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Background and Purpose: Perfluorocarbons (PFCs) are considered promising cerebral protection agents because they could combine the beneficial effects of decreased blood viscosity with enhanced oxygen-carrying capacity and oxygen tissue delivery, but trials of PFCs as hemodilutants have been very limited. We evaluated fluoromethyloadamantane (FMA), a new perfluorocarbon compound, as an isovolemic hemodilutant and compared it with low-molecular-weight dextran 40 (D40) and a control group., Methods: Through a transorbital craniectomy, the internal carotid, anterior, and middle cerebral arteries were coagulated to create a cerebral infarction in anesthetized, mechanically ventilated rabbits. No other experimental procedure was performed in control animals. In the two other groups, hemodilution was commenced 30 minutes after the arterial occlusion with either D40 or FMA. Hemodynamic parameters and brain and systemic temperature were monitored throughout the experiments. All animals were killed 6 hours after the arterial occlusion., Results: Hemodynamic and metabolic parameters and blood oxygen content were not affected by the infusion of either FMA or D40. Brain and systemic temperature remained constant. The ratio of infarct volume to the hemispheric volume was 19.6 +/- 3.7% in the FMA group (n = 17), 19.9 +/- 4.6% in the D40 group (n = 16), and 40.3 +/- 5.7% in the control group (n = 17). The difference in infarct volume of both FMA and D40 animals compared with controls was statistically significant (P < .01) when tested with Student's t test. There was no significant difference between FMA and D40 groups., Conclusions: These results suggest that FMA has cerebral protective properties and should be purified, optimized, and further tested experimentally to develop a stable, efficient, and safe oxygen carrier, potentially suitable for clinical trials.

Clinically nonfunctioning pituitary adenomas are benign neoplasms comprising approximately 25-30% of pituitary tumors. Little is known about the pathogenesis of pituitary neoplasia. Clonal analysis allows one to make the important distinction between a polyclonal proliferation in response to a stimulatory factor versus a monoclonal expansion of a genetically aberrant cell. We investigated the clonal origin of pituitary tumors using X-linked restriction fragment length polymorphisms at the phosphoglycerate kinase and hypoxanthine phosphoribosyl-transferase genes. Restriction enzymes were used to distinguish maternal and paternal X-chromosomes, and combined with a methylation-sensitive restriction enzyme to analyze allelic X-inactivation patterns in six pituitary adenomas. All six tumors showed a monoclonal pattern of X-inactivation. These data indicate that nonfunctioning pituitary adenomas are unicellular in origin, a result consistent with the hypothesis that this tumor type is due to somatic mutation.

The double subarachnoid hemorrhage canine model was used to test the prophylactic value of immunosuppression in the prevention of cerebral vasospasm after subarachnoid hemorrhage. Dogs treated with cyclosporine A following the regimen prescribed for organ transplant procedures in patients showed a significant reduction in the severity of angiographic constriction of cerebral arteries. While basilar artery diameter after double experimental subarachnoid hemorrhage in a series of untreated dogs (n = 34) averaged 65% of baseline diameter, arterial diameter in dogs treated prophylactically (n = 18) with 6 mg/kg/day cyclosporine A and adjunct low-dose steroid averaged 80% of baseline diameter, for a mean reduction in the severity of chronic arterial constriction of 42%. More important than the average effect, however, is the statistical observation that this mean improvement was obtained primarily by a dramatic reduction in the incidence of severe cerebral vasospasm, the situation most likely to account for morbidity and mortality after aneurysmal rupture.

Peroxidase-containing cell bodies were found in the ipsilateral trigeminal ganglia after horseradish peroxidase was applied to the proximal segment of the middle cerebral artery in seven cats. Cell bodies containing the enzyme marker were located among clusters of cells that project via the first division. The existence of sensory pathways surrounding large cerebral arteries provides an important neuroanatomical explanation for the hemicranial distribution of headaches associated with certain strokes and migraine.

Astrocytomas, including glioblastoma multiforme, represent the most frequent and deadly primary neoplasms of the human nervous system. Despite a number of previous cytogenetic and oncogene studies primarily focusing on malignant astrocytomas, the primary mechanism of tumor initiation has remained obscure. The loss or inactivation of "tumor suppressor" genes are thought to play a fundamental role in the development of many human cancers. Thus, we have analyzed astrocytomas of various histological malignancy grades with polymorphic DNA markers to search for specific chromosomal deletions potentially pointing to loci containing tumor suppressor genes. Loss of constitutional heterozygosity indicating chromosomal loss or deletions was most frequently seen for markers on the short arm of chromosome 17 in 50% of the informative tumors (5 of 10 informative cases) and, to a lesser extent, for markers on chromosomes 1 and 10. Deletions on chromosome 17p were seen in both low-grade and high-grade malignant astrocytomas, suggesting that this chromosome may contain a tumor suppressor gene associated with the early events in tumorigenesis. The common region of deletions on the short arm of chromosome 17 is, therefore, clearly distinct from the gene causing von Recklinghausen neurofibromatosis (NF1), a tumor syndrome associated with glial tumors that maps to the long arm of chromosome 17. The search for progressively smaller deletions on chromosome 17p in astrocytomas may be the way to clone and characterize this locus, thus leading to insights into normal and abnormal growth and differentiation of glial cells.

Diazoxide failed to safely relieve cerebral vasospasm by intracisternal injections in dogs and by intracarotid injections in monkeys despite in vitro documentation of arterial relaxation with this agent. Administration of the drug frequently produced hypotension and, in the presence of vasospasm, was associated with a high mortality rate.

Approximately 25% of patients with pituitary adenomas have no clinical or biochemical evidence for excess hormone secretion and are classified as having null cell or nonfunctioning adenomas. To characterize the cell type of these tumors, we analyzed pituitary hormone gene expression in clinically nonfunctioning pituitary adenomas using specific oligonucleotide probes for the messenger (m)RNAs encoding growth hormone, prolactin, ACTH, and the glycoprotein hormone subunits, alpha, luteinizing hormone (LH)beta, follicle-stimulating hormone (FSH)beta, and thyroid-stimulating hormone (TSH)beta. Expression of one or more of the anterior pituitary hormone genes was found in 12/14 (86%) of the patients with clinically classified nonfunctioning adenomas. Expression of one or more of the glycoprotein hormone genes (alpha, LH beta, FSH beta, TSH beta) was identified most commonly (79%) with expression of multiple beta-subunit genes in many cases. Expression of alpha-subunit mRNA was found in each of the adenomas from patients expressing one of the beta-subunit mRNAs and in three patients with no detectable beta-subunit mRNA. Although FSH beta and LH beta mRNAs were found with similar frequencies in nonfunctioning adenomas, expression of FSH beta mRNA was generally much more abundant. TSH beta mRNA was detected in only one adenoma. The levels of glycoprotein hormone subunit mRNAs were variable in different adenomas, but the lengths of the mRNAs and transcriptional start sites for the alpha- and beta-subunit genes were the same in the pituitary adenomas and in normal pituitary. Growth hormone and prolactin gene expression were not observed in the nonfunctioning adenomas, but ACTH mRNA was found in a single case. Immunohistochemistry of the adenomas confirmed production of one or more pituitary hormones in 13/14 (93%) nonfunctioning tumors, with a distribution of hormone production similar to that of the hormone mRNAs. These data indicate that pituitary adenomas originating from cells producing glycoprotein hormones are common, but are difficult to recognize clinically because of the absence of characteristic endocrine syndromes and defective hormone biosynthesis and secretion.

The unexpected finding of an extension of a neurogenic tumor from the thorax through the spinal foramen into the neural canal complicates its removal. Serious neurological complications may result from a two-stage approach, whether done first through the thorax or neural canal. Vertebral tomography or computed tomographic scanning reveals enlargement of a spinal foramen in advance of operation. Myelography confirms the probable presence of an intraspinal component. Four patients have been operated on using an approach designed to allow wide posterolateral thoracotomy and concomitant laminectomy for single-stage removal of the entire tumor. In 3 patients the diagnosis was schwannoma and in 1, neurofibroma. All had good results.

An overview of the possible factors that might contribute to the development of cerebral vasospasm is presented, with particular emphasis on the possibility that spasm arises from a malfunction of the regulatory or contractile processes in smooth muscle cells. This possibility is emphasized because the evidence for cellular damage and the delayed occurrence of vasospasm are suggestive of pathological alteration. Data regarding the development of spasm in vivo has been reviewed and, to the extent possible, correlated with in vitro studies of cerebrovascular smooth muscle contractility. Short-term in vitro studies of normal cerebral arteries may be of little relevance to the prolonged and severe cerebral vasoconstriction that occurs only after a delay of several days from the initial insult.

Profound vascular damage secondary to high-flow extracranial states has been well characterized. However, changes in cerebral vasculature secondary to high-flow states have not been studied. To determine changes related to high-flow states in cerebral vessels, a rabbit model was developed in which torrential flow was created in the vertebrals, carotids, basilar, and vessels of the circle of Willis by means of a carotid-jugular shunt after ligation of the proximal carotid. The clinical, angiographic, and histologic changes noted in the animal model include: abrupt clinical deterioration after a variable interval with some animals developing ptosis, afferent vessel dilatation and the development of prominent anastomotic channels, variable cerebral vessel histopathology--related to duration and relative proximity to the shunt--affecting all three vessel layers, plump, irregular, and clumped endothelium, denuded with adherent platelets, irregular, duplicated, and thinned internal elastic membrane, frayed with invasion of the intima by mesenchymal cells, vacuolization and necrosis of the media muscle, and invasion of adventitia by foreign cells and small blood vessels. The high-flow angiopathy seen in this model may help explain vascular changes associated with high-flow cerebral vascular lesions, as well as other types of vascular damage.

Twenty-four cats had an intravenous infusion of either Fluosol or saline and then were subjected to 2 hours of middle cerebral artery occlusion. All the animals infused with Fluosol and one-half the animals infused with saline were ventilated with 100% O2. Tissue oxygen availability and regional cerebral blood flow were measured by platinum electrodes using direct voltage recordings for oxygen measurements and hydrogen clearance curves for measurements of cerebral blood flow. With 100% oxygenation tissue oxygen availability increased significantly in the Fluosol treated animals, however, during the time of ischemia oxygen availability decreased below baseline values to about an equal level whether the animals were treated with Fluosol or saline. Regional cerebral blood flow fell to a similar value in all groups during the time of occlusion. One hour after reperfusion blood flow increased considerably above baseline values in all groups and oxygen availability also increased in all groups but particularly in the Fluosol treated animals. Overall mortality and the size of infarction 1 week after the ischemic insult were not significantly different in the three groups. Mortality was directly related to the size of the infarct which, in turn, was related to the degree of ischemia during the time of occlusion.

Nitroglycerin, long known as a safe and effective dilator of the large coronary arteries, has recently been shown to dilate the basilar artery of the dog after experimentally induced vasospasm. In this study we have evaluated the effects of intravenous nitroglycerin on local cerebral blood flow (H2 clearance technique) and intracranial pressure (intracisternal needle monitor) in normal beagle dogs (Group 1). In each of 7 dogs, infusion of nitroglycerin at rates of 3, 5, and 10 microgram/kg/min did not change blood flow in the right and left caudate nucleus, thalamus, frontal and parietal cortex. Autoregulation of cerebral blood flow remained unimpaired and intracranial pressure remained stable during nitroglycerin infusion. The effects of a combination of intravenous nitroglycerin and dopamine on local cerebral blood flow was evaluated in another group of normal beagle dogs (Group 2). Local cerebral blood flow decreased or remained unchanged in response to intravenous infusion of dopamine at low rates, increased in response to moderate rates and again decreased in response to high infusion rates. These dopamine induced changes in blood flow occurred whether or not nitroglycerin was infused simultaneously. When the vasoconstrictor activity of dopamine was blocked by phentolamine or methysergide, local cerebral blood flow increased at moderate and high infusion rates, again whether or not nitroglycerin was infused simultaneously. Our data suggest that nitroglycerin affects mainly the extracerebral capacitance arteries while dopamine affects the smaller intraparenchymal resistance vessels. Nitroglycerin has little effect on cerebral blood flow even when used in combination with dopamine.

Cerebral arteriospasm is a common complication of subarachnoid hemorrhage and is responsible for much of the brain damage which accompanies it. No pharmacologic agent has been found which regularly alleviates arteriospasm. We have evaluated the effect of continuous intravenous nitroglycerin infusion on the diameter of the basilar artery in dogs with cerebral vasospasm experimentally induced by subarachnoid blood injection. In 6 consecutive dogs, 10 minutes after beginning intravenous nitroglycerin at 100 microgram/min and at other times during 120 minutes of infusion, the diameter of the basilar artery had increased from 75 +/- 2% of control value to 114 +/- 2% of control value (p less than 0.001). In all 6 dogs, the basilar artery diameter during infusion was greater than the control value prior to creating subarachnoid hemorrhage. Intravenous nitroglycerin caused only a moderate (8%) decrease in blood pressure. Further investigation of the effects of nitroglycerin on cerebral vasospasm is warranted.