The decision to perform cardiopulmonary resuscitation
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Decision Making↗
Biomedical subjects
H L Lipton
Publications and source records attributed to H L Lipton.
Analysis of genetic variation in Theiler's virus during persistent infection in the mouse central nervous system.
The genetic changes occurring in the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) during persistent infection in the mouse central nervous system (CNS) were studied. RNase T1-oligonucleotide fingerprinting of the RNAs of 28 BeAn viruses isolated at various times postinfection (p.i.) demonstrated that mutation occurred throughout the infection. Although plaque-purified BeAn virus was used to inoculate mice intracerebrally, genetically different viruses were recovered from the CNS. One to three oligonucleotide changes were found up to Day 152 p.i., but all three viruses isolated at Day 180 had four to nine oligonucleotide changes. No pattern of oligonucleotide changes occurring in different virus isolates was found, yet three viruses isolated from different animals at Day 180 had the same four new oligonucleotides. Overall, the number of oligonucleotide changes represented a 0.1 to 1.2% change in the virus genome. In addition, the analytical two-dimensional gel technique of P.Z. O'Farrell, H.M. Goodman, and P.H. O'Farrell (Cell 12, 1133-1142, 1977) suggested that mutation occurred in all virus isolates. In nine isolates, one to three proteins were found to have charge changes, and in general, as many nonstructural proteins had charge changes as structural proteins. P20, a nonstructural protein probably equivalent to the protease described for encephalomyocarditis virus, was found to have shifted cathodally in six different viruses. Several virus isolates had doublet patterns, suggesting the possibility that within the CNS, subpopulations existed which had proteins of slightly different charge or that virus-specified proteins had been modified after translation. Finally, antigenic variation of neutralizing site(s) on BeAn virus isolates as a way for virus to evade immune surveillance and thereby maintain the persistent state was studied. The ability of mouse serum to neutralize persisting virus isolates was not significantly different from the ability to neutralize the infecting virus. Therefore, antigenic variation does not appear to be a factor in TMEV persistence.
Animals↗
Characterization of Vilyuisk virus as a picornavirus.
The V-1 strain of Vilyuisk virus, isolated from the cerebrospinal fluid of a chronic case of encephalomyelitis in Siberia and subsequently passaged 41 times in mice, was examined to determine its serological relationship to Theiler's murine encephalomyelitis virus (TMEV) and encephalomyocarditis (EMC) virus and some physicochemical characteristics of the virion. On the basis of virion size (28 nm), icosahedral symmetry, buoyant density (1.33 g/ml), sedimentation coefficient (150S), and capsid polypeptide profile, Vilyuisk virus appears to belong to the family Picornaviridae. Acute phase mouse antisera were used to study the antigenic relatedness of Vilyuisk, GDVII (the prototypic strain TMEV), and EMC viruses by enzyme-linked immunosorbent assay (ELISA). The results indicate that Vilyuisk and GDVII viruses are similar but distant subtypes, and that Vilyuisk and EMC viruses are unrelated.
Animals↗
Location and distribution of virus antigen in the central nervous system of mice persistently infected with Theiler's virus.
The present study has shown that virus can be readily detected by immunofluorescent staining in the central nervous system (CNS) of SJL mice persistently infected with Theiler's murine encephalomyelitis virus (TMEV). Considering the low CNS virus content, large amounts of virus antigen were found in the white matter, the site of demyelinating lesions. Virus antigen was detected in all animals killed after post-infection (PI) Day 21, a time which can be considered as the beginning of the persistent phase of this infection, and the appearance of virus antigen in white matter corresponded closely in time with the onset of demyelination. The pathogensis of this persistent infection can now be reasonably well reconstructed from the temporal observations made in this study. It would appear that between the second and third week PI, virus replication largely shifts from neurons in spinal cord gray matter to other cell types located in white matter. While a lower-grade persistent infection (in terms of the relative number of cells containing virus antigen) is established and maintained in cells in the gray matter and inflammatory and leptomeningeal infiltrates, cells in white matter appear to be mainly responsible for perpetuating the infection. Why these cells should supplant neurons as the most susceptible host cell during the chronic phase of the infection is discussed.
Animals↗
Characterization of Theiler's murine encephalomyelitis virus RNA.
Theiler's murine encephalomyelitis viruses are usually included in the enterovirus genus of the family Picornaviridae, although there is little physicochemical evidence to support this classification. In this report, the size of the RNA of highly virulent and less virulent representatives of the Theiler's group of viruses has been determined by sucrose gradient centrifugation and electrophoresis in agarose to be the same as that of other enteroviruses. The absence of a poly(C) residue provides evidence that these viruses are not cardioviruses or aphthoviruses. The base composition of the two members are similar to each other but differ from those of other enteroviruses. However the one- and two-dimensional maps of the ribonuclease T1 hydrolysates of the two virus RNAs show considerable differences despite their close serological similarity. Virus-specified RNA synthesis in cells infected with the more virulent strain of the virus was almost 10 times greater than that induced by the less virulent strain, in accord with the yields of virus particles.
Base Composition↗
Ultrastructural immunohistochemical localization of virus in acute and chronic demyelinating Theiler's virus infection.
Mice experimentally infected with Theiler's murine encephalomyelitis virus (TMEV) develop a persistent infection of the central nervous system (CNS). The most striking feature of this infection is the occurrence of inflammatory primary demyelination in the spinal cord white matter. The pathogenesis of myelin degeneration in this model has not been clarified, but morphologic and immunologic data suggest that the host immune response plays a major role in the production of myelin injury. Because of low virus titers in infected adult mice and of the small size of TMEV, virus particles have never been observed in this demyelinating model. Yet elucidation of the types of cells in the CNS supporting virus replication would be important for a better understanding of both virus persistence and virus-induced demyelinating pathology. The present paper is a sequential study of the localization of TMEV in the spinal cord in infected mice by ultrastructural immunohistochemical techniques. Results indicate that virus replication is mainly in neurons during the acute phase of the disease, while in the chronic phase viral inclusions are mainly found in macrophages in and around demyelinating lesions. Other cells are also infected, but to a lesser degree. In the neuronal system both axoplasmic and dendritic flow appear to facilitate the spread of virus in the CNS. In macrophages, the presence of virus particles and the association of virus with altered components of the cytoskeleton support active virus production rather than simple internalization. The macrophage appears to play an important role in both the establishment of virus persistence and in the process of demyelination in this animal model.
Animals↗
The graying of America: implications for the pharmacist.
Implications of the increased longevity of the U.S. population for the pharmacist are described. Recently, the growth of the population 65 years and older has been greater than that of the total population, and this trend is expected to continue at least until the end of the century. Because the elderly have more chronic illnesses than the younger population, the aging of the population means an increased use of prescription drugs. In addition, the sex ratio of men to women in the elderly population is decreasing; this trend is important for pharmacy practice because women at every age are prescribed and use more drugs than men. The need for prescription drugs imposes a financial burden on the elderly, many of whom live at or near the poverty level. Drugs constitute a major expense for the aged because drugs are a large percent of their out-of-pocket medical expenditures. Medication errors and noncompliance are chronic problems among the elderly because of their complex drug regimens, diminished physical activity, social isolation, physical and mental impairments, and lack of drug knowledge. In addition, the high cost of prescription drugs may contribute to medication under-use. Strategies for the pharmacist to prevent or treat noncompliance among the elderly are described. While most of the strategies have not been tested with the elderly population, practitioners working with geriatric patients have found them useful.
Aged↗
The growth of four human and animal enteroviruses in the central nervous systems of mice.
The pattern of CNS infection of our enteroviruses, Coxsackievirus A14, encephalomyocarditis (EMC) virus, GDVII virus, and Vilyuisk virus, was investigated. The regional sites of virus replication were correlated with pathological changes. These viruses were found to replicate and produce similar lesions in selected sites in the mouse CNS during acute infection. Virus antigen and histological lesions were essentially confined to the gray matter, with additional but less direct support for this being provided by virus assay of CNS regions. Virus antigen only could be confidently identified in neurons, and, histologically, neurons were observed in various stages of degeneration. The distribution of the involvement varied in the different infections. For example, EMC virus infection primarily affected the cerebral hemispheres and thalamus, while Coxsackievirus a14 infection predominantly involved the brainstem and spinal cord. GDVII and Vilyuisk virus infections more uniformly involved the entire neuraxis. There was no evidence of virus replication in the olfactory bulbs, leptomeninges, ependyma, choroid plexus, and vascular endothelium. The cerebellum was generally spared, with the cerebellar hemispheres affected only in Coxsackievirus A14 infection. It therefore appears that enteroviruses selectively infect different populations of nerve cells.
Animals↗
Theiler's murine encephalomyelitis virus group includes two distinct genetic subgroups that differ pathologically and biologically.
The intracellular development and RNA composition of Theiler's murine encephalomyelitis virus (TMEV) isolates were determined by electron microscopy, sucrose gradient centrifugation, and RNase T1 fingerprinting. Replication of FA virus, a virulent strain of TMEV, was characterized by the appearance of viral crystalline arrays in the cytoplasm of infected cells. In contrast, cells infected with the less virulent isolates (WW, TO4, BeAn 8386, and Yale) showed no crystalline arrays; instead, virions were found to be arranged between two layers of membranes in the cytoplasm of infected cells. Analysis of the RNAs of TMEV isolates showed that the RNAs were single-stranded molecules having sedimentation coefficients of 35S. RNase T1 fingerprinting of TMEV RNA revealed that striking differences between the virulent and less virulent TMEV isolates existed. Moreover, base composition analysis of RNase T1-resistant oligonucleotides of two TMEV isolates which represented the two subgroups indicated that there were no substantial oligonucleotides common to both subgroups. Based on these findings and the known difference in virulence, we suggest that the TMEV group contains two genetically district subgroups of viruses.
Animals↗
Replication of Theiler's murine encephalomyelitis viruses in BHK21 cells: an electron microscopic study.
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Animals↗
Persistent Theiler's murine encephalomyelitis virus infection in mice depends on plaque size.
Theiler's murine encephalomyelitis virus (TMEV) is an enteric pathogen of mice which causes acute and chronic neurological disorders in the natural host. When brain-derived stocks of TMEV isolates are adapted to cell culture they predominantly form either large or small plaques. In this study the type of central nervous system (CNS) infection (acute versus chronic) and the associated disease occurring in mice inoculated intracerebrally with large and small plaque strains of TMEV was investigated. Large and small plaque strains of TMEV were found to vary in virulence, type of neurological disease produced and ability to establish persistent CNS infection in mice. Two large plaque strains, GDVII and FA viruses, were highly virulent, produced acute encephalitis, but were cleared from the nervous systems of surviving animals. Therefore, it appears that these large plaque variants do not cause persistent CNS infection in mice. In contrast, five small plaque strains, DA, WW, TO4, Yale and BeAn8386 viruses, were relatively avirulent, usually produced no illness during the first month after inoculation, but readily established persistent CNS infection in mice. Persistently infected mice later developed demyelinating disease. Having identified strains of TMEV that differ regarding their ability to persist, we now hope to be able to exploit this difference in elucidating the basic mechanism(s) of TMEV persistence.
Animals↗
Purification of Theiler's murine encephalomyelitis virus and analysis of the structural virion polypeptides: correlation of the polypeptide profile with virulence.
Theiler's murine encephalomyelitis viruses (TMEV) are separable into two groups based on their biological behavior: those highly virulent isolates which are unable to cause persistent infection and the less virulent isolates which regularly produce persistent central nervous system infection in mice. Two highly virulent and five less virulent TMEV were found to have the same buoyant density (1.34 g/ml) on isopycnic centrifugation and virion structure by electron microscopy. Negatively stained virus particles purified in Cs(2)SO(4) gradients appeared to have icosahedral symmetry and measured 28 nm in diameter. Mature virions were found to possess three major structural polypeptides, VP1, VP2 and VP3, in the range of 25,000 to 35,000 daltons, and a smaller fourth major polypeptide, VP4, of 6,000 daltons on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The precursor of VP2 and VP4, VP0, which is a minor polypeptide of mature picornavirus particles, was also identified. However, a slight but consistent difference in several of the capsid polypeptides between the highly virulent and less virulent TMEV was found. VP1 was slightly larger (34,000 versus 33,500 daltons) and VP2 was slightly smaller (31,000 versus 32,000 daltons) for the highly virulent strains compared to the same polypeptide species in the less virulent viruses. VP0 was also slightly smaller (35,500 versus 36,000 daltons) for the highly virulent isolates compared to their less virulent counterparts. Finally, trypsin which was used initially in our purification procedure resulted in preferential cleavage of a 2,000-molecular-weight fragment or fragments from VP1 of only the less virulent isolates.
Centrifugation, Density Gradient↗
Schwann cell remyelination and recurrent demyelination in the central nervous system of mice infected with attenuated Theiler's virus.
Theiler's murine encephalomyelitis virus (TMEV) infection produces a chronic demyelinating disease in mice, and myelin breakdown appears to be immune-mediated. By using an attenuated TMEC strain, WW virus, to infect mice, the course of the disease was slowed and the severity of the inflammatory and glial responses were reduced. In this circumstance, most of the demyelinating lesions showed extensive remyelination, predominantly by Schwann cells. In addition, it was demonstrated that there was recurrent demyelinating activity in the central nervous system (CNS) of infected animals. It is suggested that the rapidity and intensity of demyelinating lesions may influence the potential for remyelination and that Schwann cell participation may be a more important mechanism of myelin repair than it is now thought to be. The fact that there is a recurrent demyelination in TMEV infection increases its relevance as an experimental animal model for multiple sclerosis.
Animals↗
Hereditary multiple exostoses with myelopathy.
A 58-year-old woman with hereditary multiple exostoses had slowly progressive myelopathy due to a vertebral exostosis that compressed the spinal cord at T1-2. She did not show skeletal deformities, but had numerous palpable long-bone exostoses. While CNS complications are rare in hereditary multiple exostosis, 17 other cases have been reported.
Exostoses, Multiple Hereditary↗
The TO strains of Theiler's viruses cause "slow virus-like" infections in mice.
Intracerebral inoculation of mice with tissue culture-adapted TO strains of Theiler's mouse encephalomyelitis viruses results in a clinical disease consisting of spastic paralysis due to demyelination after a lengthy incubation period. Thus, in effect, these ordinary picornaviruses are capable of causing a slow infection in their natural host, the mouse. In addition, through the use of tissue culture-adapted virus stocks, virus content in mouse tissues now can be accurately quantified by standard plaque assay.
Animals↗
Recurrent demyelination in chronic central nervous system infection produced by Theiler's murine encephalomyelitis virus.
A morphologic study of demyelination produced by Theiler's encephalomyelitis virus (TMEV) infection in C3H/He mice was performed. Demyelination in this strain of mouse was less intense and had a milder gliomesodermal response than that observed in SJL mice. As early as 80 days after infection numerous remyelinated axons were present in C3H/He mice, and later, extensive remyelination was observed and was mainly by Schwann cells. About one-third of remyelinated plaques showed recurrent demyelinating activity at 200 days. The best evidence of recurrent demyelination was the loss of myelin by abons which had been previously remyelinated by Schwann cells. In addition, acute areas of demyelination were also seen in spinal cords which contained chronic or quiescent plaques. The demonstration of recurrent demyelination in TMEV infection is important for it increases the relevance of this model to multiple sclerosis (MS). In addition TMEV infection of C3H/He mice appears to be an excellent model for further studies of Schwann cell remyelination and recurrent demyelination in the central nervous system (CNS).
Animals↗
Potentiation of experimental allergic encephalomyelitis in hamsters with persistent encephalitis due to measles virus.
To clarify mechanisms underlying acute disseminated encephalomyelitis (ADE) in patients with infection due to measles or other viruses, a new animal model was devised. Adult hamsters that had clinically recovered from acute encephalitis induced by prior intracerebral injection of the HBS strain of measles virus were challenged with neuroantigen plus adjuvant. Such hamsters, which had a high likelihood of carrying persistent HBS measles virus in the central nervous system (CNS), exhibited a significantly higher incidence of experimental allergic encephalomyelitis (EAE) following challenge as compared with simultaneously challenged but previously uninfected littermates. Occurrence of EAE in hamsters previously injected with heat-inactivated virus was not potentiated, a finding suggesting that persistence of the virus in the CNS renders that organ system more vulnerable to immunologic attack. This new model has promise for the probing of relationships between persistent viral infections of the CNS and host autoimmune responses directed against that target organ system.
Acute Disease↗