Intravenous RMP-7 increases delivery of ganciclovir into rat brain tumors and enhances the effects of herpes simplex virus thymidine kinase gene therapy.

Herpes simplex virus thymidine kinase (HSV-tk) gene therapy for brain tumors depends on ganciclovir (GCV) and its transport across the blood-brain tumor barrier (BBTB). We examined whether RMP-7, the bradykinin analog and potent BBTB permeabilizer, could enhance the efficacy of GCV treatment of brain tumors by increasing the BBTB delivery of GCV. In vitro, a significant bystander cytocidal effect of GCV was shown in mixed HSV-tk-transduced (HSV-tk+) and control vector-transduced (HSV-tk-) C6 glioma cultures. A dose-dependent cytotoxic effect of GCV on untransformed C6 cells was also shown. In vivo, rats with 100% HSV-tk+ or 100% HSV-tk- intracerebral C6 gliomas were treated for 7 days with intravenous infusions of GCV alone or with GCV and RMP-7 (2.5 microg/kg/day). The growth of HSV-tk+ and HSV-tk- gliomas decreased with increasing doses of GCV. A high dosage (100 mg of GCV/kg/day) eradicated all HSV-tk- and HSV-tk+ tumors. An intermediate dosage (5 mg of GCV/kg/day) reduced the growth of HSV-tk- gliomas by 42% if given alone, and by 88% in combination with RMP-7. A low dosage (0.5 mg of GCV/kg/day) in combination with RMP-7 enhanced the regression of HSV-tk+ gliomas by 87% compared with GCV alone. Low-dose GCV was ineffective in HSV-tk- tumors. RMP-7 increased [3H] GCV tumoral uptake by 2.6- and 1.7-fold in the tumor center and periphery, respectively. We conclude that RMP-7 could be an important adjunctive treatment for suicide gene therapy of brain tumors, while an RMP-7/GCV combination may also have a significant antitumor effect in untransfected gliomas.

Experience with use of extended length peritoneal shunt catheters.

The placement of a ventriculoperitoneal (VP) shunt is the current treatment of choice for diversion of cerebrospinal fluid associated with hydrocephalus. Although there are a host of reported potential abdominal complications related to the procedure, they are notably uncommon. The authors report their experience with the primary insertion of an extended length open-ended peritoneal tubing (120 cm) undertaken expressly to avoid the need for a lengthening procedure because of growth of the patient. In a review of new insertions of VP shunts using the extended length tubing over a 14-year period at Childrens Hospital of Los Angeles, a total 998 shunts were placed in 952 patients, with a mean follow-up period of 6.7 years. The patients experienced a total of 52 distal shunt revisions for a variety of malfunction etiologies. In patients ranging in age from premature neonate to 20 years, there was no increase in the distal complication rate, and specifically no complications were experienced that were directly related to the use of the extended length tubing. The authors conclude that the use of an extended length peritoneal shunt catheter is not associated with an increase in complications and eliminates the need to lengthen the peritoneal catheter for growth of the patient.

Neurological protection by dichloroacetate depending on the severity of injury in the paraplegic rat.

Hyperglycemia has been shown to exacerbate neurological deficit associated with central nervous system ischemia. Iodoacetate or dichloroacetate was administered intraperitoneally to rats in a study to examine the role of glycolysis in hyperglycemic exacerbation of neurological deficit. Sprague-Dawley rats were injected with saline, iodoacetate, or dichloroacetate and then made paraplegic by temporary occlusion for 10, 12, 13, or 15 minutes of the right and left subclavian arteries and the aorta distal to the left subclavian artery. Glycolytic blockage by iodoacetate was lethal in doses of 15 mg/kg or more, whereas rats receiving 10 mg/kg survived but showed no significant neurological improvement compared to the saline-treated control group. Dichloroacetate, 500 mg/kg, protected neurological function, which suggests a possible detrimental role for lactate accumulation and the benefit of maintaining tricarboxylic acid cycle activity by stimulating pyruvate dehydrogenase. The protection seen with dichloroacetate depended on the severity of ischemic injury. Dichloroacetate administration had a minimal effect on neurological outcome with occlusion periods of 13 and 15 minutes, mild improvement with 12 minutes of occlusion, and a significant protective effect with a 10-minute occlusion period. The dose-response nature of ischemic injury and neurological outcome in this rat model of paraplegia therefore appears to play an important role in determining the effect observed with a specific intervention.

The role of glucose uptake and metabolism in hyperglycemic exacerbation of neurological deficit in the paraplegic rat.

Previous studies indicate that hyperglycemia, particularly that induced by exogenous glucose administration, exacerbates neurological deficits in the rat spinal cord ischemic model. The effect of inhibition of glucose uptake (glucose transporter) and initial metabolism (hexokinase) on neurological outcome was evaluated in the present investigation using the competitive inhibitors 2-deoxyglucose (2-DG) and 3-O-methylglucose (3-OMG). Sprague-Dawley rats, weighing 200 to 300 gm each, received either 0.25, 1, or 2 gm/kg 2-DG; 2 gm/kg 3-OMG; 2 gm/kg glucose; or an equivalent volume of 0.9% saline intraperitoneally. Rats were intubated and ventilated with 1% to 1.5% halothane. The aortic arch was exposed and snares were placed on the right and left subclavian arteries and the aorta distal to the left subclavian artery. The three vessels were occluded for 10, 11, 12, or 13 minutes. Lower-extremity neurological deficits were evaluated at 1, 4, 18, and 24 hours postocclusion based on a 15-point scale (normal = 0, severe deficit = 15). Lower-extremity neurological deficits were significantly less severe in the groups treated with 2-DG (0.25 and 1 gm/kg) at 18 and 24 hours postocclusion (p less than 0.05 for 0.25 gm/kg and p less than 0.005 for 1 gm/kg, Student's t-test with Bonferroni correction). The lower 2-DG dose of 0.25 gm/kg did not significantly increase the plasma glucose level, suggesting that the glucose transporter was not markedly inhibited, and that the improved neurological outcome was more likely due to inhibition of hexokinase. The higher 2-DG dose of 1 gm/kg afforded protection despite significantly increasing the plasma glucose level, implying a strong inhibition of both the glucose transporter and hexokinase. Administration of 3-OMG, which only inhibits glucose uptake and not hexokinase, actually worsened the neurological deficit in a manner similar to that observed in rats treated with glucose. The authors conclude that the activity of the glucose transporter by itself does not significantly contribute to hyperglycemic exacerbation of neurological deficits. In contrast, the hexokinase step, at least in combination with the transporter and possibly alone, plays a significant role in hyperglycemic exacerbation of the lower-extremity neurological deficit in the paraplegic rat.

Hypervascular acoustic neuroma.

The authors present a patient with a large acoustic neuroma that exhibited an unusual vascular architecture. Magnetic resonance imaging demonstrated multiple flow voids in and around the mass. At surgery, intra- and extratumoral vascularity was arterialized due to luxurious shunting. Two attempts at removal produced severe engorgement and pulsatility of the surrounding brain, dramatically narrowing the operative exposure. Piecemeal resection of the tumor seemed to redistribute blood flow resulting in engorgement of the surrounding brain, analogous to perfusion breakthrough following AVM resection. Treatment strategies similar to those used for AVM resection may be indicated when encountering a hypervascular tumor.

High resolution magnetic resonance imaging of the rat spinal cord.

A two turn saddle shaped surface coil receiver was developed that allowed high resolution magnetic resonance imaging of the rat spinal cord. This is particularly important in laboratory animals where central nervous system regions of interest are relatively small. A continuous copper wire 1.5 mm in diameter was wound into two turns 28 mm in diameter. The saddle shape of the second turn improved the homogeneity of the signal within the region of interest and maintained sufficient field of view and depth of penetration. The quality factor (Q) for the surface coil was Q = 199 unloaded, and Q = 60 loaded. Using this surface coil with a GE CSI II 2.0 Tesla small bore magnet, spin echo T1 (TR = 500 msec, TE = 25 msec) and T2 (TR = 2000 msec, TE = 100 msec) weighted images were obtained in cross section, using 2 mm slice thickness with 2 excitations per phase encoding step. A sagittal gradient echo (rapid scan, TR = 85 msec, TE = 10 msec) was used to document reestablishment of vascular flow following ischemia. Spinal cord ischemia was induced by 14 minute temporary occlusion of spinal cord blood supply. MRI was performed at 18 hours following ischemia. There was a 1.4 fold increase in T2 image intensity in ischemic rat spinal cord (n = 4), consistent with edema formation, compared to normal rat spinal cord (n = 4). Preliminary studies show that similar high resolution images can be performed on the rat brain. This technique uses standard MRI equipment and the surface coil is made from inexpensive readily available materials. There are various animal models of cerebral and spinal cord injury that would benefit from improved high resolution MRI. This coil design may have application in larger animal models and the clinical setting.

Malignant transformation of recurrent meningioma with pulmonary metastases.

A patient presented with a histologically benign intracranial meningioma which, after multiple recurrences, underwent malignant transformation. The patient survived 18 years following initial presentation. Pulmonary metastases were present over the final 8 years. Eleven subtotal resections of the meningioma were performed, including exenteration of the right eye and a thoracotomy. Radiation therapy and chemotherapy were relatively ineffective. The problem and treatment of recurrent meningiomas is briefly reviewed.

Chondromyxoid fibroma of the temporal bone.

BACKGROUND: Chondromyxoid fibromas are benign neoplasms comprising approximately 0.5% of primary bone tumors. The occurrence of this tumor in the skull is extremely rare, with only four previously reported cases involving the temporal bone and a total of 17 cases with intracranial involvement. CASE DESCRIPTION: We describe the case of a 22-year-old man who experienced a 1-year history of headaches with progressive ear pain and mild hearing loss. Computed tomography and magnetic resonance imaging of the head demonstrated an extraaxial tumor arising from the left temporal mastoid region. A craniotomy was performed and the tumor resection required extensive drilling of the temporal bone. Grossly, the tumor consisted of a firm semigelatinous myxomatous tissue containing multiple areas of calcification and was histologically consistent with chondromyxoid fibroma. CONCLUSIONS: Complete resection is the goal of surgery. Recurrence rates of 7% to 27% have been reported, dependent on the degree of initial resection. Radiation is not recommended because of the potential for sarcomatous conversion. Reoperation may be indicated for symptomatic recurrence.

Insulin administration protects from paraplegia in the rat aortic occlusion model.

The effect of insulin induced hypoglycemia was evaluated in a rat aortic occlusion model of ischemic paraplegia. One hour before aortic occlusion, 200-250 g Sprague-Dawley rats received either 1 cc of saline or 0.5 units regular insulin in 1 cc saline. Rats were then anesthetized, intubated, and ventilated with halothane (1-1.5%). The aortic arch was exposed and snares were placed on the right and left subclavian arteries and the aorta distal to the left subclavian. The three vessels were occluded for 10 min. Lower extremity neurologic deficit was evaluated at 1, 4, 18, and 24 hr postocclusion based on a 15-point scale (0 = normal, 15 = severe deficit). Lower extremity neurologic deficit was significantly decreased in the insulin-treated group at 18 and 24 hr postocclusion (P = 0.005 and 0.006, respectively, Student's test). Blood glucose concentration was significantly lower at the time of occlusion in the insulin-treated group when compared to the saline-treated group (P = 0.001). We conclude that in this rat model of paraplegia, insulin induced hypoglycemia is associated with a reduction in lower extremity neurologic deficit produced by temporary aortic occlusion.

Paraplegia in the rat induced by aortic cross-clamping: model characterization and glucose exacerbation of neurologic deficit.

Spinal cord damage caused by ischemia is a serious, underappreciated, and relatively refractory problem in clinical practice. Research is hampered by a lack of experimental models that appropriately mimic clinical situations. A new model of paraplegia in the rat is presented and evaluated by standard neurologic deficit scoring (1, 4, 18, and 24 hours after occlusion) and by computerized activity monitoring (1 and 18 hours after occlusion). Rats underwent temporary occlusion of the thoracic aorta for 10, 15, or 20 minutes. Experimental groups received glucose (2 gm/kg) and demonstrated a significant elevation in blood glucose (p = 0.001) and were significantly more neurologically impaired at all four time periods (p less than or equal to 0.005) than the ischemic control group, which received equivalent volumes of normal saline solution. Significant differences in neurologic deficit were noted with direct clinical examination and computerized activity monitoring. With the use of the latter system, statistical differences were detected in total distance traveled and number of vertical movements. We conclude the following: (1) Paraplegia is reliably and reproducibly achieved in this rat model; (2) because of the rat's more extensive behavioral repertoire when compared with other models of spinal ischemia (e.g., rabbit), more end points can be monitored and more subtle behavioral deficits discerned; (3) computerized activity monitoring can distinguish varying degrees of neurologic deficit and correlates with clinical neurologic deficit scoring; and (4) glucose exacerbates paraplegia in this model.

Insulin administration protects neurologic function in cerebral ischemia in rats.

Hyperglycemia exacerbates neurologic damage in clinical and experimental central nervous system ischemia. The purpose of our study was to determine if insulin administration before significantly alters neurologic deficit and survival after ischemia using a newly developed rat cerebral ischemia model. One hour before the onset of ischemia, 40 200-300-g Sprague-Dawley rats received intraperitoneal injections of either 1 ml normal saline or 0.4, 0.5, or 0.6 units regular insulin in 1 ml normal saline. Rats were then intubated and ventilated with 1-1.5% halothane. The aortic arch was exposed, and snares were placed on the innominate, left carotid, and left subclavian arteries. A 20-minute occlusion was begun, and anesthesia was discontinued. Baseline plasma glucose concentration was similar (p = 0.48, Student's t test) in both groups, but it subsequently was significantly lower in the 0.4 unit insulin-treated group up to 4 hours after occlusion (p less than or equal to 0.0035, Student's t test). Neurologic deficit was scored on a 50-point scale (0 = normal, 50 = severe deficit) 1, 4, 18, and 24 hours after occlusion. In the 0.4 unit insulin-treated group the neurologic deficit score was significantly lower than in the saline-treated group 1, 4, 18, and 24 hours after occlusion (p less than or equal to 0.005, Student's t test). Survival was significantly higher (p = 0.001) in the 0.4 unit insulin-treated (1.7 unit/kg dose) group than in the saline-treated group. No rats died when preocclusion plasma glucose concentration was between 65 and 175 mg/dl.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma profiles of IL-6 and TNF with fever-inducing doses of lipopolysaccharide in dogs.

This study was designed to test the tumor necrosis factor (TNF) WEHI 164 clone 13 bioassay and the interleukin 6 (IL-6) B9 bioassay for sensitivity to endogenously produced dog TNF and IL-6 and then to use these assays to examine the associations between these cytokines and lipopolysaccharide (LPS)-induced fever. When dogs were injected with LPS (40, 10, 1, 0.1, and 0.01 microgram/kg), the resulting fever was dose dependent. A plot of plasma cytokine changes over time following LPS injections showed that the plasma TNF-like activity appeared to increase in an all-or-none dose response, whereas the increase in plasma IL-6-like activity appeared to be log dose dependent. Plasma TNF-like and IL-6-like activity were then separately plotted against temperature change (fever). Statistical analysis supported the interpretation that both TNF-like and IL-6-like activity were related to LPS-fever in an all-or-none manner, with IL-6 having a threshold region. We conclude that if these cytokines are circulating mediators of fever, they may induce fever in an all-or-none fashion.

Frontal foramina in pediatric skull in cases of congenital hydrocephalus.

PURPOSE: To describe a new observation, frontal calvarial foramina, in pediatric patients with congenital hydrocephalus secondary to central nervous system malformation. MATERIALS AND METHODS: Frontal foramina were initially identified in three female patients with Chiari II malformation. Subsequently, head computed tomographic (CT) scans in 99 patients with congenital hydrocephalus were retrospectively reviewed. CT scans in a control group of 116 patients without hydrocephalus were also retrospectively reviewed. RESULTS: Frontal foramina were found in eight of 61 (13%) patients with Chiari II malformation, in one child with Dandy-Walker malformation, and in one child with occipital horn dilatation (colpocephaly), but not in control patients. Sequential CT examinations in three patients with frontal foramina depicted gradual closure after ventriculoperitoneal shunt placement. CONCLUSION: Frontal foramina may represent an abnormality variably expressed in certain central nervous system malformations that cause congenital hydrocephalus. The presence of frontal foramina palpated or visualized on plain radiographs may help in the diagnosis of congenital hydrocephalus and central nervous system malformation.

Beta-hydroxybutyrate and response to hypoxia in the ground squirrel, Spermophilus tridecimlineatus.

1. Previous studies have suggested that elevated ketone levels are associated with increased survival time in rodents exposed to hypoxia. In this study the association between whole blood BHB (beta-hydroxybutyrate) and hypoxic survival time was investigated in hibernating and non-hibernating ground squirrels and in rats. 2. Non-hibernating ground squirrels and rats were exposed to hypoxia (4.5% O2). One hundred per cent of ground squirrels survived 1 hr of hypoxia vs 20% of rats. 3. Ketone levels were significantly higher in ground squirrels than rats during hypoxia, and rats surviving the longest had the highest ketone levels. 4. When hibernation was induced in ground squirrels there was a significant increase in beta-hydroxy-butyrate from 0.45 to 1.6 mM (P = 0.0005). 5. Ground squirrel heart mitochondrial respiratory control ratios and ATP synthesis rates indicated no preferential ketone utilization which might suggest a possible extramitochondrial role of BHB during hypoxia. 6. We conclude that elevated blood BHB levels are associated with increased hypoxic survival and they may have evolved in response to life-threatening hypoxia as experienced during hibernation.

Gamma unit facility: concept genesis, architectural design and practical realization.

The physical creation of a gamma unit facility requires the development of a broad-perspective multidisciplinary plan. The primary goal is radiosurgical treatment of intracranial lesions in a functional environment. The practical realization of a facility optimally designed for patient treatment is dependent on factors which include the facility setting, architectural goals, radiation safety requirements, and patient and medical team needs. This necessitates combined intellectual resources from neurosurgery, radiation oncology and physics, anesthesia, radiology, nursing, administration, and architectural and engineering teams. We undertook the development of a gamma unit facility which optimized the ergonomics and efficiency of patient evaluation, care and treatment, given the instrument requirements. This general plan based on our experience can be used for the development of other gamma unit facilities.