Measles virus matrix protein gene expression in a subacute sclerosing panencephalitis patient brain and virus isolate demonstrated by cDNA hybridization and immunocytochemistry

Summary Subacute sclerosing panencephalitis (SSPE) is a rare, fatal disease of children caused by a persistent measles virus infection of the central nervous system. A defect in synthesis of measles virus matrix (M) protein may be a factor in virus persistence in the brain. This study details attempts to detect expression of M protein in the brain of an SSPE patient, in the cell-associated virus isolated from this brain, and in brains of ferrets inoculated with the isolate. In situ hybridization with a tritiated cloned cDNA probe was used to search for RNA encoding M protein. Immunostaining with monospecific antiserum and the avidin-biotin-peroxidase technique was done to locate the polypeptide. The data obtained indicate that although nucleotide sequences coding for M protein were detected in the patient and ferret brains, expression of M protein in these tissues could not be detected. In the cultured SSPE virus isolate, the results were the same until the infected cells were examined by electron microscopy and a very limited expression of M protein was revealed. This suggests either diminished synthesis and/or rapid degradation of M protein in this cell-associated virus strain.This paper is dedicated to the late Dr. George A. Jervis, first Director of the Institute for Basic Research, Physician and Scientist, for his humanity and many contributions to the mentally retarded and developmentally disabled.     

Marginal glioneuronal heterotopias in nine cases with and without cortical abnormalities

Nine cases of marginal glioneuronal heterotopias over the cerebral cortex were reviewed from the morphological point of view. There were developmental disabilities in all cases except one (case 8), who was stillborn. All subjects died before 1 year of age except one (case 5). The common features of small glioneuronal heterotopias and abundant heterotopic glioneuronal proliferation are described. The correlation of glioneuronal heterotopias with polymicrogyria and other cortical malformations, as well as their appearance over a normal cortex, are described. The glioneuronal heterotopias are considered to be a separate type of malformation that could arise during the second half of intrauterine life. A breach of the neuropial border seems to be the most acceptable pathomechanism for our presented cases. Their morphological features indicate that damage to this barrier leads to involvement of glioneuronal heterotopias in fusion of opposite cortical convolutions.     

Young adult-form of dementia with neurofibrillary changes and lewy bodies

Summary Alzheimer's neurofibrillary tangles, Lewy bodies and chromatolytic neurons were found in the brain at autopsy of a 28-year-old male with pyramidal and extrapyramidal signs, and severe dementia of 7-year duration prior to his death. Review of histological material showed generalized changes involving both cortical and subcortical structures. These changes were characterized by the presence of neurofibrillary tangles, Lewy bodies and chromatolytic neurons. Neuritic plaques were not found. There was also loss of neurons and gliosis in the prefrontal cortex, hippocampus, amygdaloid nucleus, basal ganglia, midbrain and pons. There were spongiform changes due to loss of neurons. Myelin stain showed pallor of myelin in long tracts and in subcortical regions. The neurofibrillary tangles were mostly composed of Alzheimer's paired helical filaments (PHF). PHF were immunostained with both polyclonal and monoclonal antibodies to PHF and the microtubule-associated protein tau. Some Lewy bodies were immunolabelled with monoclonal antibodies to PHF. To the best of our knowledge it is the first reported case of a young adult-form of dementia with extensive formation of neurofibrillary changes and Lewy bodies.Supported in part by grants from the NIH NS18105 and POINS04220     

Detection of scrapie-associated fibrils (SAF) and SAF proteins from scrapie-affected sheep

Scrapie-associated fibrils (SAF) were detected by negative-stain electron microscopy in the brains (by two different isolation procedures) and spleens of sheep naturally and experimentally infected with scrapie. Although the numbers of SAF varied from case to case, the yield of SAF from brains of naturally affected sheep was lower than that from experimentally affected sheep. SAF-specific, protease-resistant proteins (PrPs) were detected by silver staining and western blot analysis in most samples of brain from experimentally affected sheep. PrPs, however, could be detected in only a limited number of natural cases of sheep scrapie because of the lower yields of SAF. PrPs from sheep SAF appear biochemically and antigenically similar to PrPs from other species infected with unconventional agents. This study further establishes the unique association of SAF and PrPs with natural or experimentally induced scrapie in its natural host.     

The spatio-temporal pattern of Wallerian degeneration in the Rhesus monkey optic nerve

Summary Three patterns of degeneration were distinguished in the Rhesus monkey optic nerve following eye enucleation. (1) A traumatic zone, extending for 1 to 2 mm from the site of transection and characterized by a rapid infiltration of haematogenous macrophages, the rapid degeneration and removal of all neural elements and the formation of astrocytic scar tissue within 35 days. (2) A conical zone, closely associated with the central retinal blood vessels, in which the pattern of degeneration was similar to the traumatic zone except that the onset was delayed and the removal of debris was slower. There was extensive vesiculation of myelin sheaths in these two zones which was indicative of haematogenous cell infiltration. (3) The remainder of the nerve underwent classical Wallerian degeneration in which endogenous cells slowly phagocytosed the degenerating nerve fibres. These observations are considered relevant to the controversy concerning the identification of the macrophage involved in Wallerian degeneration; many studies have described the macrophage within the area of trauma rather than the macrophage involved at some distance from the site of trauma.Supported by Grants 692-B-2 from the National Multiple Sclerosis Society; NS 02255 and NS 08180 from the National Institutes of Health and a grant from the Alfred P. Sloan Foundation     

Identification of IgG subclasses'' oligoclonal bands in multiple sclerosis CSF

IgG subclasses' oligoclonal bands in unconcentrated CSF from MS patients were detected by isoelectric focusing in agarose gel with subsequent immunoblotting using mouse monoclonal antibodies to human IgG subclasses and double-antibody avidin-biotin-alkaline phosphatase system. All MS CSF showed presence of oligoclonal bands specific to the IgG1 subclass; in addition, several of these samples also had oligoclonal bands specific to IgG3, IgG2, or IgG4, in order of decreasing frequency. Since the CSF of a greater number of MS patients showed oligoclonal bands specific to the IgG1 and IgG3 subclasses, the findings are consistent with those reported in patients with chronic viral infections and autoimmune diseases.     

Body weight and coronary disease risk: patterns of risk factor change associated with long-term weight change. The Normative Aging Study

Previous studies have suggested that excess body weight increases coronary disease risk by modification of the levels of other risk factors and in addition may contribute to overall risk independently. Few studies, however, have systematically characterized long-term change in risk factors with specific changes in overall weight while they have controlled for the effects of multiple potential confounders. Also, very little information is available on the differential impact of weight change on risk factor changes with advancing age. The present investigation used 15 years of longitudinal data collected on 1,396 men participating in the Veterans Administration Normative Aging Study in Boston, Massachusetts. Multiple regression analysis was used to predict change in each of eight putative coronary disease risk factors from change in weight and the interaction between weight change and age. These included blood pressure, serum cholesterol, triglycerides, fasting and two-hour postprandial blood glucose, uric acid, and forced vital capacity of the lungs. After controlling for initial levels of the risk factor, weight, age, and smoking status, change in weight remained a significant predictor of long-term change in each of the risk factors studied. In addition, the interaction between weight change and age was significant for fasting glucose, uric acid, and forced vital capacity, indicating that the effect of weight gain on uric acid and forced vital capacity was greater in younger men whereas the effect of weight gain on fasting glucose was greater in older men.     

Sequential appearance of anionic domains in the developing blood-brain barrier

The distribution of anionic sites in the walls of mouse brain micro-blood vessels (MBVs) during development and maturation of the blood-brain barrier (BBB) was studied by electron microscopy. Cationic colloidal gold (CCG) and Lowicryl K4M-embedded brain samples obtained from mouse fetuses (13th and 19th days) and from 1-, 5-, 12- and 24-day-old and adult mice were used. The labeling of anionic sites with CCG was more intense on the abluminal than on the luminal front of the endothelial cells (ECs) in fetuses and in newborn mice. Only a few anionic sites appear on the luminal front of the ECs of proliferating blood vessels invading the neural tissue in 13-day-old fetuses. They become slightly, although steadily, more abundant during further stages of development, and their number rapidly increases between the 12th and 24th day of life at which time they attain the density typical for mature animals. The maturation of the basement membrane (BM), which occurs during the myelinization period (12th-24th day of life), also coincides with an increasing concentration of anionic sites. These observations suggest that the gradual appearance of anionic sites on both fronts of the endothelium, as well as in the developing and maturing BM, represents one of the mechanisms responsible for differentiation of cerebral microvasculature into BBB-type MBVs.     

Pathogenesis and pathology of scrapie after stereotactic injection of strain 22L in intact and bisected cerebella

The mechanisms involved in the spread of scrapie within the brain remain unclear. To examine this issue the 22L scrapie strain was injected in one side of the cerebellum of mice in which the cerebellum had been bisected prior to injection. Another group of animals received the same injection into intact cerebella, i.e. without prior bisection. We found that bisection of the cerebella delayed the spread of scrapie agent from the injection site to the contralateral side of the cerebellum and that the occurrence of vacuolization was not as extensive and was markedly delayed in the uninjected side compared to its occurrence after injection in the intact cerebellum. Replication of agent in an area preceded the development of vacuolization in that area by several weeks. There was marked loss of Purkinje cells on the injected side of bisected cerebella, with no loss seen on the uninjected side. The incubation period of scrapie disease in mice injected after cerebellar bisection was significantly longer than after the injection of intact cerebella. The results in this study suggest that the scrapie agent spreads along intact nerve cell tracts, probably by axonal transport.