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The ocular morphological findings of three methyl alcohol-intoxicated rhesus monkeys with optic disc swelling was investigated with light and electron microscopy in conjunction with intravascular horse radish peroxidase. Alterations observed in the optic nerve head were confined to the axons and consisted of swelling and clustering of the mitochondria, disruption of the neurotubules, the formation of vesicles, and enlargement of the axon segments in the prelaminar region. Swelling of the oligodendroglial cytoplasm in contact with the axons and of the astrocytes was seen in the retrolaminar optic nerve and the intraorbital optic nerve. Alterations were not observed in the retina. It is hypothesized that the alterations in the axons are the result of disrupted axoplasmic flow. Possible mechanisms relating methyl alcohol intoxication to disruption of axoplasmic flow are discussed.

Space-occupying lesions of the basal ganglia are a rare cause of extrapyramidal dysfunction in children. Metastatic pineal germinoma in both basal ganglia produced dystonia in a 12-year-old boy. The literature is reviewed. Extrapyramidal manifestations in the child are compared with previously reported cases of basal ganglia neoplasms.

A case is presented of subarachnoid hemorrhage from an arteriovenous malformation (AVM) involving the left middle cerebral artery in the circle of Willis, seen in association with multiple anomalies of the circle. This is an extremely unusual location for such a malformation. The possible etiology of the AVM and its relationship to the associated anomalies is discussed.

The sequential changes that occur during regeneration of cerebral microvessels was studied in young mice after a local freeze-injury. The immediate breakdown in the blood-brain barrier to horseradish peroxidase was followed by dissolution of cells in the vessel wall although the basal lamina was preserved. This residual basal lamina formed the pathway for the orderly regeneration of microvessels. Three days after injury, reactive endothelial cells with prominent pinocytosis and patent interendothelial channels were present at the edge of the lesion. By 5 days, endothelialization of necrotic vessels was in progress with patent vascular channels and tight junction formation. Establishment of astrocytic contacts or perivascular fibrosis by 7 days was generally followed by reconstitution of normal vascular morphology and integrity at 15 to 35 days after injury.

Adenosine receptors have been identified on brain cortical membranes and microvascular preparations. However, they have not been demonstrated on specific microvascular elements in isolation. 2-3H-chloroadenosine was used as a ligand to investigate the presence of adenosine receptors on isolated mouse cerebral smooth muscle membranes. The binding studies reveal the presence of a high affinity binding site with a Kd value of 33.3 nM and a maximal binding capacity (Bmax) of 283 fmol/mg protein. These findings demonstrate that there is an adenosine receptor on cerebral smooth muscle membranes.

gamma-Glutamyl transpeptidase (gamma GTP) is an enzyme found in cerebral capillary endothelial cells, the presumed site of the blood-brain barrier, but not in endothelial cells lining blood vessels in other parts of the body. Using a line of mouse cerebral microvessel endothelial cells (ME-ly cells) and a sensitive colorimetric assay to measure gamma GTP levels we demonstrated that primary cultures of mouse astrocytes and a line of rat C6 glioma cells released a soluble product(s) that induced the production of gamma GTP in cultured endothelial cells by 34% and 39%, respectively, over control levels. Cerebrovascular smooth muscle cells had no significant effect on gamma GTP levels in ME-ly cells, and the astrocyte product(s) had no effect on rabbit aortic endothelial cells. The induction of gamma GTP levels in ME-ly cells was apparent after one day of exposure to the astrocyte product(s) and increased in magnitude with increasing time of exposure of the ME-ly cells to the product(s). Removal of the product(s) from the ME-ly cells resulted in a return to control levels of gamma GTP in the ME-ly cells within 2 days. The presence of a protein synthesis inhibitor during incubation with the product(s) blocked the induction of gamma GTP in ME-ly cells, and treatment of the product(s) with 200 U/ml TPCK-trypsin destroyed its inductive properties.(ABSTRACT TRUNCATED AT 250 WORDS)

The neuropathological basis for myoclonic encephalopathy associated with neuroblastoma has never been demonstrated. In our 6-year-old patient, the brain changes were restricted to the cerebellum and consisted of demyelination, gliosis, and loss of Purkinje's cells.

We present a case of bilateral herpes simplex and cytomegalovirus retinitis and concurrent encephalitis following acyclovir therapy in a homosexual male with the acquired immune deficiency syndrome (AIDS). At autopsy, herpes simplex virus antigens were readily detected in all retinal layers, retinal pigment epithelium, and choriocapillaris, using an immunoperoxidase technique, whereas herpes simplex antigens in the brain were localized in restricted foci of vascular and subependymal parenchymal cells. Cytomegalovirus antigens were identified in cells in all layers of retina, in retinal pigment epithelium, and in subependymal parenchymal cells in the brain. No cytomegalovirus antigens were detected in any vascular endothelium, in choroid, or anterior to the ora serrata. The widespread expression of herpes simplex virus antigens in this patient's retinas is in marked contrast to the restricted foci of herpes simplex antigens limited to the subependymal region of the brain, and is similar to that seen in murine models of herpes simplex retinitis produced by acyclovir-resistant viral mutants.

The geometry of the vascular system is such that the surface area to volume ratio changes dramatically as a unit volume of blood circulates. Thus, it faces a surface area that is some 1000 times larger in the capillaries than in larger vessels. To approach the in vivo situation an in vitro model for the microcirculation was developed that uses endothelium cultured on microcarrier beads. Details of the culture method are presented. The cultures form confluent monolayers around the beads and resist removal by vigorous vortex mixing. Viability of the cells on the microcarrier is 100 per cent. The microcarrier cultures are packed into small columns (0.3 to 1.0 ml.) forming a perfusion system and used for studies of the binding of thrombin and platelet factor 4, for the demonstration of anticoagulant properties of the cells, for studies of the interaction between endothelium and platelets, and for the demonstration of prostacyclin release.

Astroglial cells, both normal and neoplastic, secreted a product that stimulated glucose uptake by cerebral microvessel endothelial cells by 23% and 50%, respectively. Neither cerebral microvessel smooth muscle cells nor oligodendrocytes affected endothelial cell glucose uptake. The astrocytic product(s) did not affect glucose uptake by aortic endothelial cells. The effect on the cerebral microvessel endothelial cells increased with increasing time of exposure of the cells to the astroglial product(s), and required the constant presence of the astrocytic product to be maintained. The presence of a protein synthesis inhibitor during endothelial cell exposure to the astroglial conditioned medium blocked the stimulation of glucose uptake. Treatment of the astrocytic product with a protease destroyed its effectiveness. These results support the hypothesis that astrocytes induce the expression of at least one blood-brain barrier property by the cerebral microvasculature, and suggest that this induction may be produced by a protein released by the astrocytes.

The acquired immunodeficiency syndrome (AIDS) is characterized by a severe idiopathic deficiency in T-cell mediated immunity. Homosexuals, intravenous drug abusers and Haitians are predominantly affected, predisposing them to opportunistic infections and neoplasms. In this study, the central nervous system (CNS) was examined at autopsy in 29 AIDS patients. Significant CNS complications occurred in 55%, mainly related to opportunistic infections similar to those seen in patients with other causes of immunosuppression. Progressive multifocal leukoencephalopathy (three cases), cytomegalovirus (CMV) encephalitis (five cases), cryptococcal meningitis (four cases), Mycobacterium avium-intracellulare (three cases), and toxoplasmosis (one case) were found. Widespread microglial nodules were observed in 20 patients, 80% of whom had CMV inclusions elsewhere at autopsy. Primary cerebral lymphoma (one case) and lymphomatoid granulomatosis (one case) were present. Subarachnoid (five cases) and intraparenchymal (three cases) hemorrhage was seen although these were not usually clinically significant. A single case of embolic arterial obstruction with cortical infarction was due to non-bacterial thrombotic endocarditis.

An ultrastructural study utilizing horseradish peroxidase was performed to determine the mechanism and consequences of leakage of vascular protein following injury of the optic nerve. Unilateral optic nerve injuries were produced in four rhesus monkeys by making a cautery lesion on the retrobulbar portion of the optic nerve. Optic disc changes were followed with stereo fundus photography and fluorescein angiography. Three to 14 days after injury horseradish peroxidase was given intravenously and the tissue was prepared for electron microscopy, including serial sections of selected tissue blocks. Fundus photography and fluorescein angiography showed edema of the optic disc in two animals. There was leakage of horseradish peroxidase into the optic nerve head from the optic nerve lesion and the peripapillary choriocapillaris. Although the pathway of horseradish peroxidase leakage in the injured optic nerve was not entirely clear, serial sections indicated intraendothelial channels as one possible route. Alterations of the optic nerve head were confined to the axon segments anterior to the injury, and included aggregation of mitochondria, disruption of neurotubules, and swelling. These findings suggest that optic nerve injury produces damming of axoplasmic flow and that swelling of the optic nerve head is the result of axon enlargement.

Adenosine uptake by cultured cerebral endothelium is a carrier-mediated process. The Km value for adenosine uptake is 5.0 microM and the vmax is 1.15 nmol/min/mg cell protein. The uptake system is inhibited by the adenosine analog 2-chloroadenosine at low adenosine concentrations. The results prove the existence of a nucleoside transport system associated with cerebral capillary endothelium.

An endothelial cell line has been established from a primary culture of cerebral microvessels isolated from Swiss-Webster mice. The microvessels were isolated by a mechanical dispersion and filtration technique. The cells that emerged from these microvessels, maintained in organoid cultures, proliferated and formed plaques of a single or mixed cell type. The endothelial cell line, designated ME-2, was isolated from one such morphologically homogeneous cell plaque, using both cloning ring techniques and C6 glioma-conditioned medium. An endothelial specific antiserum was made in rabbits and was used immunocytochemically to confirm the cell type of origin of the ME-2 cell line. Not only did the cell type specific antiserum react exclusively with endothelial cells in vivo, but in the brain the antiserum localized preferentially to the luminal membrane of the endothelium. The ME-2 endothelial cells have retained several of their unique properties such as cytomorphology, growth characteristics, and cell type specific surface antigens throughout the life of the line (in one case 40 passages before senescence).

BALB/c splenic lymphocytes were activated by co-culturing in vitro and in vivo with an endothelial cell line derived from outbred mouse brain capillaries. The lymphocytes underwent proliferation, and after intravenous injection into syngeneic mice, vasculitis was found in lungs, brain, and other organs between 3 and 8 days postinjection. Controls consisted of normal lymphocytes, lymphocytes activated by phytohemaglutinin in vitro, and lymphocytes activated in vivo by cultured fibroblasts or Freund's complete adjuvant. The control lymphocytes did not cause vasculitis when injected into syngeneic mice. Lymphocytes activated by endothelium displayed nonspecific cytotoxicity by 51Cr release against both endothelial and fibroblast cell lines.

In two siblings with limb-girdle muscle weakness and episodic headaches and vomiting from early childhood, progressive neurologic degeneration later developed, and both children died. In one child, corticosteroids induced improvement in both cerebral and muscular symptoms that lasted 1 year. This patient had elevated blood, urine, and spinal fluid lactate levels, together with increased cardiac output and oxygen consumption at rest. Several muscle fibers were characterized by a "ragged red" appearance with the trichrome stain. Subsarcolemmal and intermyofibrillar excess of mitochondrial oxidative enzyme reaction product was correlated with abnormal mitochondrial aggregates by electron microscopy. The brain revealed focal areas of cortical degeneration and necrosis with adjacent gliosis or edema. Ferrocalcific deposits were prominent in the globus pallidus. The other sibling had similar changes in the brain at autopsy. This familial multisystem disorder especially involving the brain, skeletal muscle, and heart appears to represent a defect in some mitochondrial oxidative mechanism.

The application of immunologic techniques to tissue sections has added a new dimension to the investigation and classification of various processes. Virtually every section of diagnostic pathology has been enhanced by using specific monoclonal antibodies or polyclonal antiserum. Neoplasms formerly diagnosed as poorly differentiated or anaplastic may be precisely identified as to their origin through the use of specific membrane or cytoplasmic markers. Other cellular products, including viruses, hormones, enzymes or highly specific proteins, are also available to study neoplastic and nonneoplastic processes. New and more specific reagents are regularly becoming available for the diagnostic repertoire of pathologists. We present some of the principles of diagnostic immunopathology to show the scope and importance of the techniques.

Tritiated glucose analogues 3-O-methylglucose (3-OMG) and 2-deoxyglucose (2-DG) were used to study glucose uptake properties in established lines of cultured mouse cerebral microvessel endothelium. Uptake of both analogues was similar in terms of rate and absolute amount for the first two minutes. Thereafter, intracellular accumulation of 2-DG continued at a more rapid rate because of intracellular phosphorylation of this substrate. The uptake of 3-OMG uptake was temperature-dependent, independent of Na+, and not inhibited by ouabain or 2,4-dinitrophenol. Phloretin and cytochalasin B both significantly inhibited 3-OMG uptake. Other hexoses in high concentration acted as competitive inhibitors at the endothelial cell membrane. Pre-incubation of cells with 50 mM D-glucose resulted in higher levels of 3-OMG accumulation than in control cells (counter-transport phenomenon). In contrast to findings at the blood-brain barrier in vivo, insulin was found to stimulate 3-OMG uptake. Maximal stimulation of approximately 3-fold was found at ambient insulin concentrations of 1,000 ng/ml or higher. The findings provide support at the cellular level for some components of the model of carrier-mediated glucose transport across the blood-brain barrier which has been postulated to exist in vivo. The effect of insulin is discussed in the light of new data that show stimulation of glucose analogue transport into isolated cerebral capillaries.

Most mass lesions of the internal auditory canal and cerebellopontine angle are neoplastic, expansile, and eventually symptomatic. We report two cases of neurogenic hamartomas at these anatomic sites. In a patient with unrelated auditory or vestibular symptoms, such a developmental lesion might result in false-positive posterior fossa contrast results.