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Biomedical subjects

J C Goodman

Publications and source records attributed to J C Goodman.

At least 55 records · Page 3Linked to original sources
PubMed1995

Adenovirus-mediated gene therapy in an experimental model of breast cancer metastatic to the brain.

We investigated the therapeutic efficacy of adenovirus-mediated gene therapy to treat malignant mammary tumors in vitro and in vivo in the brain. A mammary adenocarcinoma cell line derived from Fischer rats (13762 MAT B III; MAT-B) was used. In vitro studies demonstrated that the MAT-B cells could be efficiently transduced with a replication-defective adenovirus (ADV) vector that carried the herpes simplex virus gene for thymidine kinase (ADV-tk), and that ADV-tk transduction rendered the MAT-B cells sensitive to killing, in a dose-dependent manner, with ganciclovir (GCV). An animal model of a mammary tumor metastatic to the brain was produced by injecting MAT-B cells into the caudate nucleus of Fischer rats. Seven days after MAT-B cell injection, when the tumors were approximately 5 mm2 in cross-sectional size, the tumors were injected with ADV-tk or a control adenovirus vector containing the beta-galactosidase (beta-Gal) gene (ADV-beta gal). After vector injection the animals were treated with GCV or with saline for 6 days. Sixteen days after tumor cell injection, the brains were examined histologically. The rats that were injected with ADV-beta gal and treated with GCV or saline, and those that were injected with ADV-tk and treated with saline had large tumors, whereas the rats that were injected with ADV-tk and treated with GCV had no visible tumor tissue at the site of tumor cell injection. In survival studies animals treated with ADV-tk+GCV survived a significantly longer time than animals treated with ADV-beta gal+GCV. Our results demonstrate that the recombinant adenoviral vector containing the tk gene confers GCV cytotoxic sensitivity to mammary tumor cells in vitro and in the brain, and suggest that this treatment strategy may be useful in treating somatic tumors that metastasize to the brain.

Adenocarcinoma↗
PubMed1995

SjvO2 monitoring in head-injured patients.

Jugular venous oxygen saturation (SjvO2) measures the balance between cerebral oxygen delivery and cerebral oxygen consumption. Abnormalities that increase oxygen consumption (e.g., fever or seizures) or that decrease oxygen delivery (e.g., increased ICP, hypotension, hypoxia, hypocapnia, or anemia) can decrease SjvO2. Measuring SjvO2 continuously in the ICU in 177 patients with severe head injury, jugular venous desaturation (SjvO2 < 50%) was identified at least once in 39% of the patients. Approximately half of the episodes of desaturation were due to intracranial hypertension and half were due to systemic causes. The occurrence of one or more episodes of desaturation was strongly associated with a poor outcome, suggesting that the reduction in oxygen delivery identified with the SjvO2 monitoring contributed to the neurological injury. In the operating room, jugular venous desaturation was identified in 6 of 8 patients who were monitored during emergency evacuation of a traumatic intracranial hematoma. The lowest SjvO2 observed was 28%. In all 8 cases, the SjvO2 increased, from 47 +/- 10% to 63 +/- 5% after evacuation of the hematoma. Additional data supporting the hypothesis that these secondary insults identified with the SjvO2 monitoring contribute to the patient's neurological injury come from measurement of the extracellular concentrations of lactate and excitatory amino acids in the brain using microdialysis. Lactate concentration increased from 0.9 +/- 0.3 to 2.4 +/- 0.5 mumol/L and glutamate increased from 11.5 +/- 8.5 to 55.0 +/- 10.4 mumol/L during 8 episodes of jugular venous desaturation in 7 of 22 patients monitored with microdialysis. SjvO2 identifies global reductions in cerebral oxygenation due to a variety of causes, and is useful as a monitor for secondary insults in patients with severe head injury.

Adult↗
PubMed1994

Adenovirus-mediated gene therapy of experimental gliomas.

The efficacy of adenovirus (ADV)-mediated gene therapy to treat brain tumors was tested in a syngeneic glioma model. Tumor cells were transduced in situ with a replication-defective ADV carrying the herpes simplex virus thymidine kinase (HSV-tk) gene controlled by the Rous sarcoma virus promoter. Expression of the HSV-tk gene enables the transduced cell to convert the drug ganciclovir to a form that is cytotoxic to dividing cells. Tumors were generated in Fischer 344 rats by stereotaxic implantation of 9L gliosarcoma cells into the caudate nucleus. Eight days later, the tumors were injected either with the ADV carrying the HSV-tk (ADV-tk) gene or a control ADV vector containing the beta-galactosidase (ADV-beta gal) gene and the rats were treated with either ganciclovir or saline. Tumor size was measured 20 days after implantation of 9L cells or at death. Rats treated with ADV-beta gal and ganciclovir or with ADV-tk and saline had large tumors. No tumors were detected in animals treated with ADV-tk and with ganciclovir at doses > or = 80 mg/kg. An infiltrate of macrophages and lymphocytes at the injection site in animals treated with ADV-tk and ganciclovir indicated an active local immune reaction. In survival studies, all animals treated with ADV-tk and ganciclovir have remained alive longer than 80 and up to 120 days after tumor induction whereas all untreated animals died by 22 days. These results demonstrate that ADV-mediated transfer of HSV-tk to glioma cells in vivo confers sensitivity to ganciclovir, and represents a potential method of treatment of brain tumors.

Adenoviridae↗
PubMed1994

Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo.

The therapeutic efficacy of adenovirus-mediated herpes simplex virus thymidine kinase (HSV-tk) gene transduction of rat C6 glioma cells followed by ganciclovir (GCV) administration was studied in tumors generated in the brains of nude mice. C6 glioma cells were efficiently transduced in vitro by a replicative-defective recombinant adenovirus carrying the HSV-tk gene (ADV/RSV-tk) that rendered them sensitive to GCV in a dose-dependent manner. Tumors were generated by stereotaxic intracerebral injection of 1 x 10(4) C6 cells in nude mice. After 8 days of tumor growth, 3 x 10(8) ADV/RSV-tk viral particles were injected into the tumors and the mice subsequently were treated with GCV for 6 days. Tumor size in untreated and treated animals was compared 20 days after tumor implantation. The mean cross-sectional area of the tumors in the treated animals was 23-fold smaller than in control animals and the tumor volume was reduced by > 500-fold. These results demonstrate that the recombinant adenoviral vector can function as an efficient gene delivery vehicle for the treatment of gliomas by in vivo gene therapy.

Adenoviridae↗
PubMed1994

Scalp hibernoma: case report and literature review.

Hibernomas are uncommon, benign neoplasms derived from the remnants of fetal brown adipose tissue. A review of the world literature revealed 105 cases, with the interscapular location the most common. Typically, hibernomas are asymptomatic and slow-growing. Adequate treatment usually consists of simple excision. We describe the second documented case of a scalp hibernoma.

Humans↗
PubMed1994

Lateral cortical impact injury in rats: pathologic effects of varying cortical compression and impact velocity.

Direct lateral cortical impact through the intact leptomeninges using a pneumatically driven piston produces increasingly severe pathophysiologic derangements with increasing cortical deformation. We studied the histopathologic correlates of cortical impact injury produced by 2 mm, 2.5 mm, and 3 mm deformation in the rat at 5 m/sec. Additionally, the effect of impact velocity at a 2.5 mm deformation was assessed at 1 m/sec, 3 m/sec, and 5 m/sec. The brains were examined 14 days after injury. Cortical contusion maximum cross-sectional area, volume, and the percentage CA1 and CA3 hippocampal neuronal loss correlate with cortical deformation and impactor velocity. Contusion volume increased with increasing cortical deformation. Deformations of 2, 2.5, and 3 mm at 5 m/sec produced contusion volumes of 4.59, 8.9, and 21.68 mm3, respectively. At a fixed cortical deformation of 2.5 mm, contusion volume increased with increasing impact velocity. Impact velocities of 1, 3, and 5 m/sec produced contusion volumes of 5.79, 7.42, and 8.9 mm3, respectively. Hippocampal CA3 neuronal loss increased with increasing cortical deformation. Deformations of 2, 2.5, and 3 mm at 5 m/sec produced neuronal loss of 29%, 48.3%, and 79.5%, respectively. At a fixed cortical deformation of 2.5 mm, hippocampal CA3 neuronal loss increased with increasing impact velocity. Impact velocities of 1, 3, and 5 m/sec produced neuronal loss of 18.25%, 33.75%, and 48.3%, respectively. Hippocampal CA1 neuronal loss was also seen and paralleled cortical deformation and impact velocity. Cortical deformation and impact velocity are critical parameters in producing cortical contusion and must be considered when comparing results using this model.

Animals↗
PubMed1994

Malignant meningioma in Gorlin's syndrome: cytogenetic and p53 gene analysis. Case report.

Gorlin's syndrome, also known as multiple basal cell carcinoma syndrome, is a familial tumor condition with autosomal-dominant inheritance. Patients develop multiple basal cell carcinomas beginning in childhood. They also have a typical dysmorphic facies, skeletal malformations, and a particular type of epithelial cyst of the jaws. Recent evidence localizes a Gorlin's syndrome locus on chromosome 9 at band q31. Both tumors and malformations of the central nervous system occur with Gorlin's syndrome. Medulloblastoma is the primary brain tumor most frequently associated with this syndrome; over 40 such cases have been reported. However, only seven cases of meningioma associated with Gorlin's syndrome have been described. The authors report the case of a woman with Gorlin's syndrome whose mother and maternal grandfather also had the condition. The patient was found to have a medulloblastoma at 4 years of age and presented with a large bifrontal meningioma at 19 years of age. The meningioma was histologically malignant and had a complex karyotype with multiple translocations including a t(5;9) with the breakpoint on chromosome 9 located at 9q32. The constitutional karyotype of the mother was normal. No mutations of exons 5 to 9 of the p53 gene were detected using single-stranded conformational polymorphism analysis.

Adult↗
PubMed1994

Calorie sources and recovery from central nervous system ischemia.

OBJECTIVES: Glucose is the primary substrate for the energy requirements of the nervous system. Nevertheless, administration of glucose to critically ill patients with central nervous system trauma may have adverse effects on their neurologic recovery. The purpose of this study was to evaluate the effects of other sources of nonprotein calories on spinal cord lactate accumulation and on electrophysiologic recovery after a period of severe spinal cord ischemia. DESIGN: Two randomized, blinded studies were performed: one of glycolytic energy substrates (fructose, xylitol, sorbitol, glycerol) and one of ketogenic energy substrates (beta-hydroxybutyrate, acetate, butyrate). SETTING: College teaching hospital laboratory. SUBJECTS: New Zealand albino rabbits (weight 3.5 to 4.5 kg). INTERVENTIONS: After infusion of the randomly assigned treatment, temporary ischemia was produced in the lumbosacral spinal cord by occluding the abdominal aorta with a balloon catheter. MEASUREMENTS AND MAIN RESULTS: Blood concentrations of glucose, lactate, pyruvate, and ketone bodies and spinal cord dialysate concentration of lactate were measured before and after infusion of the assigned treatment, and during ischemia and during the first 2 hrs after reperfusion. Spinal somatosensory evoked potentials were recorded during ischemia to assure a similar severity of ischemia in all animals and during the first 2 hrs after reperfusion as a measure of electrophysiologic recovery. Infusion of the glycolytic nutrients xylitol and fructose increased blood glucose and lactate concentrations, and resulted in increased lactate accumulation in the spinal cord during ischemia and resulted in a significantly poorer recovery of the spinal somatosensory evoked potential than infusion of saline. Infusion of sorbitol and glycerol did not have these adverse effects in the doses administered. None of the ketogenic nutrients increased blood glucose concentration or increased lactate accumulation in the spinal cord during ischemia when compared with infusion of saline. Infusion of butyrate and acetate caused arterial hypotension and resulted in a poorer recovery of the spinal somatosensory evoked potential than saline. Infusion of beta-hydroxybutyrate did not have an adverse effect on blood pressure or on evoked potential recovery. CONCLUSIONS: Glycerol, sorbitol, and beta-hydroxybutyrate deserve further evaluation as potential nonprotein calorie sources in patients with neurologic injury. Xylitol and fructose are not suitable since these substrates resulted in hyperglycemia and increased lactate accumulation in the central nervous system, and had detrimental effects on electrophysiologic recovery after ischemia. The short-chain fatty acids (acetate and butyrate) also had adverse effects on electrophysiologic recovery after ischemia, probably because of their hypotensive effects when given intravenously, rather than from the effects of their metabolism.

Analysis of Variance↗
PubMed1993

Glycine: an important potential component of spinal shock.

Amino acid neurotransmitters (AANTs) play a major role in maintenance of muscle tone. Abnormal AANT concentrations are associated with hyper- or hypotonic states. Flaccidity from spinal shock commonly occurs after spinal cord injury (SCI) and may be associated with changes in AANT concentrations. Ischemic SCIs created in the lumbar region of rabbits by intraaortic balloon occlusion produced spastic or flaccid injuries. Microdialysis sampling of AANTs from the injured segmental structures was done 3 days after SCI. Evoked potentials were used to monitor spinal cord stability. No significant changes in AANT levels occurred in the spastic or flaccid group after 4 hour sampling. However, flaccid animals had baseline glycine levels 2-3 times higher (p < 0.001) than spastic animals or controls. High concentrations of the inhibitory AANT glycine is associated with flaccidity following SCI, or spinal shock, but not spasticity. Glycinergic compounds directed toward suppression of excess muscle tone deserve further study.

Amino Acids↗
PubMed1993

DFMO reduces cortical infarct volume after middle cerebral artery occlusion in the rat.

Ornithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis, is induced in ischemic tissue and may mediate vasogenic edema and delayed neuronal death. We determined the effects of alpha-difluoromethylornithine (DFMO), a specific inhibitor of ODC, on infarct size and ODC activity in a rat model of transient focal ischemia. DFMO blocked the ischemia-induced increase in ODC and significantly reduced infarct volumes by 57-45%, depending upon the treatment regimen. These studies suggest that polyamine metabolism plays a role in the development of cerebral infarction after focal ischemia and that DFMO may be useful in limiting injury after a stroke.

Animals↗
PubMed1993

Spinal epidural corticomotor evoked potentials as a predictor of outcome from ischaemic myelopathy.

Corticomotor evoked potentials have been suggested to accurately reflect neurological function, particularly with regard to the integrity of the spinal cord. However, the utility of these potentials to evaluate graded, chronic injury has received little attention. Using a rabbit model of ischaemic spinal cord injury we recorded corticomotor evoked potentials before, during, immediately after, and three days after producing an ischaemic spinal cord injury by inflating an intraaortic balloon. The animals sustained a stable mild, moderate, or severe neurological deficit. All ischaemic injured animals demonstrated near loss of the corticomotor evoked potential after the timed balloon occlusion period. Mildly injured animals did not demonstrate significant differences in corticomotor evoked potentials at reperfusion of three days post injury, when compared to controls. However, moderate and severely injured animals revealed significant reduction in late latency component amplitudes by > 50% and > 90%, respectively, when compared to controls. Changes in corticomotor evoked potential features are associated with altered neurological function after graded spinal cord injury.

Animals↗
PubMed1993

Spectral analysis of corticomotor evoked potentials in spinal cord injury. Part 1. Acute studies.

A model of graded spinal cord injury using ischaemia has been developed by using balloon occlusion of the abdominal aorta in rabbits. This model has been used to test pharmacological agents thought to provide protection against spinal cord injury based on changes in corticomotor evoked potentials (CMEPs). These highly reproducible signals are percutaneously recorded from the spinal cord in response to cortical stimulation and accurately reflect the degree of residual spinal cord function. The present study focused on the power spectra of CMEPs to clarify alterations in post-injury signals. This added dimension of previously unreported CMEP analysis will augment future applications of the current model.

Acute Disease↗
PubMed1993

Spectral analysis of corticomotor evoked potentials in spinal cord injury. Part 2. Chronic studies.

Corticomotor evoked potentials (CMEPs) have been suggested to accurately reflect neurological function, particularly with regard to the integrity of the spinal cord. However, the utility of these potentials to evaluate graded, chronic injury has received little attention. Frequency analysis has been suggested by the authors to be a method of simplifying interpretation of these complex signals. Ischaemic spinal cord injuries were produced in rabbits causing mild, moderate, or severe neurological deficits. CMEPs were recorded before, during, immediately following, and three days after injury. Alterations in the features of the power spectra reflected the degree of neurological injury. CMEP power spectra may predict neurological outcome and augment currently used electrodiagnostic tests.

Animals↗
PubMed1993

Segmental recovery of amino acid neurotransmitters during posterior epidural stimulation after spinal cord injury.

Epidural spinal cord stimulation (SCS) has been used as an effective method for managing pain and spasticity for over two decades. However, the mechanisms of these beneficial effects are largely unknown. Since neurotransmitters are likely to be involved, we examined the relationship between SCS and local segmental amino acid release into the spinal cord extracellular space. Microdialysis was performed during continuous epidural SCS in animals subjected to ischemic spinal cord injury. Recovery of amino acid neurotransmitters from stimulated, injured animals was compared to that from a control group. Evoked potentials from the cortex and spinal cord were recorded to insure adequate stimulation and stable cord function. A significant increase in the concentrations of glycine and taurine was seen before, during, and after 90 minutes of continuous stimulation and was independent of the degree of injury. Levels of the other putative amino acid neurotransmitters were not significantly elevated. These results suggest that amelioration of pain or spasticity by epidural SCS may result from maintenance of post-injury elevation in baseline glycine and taurine levels.

Amino Acids↗
PubMed1993

The relationship between hormonal mediators and systemic hypermetabolism after severe head injury.

The relationships of hormonal mediators to the systemic hypermetabolism and catabolism of head injury were studied in 15 patients with severe head injuries. Resting energy expenditure (REE), urinary nitrogen balance, and plasma glucose concentration were measured daily for the first 2 weeks after injury as the major indicators of hypermetabolism. These dependent variables were correlated with daily measurements of urinary epinephrine, norepinephrine, metanephrine, normetanephrine, dopamine, and cortisol, and with plasma levels of insulin, glucagon, and C-reactive protein. Urinary catecholamine and cortisol excretion were markedly elevated in these patients throughout the 2 weeks of study. Catecholamine excretion peaked between days 7 and 10, whereas cortisol excretion tended to be highest on day 5 after injury. Urinary levels of norepinephrine, normetanephrine, and cortisol were highest in the two patients with Glasgow Coma Scale scores of 4. Plasma insulin and glucagon concentrations were elevated on day 1 after injury and tended to increase throughout the 2-week period of study. The variables significantly associated with REE were the severity of injury, reflected by the GCS score, the urinary excretion of norepinephrine during the first 2 days after injury, and the urinary excretion of epinephrine and norepinephrine during days 3 to 7 after injury. A negative nitrogen balance was associated with the urinary excretion of epinephrine and norepinephrine, with caloric balance, and with plasma C-reactive protein during days 1 and 2 after injury. During days 3 to 7, a negative nitrogen balance was associated with the urinary excretion of epinephrine and norepinephrine and with caloric balance, and during days 8 to 14, a negative nitrogen balance was associated primarily with urinary cortisol excretion.

Adult↗