Anoxic injury of endothelial cells causes divergent changes in protein kinase C and protein kinase A signaling pathways.

Alterations in protein kinase C (PKC) and cAMP-dependent kinase have been documented in anoxic brain injury. However, the regulation of these signaling enzymes in the cerebrovasculature has not been explored. In this study, cultured brain endothelial cells exposed to anoxic injury (anoxia--20 min/reoxygenation--40 min) showed both a significant increase (p < 0.001) in PKC and decrease (p < 0.01) in cAMP-dependent kinase activity. Analysis of PKC by Western blot indicated an increase in kinase level in response to anoxic injury, whereas there was no change in the level of cAMP-dependent protein kinase, as measured by labeled cAMP binding. Inhibition of nitric oxide synthase did not affect these changes. Addition of the nitric oxide-releasing compound sodium nitroprusside caused a dose-dependent increase in the activity of both signaling systems in endothelial cells. These data demonstrate that anoxic injury of brain endothelial cells in culture causes significant and divergent changes in signaling kinase activity. Abnormalities in brain endothelial PKC and cAMP-dependent kinase could have important consequences for the blood-brain barrier in anoxic brain injury.

Changes in the binding capacity of hepatic membranes for epidermal growth factor during multistage hepatocarcinogenesis in rats.

To study changes in hepatic capacity for binding epidermal growth factor (EGF) during 2-acetylaminofluorene (2-AAF)-induced, multistage hepatocarcinogenesis, a 5 cycle protocol of discontinuous 2-AAF administration was used to produce hepatocarcinogenesis in rats. The hallmark of the 5 cycle protocol is that rats fed 1 to 3 cycles of 2-AAF are at low risk for cancer, while rats fed 2-AAF for 4 or 5 cycles are at high risk for cancer. EGF binding by liver membranes was found to be lowered to 20-25% of control throughout the 5 cycle regimen. When the persistence of lowered EGF binding was tested by returning rats fed 2-AAF for 1 to 3 cycles to diet without 2-AAF for 3 weeks, binding was found to recover to 80 to 90% of values for control rats. In contrast, for rats fed 2-AAF for 4 or 5 cycles, EGF binding capacity remained low, 30 to 40% of control, following placement of rats on diet without 2-AAF for 3 weeks. Immunochemical analysis indicated a close correspondence between changes in EGF receptor levels and changes in the above EGF binding levels. These studies show that during the 2-AAF protocol, the 2-AAF-mediated loss in hepatic EGF binding capacity and EGF receptor protein undergo a transition from a reversible loss to a persistent loss in binding capacity, and EGF receptor protein, as rats underwent a change from low to high risk for developing hepatocarcinomas. The persistent decrease in hepatic EGF binding level may be associated with the progression stage of hepatocarcinogenesis.

cAMP-dependent protein kinase in cerebral microvessels in aging and Alzheimer disease.

The purpose of this study was to compare the effects of aging and Alzheimer disease (AD) on the important intracellular signaling enzyme cAMP-dependent protein kinase A (PKA) in cerebral microvessels. PKA activity and levels were measured in microvessels isolated from the brains of adult and aged rodents as well as from the cerebral cortices of AD and elderly control patients. The results showed that cerebral microvessels from aged rats have significantly (p < 0.01) higher PKA activity and levels when compared to cerebral microvessels from adult rats. In contrast, no significant difference was found between PKA activity or levels in cerebral microvessels from AD patients when compared to controls. These results indicate that in cerebral microvessels both PKA activity and levels increase with age but are unaffected by AD. The data suggest that protein phosphorylation in brain microvessels may be affected differentially by aging and dementia.

Glioneurocytoma: tumor with glial and neuronal differentiation.

We report two cases of low-grade glioma in which multiple cellular components, including cells with dense-core granules consistent with "neurocytes," were identified on electron microscopic studies. The first patient was an apparently normal boy until the onset of seizures at age 10 months. Initially, the seizures improved with phenobarbital treatment, but good seizure control was never achieved. Computed tomographic scan at age 23 months showed a calcified, nonenhancing left parietal mass. This tumor was composed of sheets of cells with clear cytoplasm and round to oval nuclei. Mucinous intercellular material stained positively with periodic acid-Schiff, mucicarmine, and alcian blue stains. Foci of calcification were evident. The second patient was a 13-year-old boy with a left parasagittal parieto-occipital mass who presented with a 4-month history of seizures and declining school performance. The tumor was composed of sheets of astrocytes with dark, hyperchromatic, pleomorphic nuclei in a fibrillary and microcystic background. The tumor contained the pleomorphism seen in the adult variant of pilocytic astrocytoma, as well as the microcystic component seen in the juvenile variety. Ultrastructurally in both cases, there were occasional tumor cells having round to oval nuclei with moderate amounts of cytoplasm containing 150- to 250-nm-diameter dense-core granules. These cells were admixed with the majority of tumor cells, which in case 1 had the ultrastructural features of astrocytes and oligodendrocytes and in case 2 had features of protoplasmic or pilocytic astrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Dorsal root entry zone lesions for intractable pain after trauma to the conus medullaris and cauda equina.

This review was undertaken to determine the efficacy of using dorsal root entry zone (DREZ) lesions to treat intractable pain caused by trauma to the conus medullaris and cauda equina. Traumatic lesions of this area are unique in that both the spinal cord and the peripheral nerve roots are injured. Although DREZ lesions have been shown to relieve pain of spinal cord origin in many patients, they have been shown not to relieve pain of peripheral nerve origin. Therefore, 39 patients with trauma to the conus medullaris and cauda equina who underwent DREZ lesioning for intractable pain were reviewed retrospectively. The results of this review demonstrate the efficacy of DREZ lesions in these patients. At a mean follow-up period of 3.0 years, 54% of patients were pain-free without medications, and 20% required only nonnarcotic analgesic drugs for pain that no longer interfered with their daily activities. Better outcomes were noted in patients with an incomplete neurological deficit, with pain having an "electrical" character, and with injuries due to blunt trauma. Operative complications included weakness (four patients), bladder or sexual dysfunction (three), cerebrospinal fluid leak (two), and wound infection (two), but overall, 79.5% of patients (31 of 39) were without serious complications. Complications were limited to patients with prior tissue damage at the surgical exploration site and were most prevalent in patients who underwent bilateral DREZ lesions. In conclusion, this preliminary report suggests that DREZ lesions may be useful in combating intractable pain from traumatic injuries to the conus medullaris and cauda equina, with some risk to neurological function that may be acceptable in this group of patients.