented with symptomatic hydrocephalus. One patient had a complete surgical resection, eight had subtotal resections, and two had biopsies only. One patient refused any treatment or follow-up review and died 6 months after diagnosis. The five patients with positively staged disease had progression either focally or in the spine 8 to 49 months (median, 10 mo) after initial diagnosis and died 1 to 20 months after recurrence; the median overall survival time from the date of surgery was 30 months. In contrast, all five patients with negatively staged disease were alive without disease progression after a median of 26 months of follow-up. Our retrospective review shows that the extent of disease at diagnosis seems to be an important prognostic factor for pineoblastomas, as is true for medulloblastomas and other primitive neuroectodermal tumors. Initial staging should include examination of the cerebrospinal fluid and magnetic resonance imaging of the spine. Although patients with pineoblastomas are often treated with adjuvant systemic chemotherapy after craniospinal irradiation, the benefits of this approach are unclear.
BACKGROUND: Several cases of cauda equina syndrome after continuous spinal anesthesia have been recently reported. One possible etiology is toxic exposure of the sacral roots resulting from intrathecal maldistribution of a relatively large dose of local anesthetic. The current experiments sought to determine whether a local anesthetic solution, injected intrathecally to produce a restricted distribution of anesthesia, could result in a sacral deficit. In addition, we sought to test the hypothesis that, when equal volumes are administered intrathecally, significant differences exist in the potential to three commonly used anesthetic solutions to induce sensory impairment. METHODS: Thirty-two rats were implanted with intrathecal catheters to permit repetitive infusion of local anesthetic. Animals were randomly assigned to four groups of eight to receive either 5% lidocaine with 7.5% dextrose; 0.75% bupivacaine with 8.25% dextrose; 0.5% tetracaine with 5% dextrose; or normal saline. Each rat received, in sequence, a 1-h (60 microliters), a 2-h (120 microliters), and a 4-h (240 microliters) infusion; the infusions were separated by a 4-day rest period. Sensory function was assessed using the tail-flick test, which was performed immediately before each infusion and 6 days after the last infusion by an investigator blinded to the solution infused. RESULTS: There was no significant difference in baseline tail-flick latencies for the four groups. Tail-flick latency for the lidocaine group was significantly prolonged when compared with the bupivacaine, tetracaine, and saline groups. This difference was apparent after the first infusion and persisted throughout the study. CONCLUSIONS: In the rat, restricted anesthetic distribution can be achieved, and sensory impairment may result. These findings further support an etiology of local anesthetic neurotoxicity for recent clinical injuries after continuous spinal anesthesia. The functional model described appears to be suitable for in vivo study of local anesthetic neurotoxicity.
BACKGROUND AND OBJECTIVES: Glucose is a common component of anesthetic solutions used for spinal anesthesia. However, its possible contribution to recent injuries occurring with spinal anesthesia has not been adequately addressed. Accordingly, the present studies compare the functional and morphologic effects of intrathecally administered glucose with those of lidocaine. METHODS: Twenty rats, implanted with intrathecal catheters, were divided into three groups to receive a 1-hour infusion of 5% lidocaine (n = 6), 10% glucose (n = 7), or normal saline (n = 7). Four days after infusion, animals were evaluated for persistent sensory impairment using the tail-flick test. Three days later, the animals were sacrificed, and the spinal cord and nerve roots were examined by a neuropathologist blinded to the solution received and the results of sensory testing. RESULTS: Lidocaine-treated animals exhibited persistent sensory impairment, whereas glucose- and saline-treated animals did not. Neuropathologic evaluation revealed moderate to severe nerve root injury in lidocaine-treated animals. Histologic changes in glucose- and saline-treated animals were minimal, similar, and restricted to the area adjacent to the catheter. Morphologic damage associated with lidocaine preferentially affected the nerve roots, with relative sparing of the spinal cord and dorsal root ganglia. CONCLUSIONS: These results suggest that, at clinically relevant concentrations, glucose does not induce neurologic injury, providing indirect evidence that recent clinical injuries occurring after spinal anesthesia resulted from a neurotoxic effect of the local anesthetic. Additionally, the present studies suggest that deficits resulting from neurotoxicity of intrathecally administered anesthetic result from injury to the axon.
This report describes the results of CT-guided stereotactic brain biopsies performed on 50 consecutive dogs using a modified Pelorus Mark III Stereotactic System. Based on available histopathologic samples (stereotactic biopsy [n = 50], surgery [n = 17], necropsy [n = 9]) the patient population consisted of 34 dogs with primary brain tumors, 2 with invasive nasal adenocarcinomas, and 13 with non-neoplastic brain lesions. Brain tissue was not obtained from one dog. In 22 dogs a final diagnosis was made from tissue subsequently obtained from surgical resection or at necropsy. The final diagnosis was in agreement with the stereotactic biopsy diagnosis in 20 of these 22 dogs. In 17 other dogs without follow-up, stereotactic biopsy provided a diagnosis of a specific primary brain tumor subtype. Postoperative complications associated with the biopsy procedure were assessed in 41 dogs. The other 9 dogs either went directly to surgery (n = 7) or were killed (n = 2) immediately after the biopsy procedure. Thirty-six dogs recovered without apparent clinical complications. Postoperative clinical complications in the remaining 5 dogs included transient epistaxis (1 dog), transient exacerbation of cerebellar signs (1 dog), obtundation progressing to coma (1 dog), and medically uncontrollable seizures (2 dogs). The latter 3 dogs with severe neurologic complications all had large primary brain tumors and had been receiving high doses of phenobarbital and glucocorticoids to control seizures at the time of biopsy. These results suggest that this CT-guided biopsy procedure can provide an accurate pathologic diagnosis of brain lesions detected by CT and MR neuroimaging. Further refinement of both technique and case selection is expected to reduce the rate of clinical complications and to improve the accuracy of the procedure.
Matrigel, an extracellular matrix material, has been used to promote growth of experimental tumors. SF-767, a human glioblastoma cell line, is used in brain tumor research. We investigated Matrigel induced changes in tumor latency, growth rate, cell yield, plating efficiency, and histology of SF-767 tumors in athymic mice. Low volume (0.1 ml) Matrigel did not increase growth rate in comparison with control tumors but appeared to promote uniformity in growth. High volume (0.5 ml) Matrigel increased the initial rate of tumor growth, increased cell yield and produced tumors with a centralized area of residual Matrigel and necrotic cells, with viable cells on the periphery of the mass. On average, tumors grown with Matrigel had shorter latency periods and lower plating efficiencies. We conclude that important characteristics of the SF-767 tumor model, which may be important when evaluating efficacy of anticancer agents, are altered by Matrigel.
UNLABELLED: BACKGROUND-MATERIALS-METHODS: We initiated the studies reported in this paper to establish baseline growth data for tumors produced by several human brain tumor cell lines. Female athymic mice were injected with five established human glioblastoma cell lines subcutaneously. We optimized implantation conditions in SF-767 cells by evaluating tumor take and growth characteristics, and resulting growth data were compared to 2 other cell lines. RESULTS-CONCLUSIONS: Three (SF-767, U-251 MG-NCI, and U-87 MG) of the 5 cell lines produced solid, ellipsoid tumors. For SF-767 cells, the best tumor growth parameters were achieved when 3.0 x 10(6) cells in 0.1 ml medium containing fetal calf serum were injected unilaterally. These conditions produced a high percentage of usable tumors (77.6%) that were detectable approximately 3 days after implantation and reached a size of 100 mm3 in 23 days. Comparison of several growth characteristics of the tumors produced by the 3 cell lines revealed that SF-767 tumors displayed the most uniform growth rates, the fastest doubling times, and the most uniform usable group of tumors (> 100 mm3). U-87 MG and U-251 MG-NCI had a similar histopathologic appearance while SF-767 had a different histology. Our results indicate that these 3 human glioblastoma cells produce flank tumors that exhibit decidedly different growth parameters. We are currently using all 3 of these human brain tumor xenograft models in other in vivo studies.