Transmission of Creutzfeldt-Jakob disease from man to the guinea pig.

Intracerebral and intraperitoneal inoculation of two guinea pigs with biopsy material from a patient with Creutzfeldt-Jakob disease produced a similar fatal encephalopathy characterized by status spongiosus 422 and 512 days after inoculation. Serial transmission of this disease from guinea pig to guinea pig was achieved in subsequent passages.

Cholera toxin-peroxidase: changes in surface labeling of glioblastoma cells with increased time in tissue culture.

Cholera toxin coupled to peroxidase yielded a highly specific ultrastructural marker of plasma membrane monosialogangliosides. Studies with cultures of brain and brain tumors suggested that long-term culture of tissue in monolayers results in eventual loss of surface monosialogangliosides.

Viremia in experimental Creutzfeldt-Jakob disease.

Inoculation of the buffy coat of blood from guinea pigs infected with Creutzfeldt-Jakob disease resulted in passage of this disease to recipient animals. This demonstrates that there is a viremia in experimental Creutzfeldt-Jakob disease. These findings suggest that the hematogenous route may be implicated in the human infection and that the disease may possibly be transmitted by blood transfusions.

Amount of satellite DNA in four experimentally induced tumors of the central nervous system. Quantitative changes in a glioblastoma producing C-type particles.

The quantitative preservation of satellite NA was studied in several central nervous system (CNS) neoplasms; four tumor lines deriveo from 3-methylcholanthrene implantation into the CNS of mice were compared with brain and tissue cultures of normal mouse cells by analytical centrifugation in cesium chlorie. Three tumors showed no detectable difference from normal cells; nuclear and whole cell preparations were comparable. Only a glioblastoma line proucing C-type particles (TC509) revealed a significant difference from normal cells and exhibited a decrease of approximately 20% in satellite DNA or 2% of the total DNA on repeated examination for 1 year. C-type RNA virus may be related to relative decreases in satellite DNA observed in TC509.

Creutzfeldt-Jakob disease.

The historical aspects of spongiform encephalopathies, Creutzfeldt-Jakob disease (CJD) and kuru of man, as well as scrapie and transmissible mink encephalopathy, are outlined. Transmissions of these diseases to animal hosts are presented, with emphasis on CJD transmissions to guinea pigs, hamsters, and mice. The relationship of CJD to scrapie with reference to the pathological findings is discussed. In CJD the incubation period is cut in half in guinea pigs and hamsters in the second passage. The spongiform changes occurring in the neuropil are reviewed. These changes are related to the type of inoculum, e.g., there is more vacuolization after inoculation with brain, and less after inoculation with spleen. Spongiform changes are also dependent upon the route of inoculation; these are more severe in intracerebral inoculation compared to intraperitoneal inoculation. Viremia is present. Maternal transmission and lateral transmission are absent. No virus-like particles are detected, and no other organisms are visible by electron microscopy. Isolations of the causative agent and strains of the agent in spongiform encephalopathies remain elusive. The hypotheses concerning the nature of the agent are critically reviewed. Novel data on the production of tumors derived from CJD brains are presented. Tissue culture cells arising from such brains become permanent lines and are similar to neoplastic lines. When such CJD lines are injected subcutaneously into nude mice, malignant neoplasms are formed. No evidence of an infectious etiology in Alzheimer's disease exists. Reported similarities between this disease and CJD are reviewed. Animal models of CJD are useful for the investigation of dementias.

Ultrastructural findings in experimental Creutzfeldt-Jakob disease in guinea pigs.

Brains from six clinically ill guinea pigs from various serial passages infected with brain homogenate from a patient with Creutzfeldt-Jakob disease were studied by light and electron microscopy. There were no appreciable morphologic differences among the animals at different passages. Light microscopy revealed clearing, swelling, and vacuolar changes in neurons and astrocytes. These changes occurred in both perikarya and cell processes. Large isolated vacuoles in the neuropil appeared to develop by progressive fusion between swollen cellular processes. By electron microscopy many neuronal processes contained degenerating organelles, osmiophilic bodies, membranous bodies and approximately 10 mm filamentous structures. In addition, vacuoles and membranous inclusions were seen in some neuronal nuclei, changes which have not been previously observed in spongiform encephalopathies.

In vitro transformation elicited by Creutzfeldt-Jakob-infected brain material.

Previous studies indicated that tissue culture cells derived from Creutzfeldt-Jakob disease (CJD) brains possess neoplastic properties. In order to see if CJD brain material could itself transform cells in vitro, BALB/C-3T3 and normal hamster brain monolayer cultures were exposed to whole brain homogenate or synaptosomal-mitochondrial fractions derived from CJD or control brains. Cells were exposed for seven days to CJD or control brain material, washed, and then passaged at weekly intervals. Transformation was evaluated by loss of contact inhibition, replication of cells with absent or low serum content of the medium and significant colony formation in soft agar. Seven parallel experiments were done, and six were viable. All cultures exposed to CJD material containing greater than or equal to 10(4) LD50 infectious units were positive for transformation (five of six studies); the single negative experiment contained only 2 X 10(3) infectious units. Definitive transformation could be observed at 12-16 weeks after application of both mouse and hamster CJD material. BALB/C-3T3 cells exposed to control hamster or mouse brain material were studied for greater than 120 passages in vitro and showed no comparable changes or evidence of spontaneous transformation, i.e. they required serum for replication and produced essentially no colonies in soft agar. Similarly, a normal adult hamster brain culture exposed to control brain material showed no evidence of transformation, whereas the identically passaged normal brain culture exposed to CJD material not only became a permanent line, able to grow in soft agar, but also was capable of producing tumors in nude mice. Thus CJD transformation was not confined to special potentials of "permanent" BALB/C-3T3 cells. These experiments suggest that a genomic alteration can be effected by CJD material.

Creutzfeldt-Jakob infection increases adenylate cyclase activity in specific regions of guinea pig brain.

Creutzfeldt-Jakob disease is a slow, infectious, progressive neurological disorder which results in human dementia. Synaptic membranes from various brain regions of guinea pigs infected with Creutzfeldt-Jakob disease show increased guanyl nucleotide- or 5-hydroxytryptamine-mediated activation of adenylate cyclase. This increased enzyme activity appears due, primarily, to facilitated 'coupling' between the GTP-binding protein which stimulates adenylate cyclase (GNs) and the catalytic moiety of that enzyme rather than increased sensitivity to 5-hydroxytryptamine. It is possible that this phenomenon is due to direct effects of the Creutzfeldt-Jakob infectious agent, or a pathological product resulting from that agent, upon synaptic membrane adenylate cyclase.

Transmission of Alpers' disease (chronic progressive encephalopathy) produces experimental Creutzfeldt-Jakob disease in hamsters.

We successfully and serially transmitted to outbred and inbred strains of hamsters the brain tissue of a 2 1/2-year-old girl with a chronic progressive encephalopathy (Alpers' disease) characterized postmortem as a spongiform encephalopathy. In all hamster strains we produced a spongiform encephalopathy. The light and ultrastructural changes in the brain of hamsters, as well as the clinical signs of experimental disease, are identical to those obtained in transmission experiments of human Creutzfeldt-Jakob disease (CJD). CJD infection may be more widespread than previously recognized and can be manifested in infancy.

Ependymomas of the spinal cord.

Many patients with spinal cord ependymomas (SCE) undoubtedly benefit from post-operative radiation therapy; however, because of the wide variability in the total doses given, the optimal post-operative dose for SCE remains unclear. Several recent papers recommend total doses of 4000 rad to 5000 rad in 4 1/2 to 6 weeks. Unfortunately, only a small number of patients reported in the literature have been consistently treated to these high dose recommendations. Nine consecutive adult patients with SCE have been treated in a consistent way at Yale-New Haven Hospital with total doses of approximately 4500 rad to 5000 rad at 180 rad to 200 rad per day. The acute and chronic morbidity from such treatment has been minimal and no patient has had a local recurrence at 8 months to 8 years following treatment.

Immunohistochemistry of capillary hemangioblastoma. Immunoperoxidase-labeled antibody staining resolves the differential diagnosis with metastatic renal cell carcinoma, but does not explain the histogenesis of the capillary hemangioblastoma.

We used a battery of antigens to determine whether immunohistochemistry can (a) contribute to resolving the histogenesis of the stromal component of the capillary hemangioblastoma, and (b) answer cases of difficult pathologic differential diagnosis with metastatic clear cell carcinoma. The stromal cells of the capillary hemangioblastoma are antigenically polymorphous and may express immunoreactive erythropoietin, renin, keratin, Leu M1, Leu 7, actin, neuron-specific enolase, S100 protein, and glial fibrillary acidic protein. However, the use of epithelial membrane antigen allows certain histopathologic distinction between capillary hemangioblastoma and metastatic clear cell carcinoma.

Diaphragm pacing: histopathological changes in the phrenic nerve following long-term electrical stimulation.

Phrenic nerves were obtained at autopsy from 7 patients with chronic ventilatory insufficiency. One or both nerves had been subjected to electrical stimulation to pace the diaphragm for about 2 months to 4 years. Sections of the nerves made from above, at the level of, and below the site of application of the cuff electrode were studied microscopically. In most specimens, focal areas of demyelination were seen ranging from severity from swelling and fragmentation of isolated fibers to focal myelin destruction with phagocytic activity and total removal of myelin with fibrosis. Some axone loss was seen. The fact that the nerves from 2 patients, each stimulated for about 2 years, showed no changes suggests that injury to the nerve was not caused by the electrical stimuli but rather was secondary to the technique of application and fixation of the cuff electrode to the nerve.

Malignant glioma of the optic chiasm eight years after radiotherapy for prolactinoma.

A 41-year-old man had rapidly progressive visual loss caused by a malignant glioma that developed in the optic chiasm eight years after radiation therapy for a recurrent prolactinoma. Radiation-induced glioma should be considered as a cause of progressive visual loss in patients who have received irradiation in the region of the sella turcica.

Human eastern equine encephalitis. Electron microscopic study of a brain biopsy.

An electron microscopic study was done on brain biopsy tissue from an eight-month-old female with acute eastern equine encephalitis diagnosed by indirect immunofluorescence. Rare clusters of round virions were found almost exclusively in the extracellular space. All virions observed had spiked envelopes, and their sizes averaged approximately 55 nm. Also found were rare enveloped virions along with degenerate organelles in a membrane-bound structure in the cytoplasm of macrophages. Intracytoplasmic development of virions was not found. Tubuloreticular complexes were seen in the endothelial cells and macrophages. This is the first report of an electron microscopic study on biopsy material from a case of human eastern equine encephalitis. It will extend the usefulness of brain biopsy in the diagnosis of acute encephalitis.

Renin in glioblastoma multiforme and its role in neovascularization.

Significant proliferation of capillaries with hyperplastic vascular endothelium is one of the characteristic histologic features of glioblastoma multiforme (GBM). It has been shown that the renin-angiotensin II cascade stimulates new vessel formation. The presence of renin in several types of highly vascularized neoplasm suggests that it may also be implicated in the mechanism of tumor angiogenesis. In order to study the possible relationship of renin to GBM, immunohistochemical search for human renin was carried out in ten instances of such a tumor. Eight of these cases demonstrated renin-containing neoplastic astrocytes, whereas seven cases of reactive gliosis and six cases of low-grade astrocytoma revealed no renin-containing cells. The immunostaining was not present after preabsorption of the renin antiserum with pure human renin or substitution of preimmune serum for the specific renin antiserum. Because it has also been demonstrated that a product of renin, angiotensin II, has angiogenic properties, it seems reasonable to postulate that renin, through angiotensin II, may play a role in the mechanism of GBM-associated neovascularization.

Ganglioside alterations in guinea pig brains at end stages of experimental Creutzfeldt-Jakob disease.

Gangliosides were isolated from guinea pig brains at the end stages of experimental Creutzfeldt-Jakob disease. Quantitative analyses revealed marked decreases of ganglioside levels in pathologically devastated tissues such as cerebral cortex (-21%), basal ganglia and thalamus (-18%), and brain stem (-23%). The cerebellum revealed only minor pathological abnormalities and its ganglioside level remained unchanged. Thin-layer chromatography of the Creutzfeldt-Jakob brain gangliosides showed aberrant ganglioside patterns in all regions studied, including the cerebellum. With some exceptions, a trend in ganglioside pattern changes was detected which consisted of proliferation of GM3, GD3, GD2 and loss of GM1, GD1a, GD1b and GT1b.

Neuronal alterations in experimental Creutzfeldt-Jakob disease: a Golgi study.

Neuronal alterations in the cortex of hamsters with experimental Creutzfeldt-Jakob disease (CJD) were studied utilizing the rapid Golgi and Golgi-Hortega methods. In terminally ill hamsters many pyramidal neurons showed a considerable decrease in the number of dendritic spines often with moderate irregularities in size. The shafts of apical dendrites in some cortical pyramidal neurons were tortuous. Occasional neuronal cell bodies were irregular in contour and showed hole-like empty spaces. Two types of focal swellings, which involved both axons and dendrites, were observed; focal swellings were either semitranslucent or darkly impregnated. Possible mechanisms for the pathogenesis of the semitranslucent and dark swellings are discussed. The neuronal changes showed no preponderance for a particular neuronal group or for selective segments of individual neurons.

Cerebral glycosidases in experimental Creutzfeldt-Jakob disease.

In Creutzfeldt-Jakob disease (CJD), there are prominent ultrastructural alterations of the plasma membrane, which contains many glycolipids and glycoproteins. Glycosidases can degrade glycolipids and glycoproteins. Gangliosides, a subset of glycolipids, are decreased in amount at the terminal stages of CJD, and CJD infectivity is closely associated with membrane rich fractions. We therefore studied 10 glycosidases, and found a statistically significant increase in beta-xylosidase, beta-glucuronidase, N-acetyl-beta-D-glucosaminidase and N-acetyl-beta-D-galactosaminidase activities in CJD. In contrast, alpha-glucosidase, beta-glucosidase, alpha-galactosidase, alpha-mannosidase, alpha-fucosidase, and beta-galactosidase were not significantly changed. The above results are consistent with degenerative membrane changes observed morphologically, and with increased degradation of sugar residues on lipids and/or proteins. These changes may be effected by the accumulation of the CJD agent in cell membranes. We suggest that the higher activities of these enzymes in CJD may be partially responsible for some of the structural and biochemical alterations in CJD infected brains.

Pineal apoplexy associated with anticoagulant therapy. Case report.

A case is presented with the acute development of a pineal region syndrome secondary to hemorrhage into a pineal cyst in a patient who was under anticoagulant therapy. Resolution of the symptoms and signs followed excision of the lesion.