Application of distance geometry to 3D visualization of sequence relationships.
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SUMMARY: We describe the application of distance geometry methods to the three-dimensional visualization of sequence relationships, with examples for mumps virus SH gene cDNA and prion protein sequences. Sequence-sequence distance measures may be obtained from either a multiple sequence alignment or from sets of pairwise alignments. AVAILABILITY: C/Perl code and HTML/VRML files from http://www.nibsc.ac.uk/dg3dseq/ (+info)
Failure of measles virus to activate nuclear factor-kappa B in neuronal cells: implications on the immune response to viral infections in the central nervous system.
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Neurons are postmitotic cells that foster virus persistence. These cells lack the HLA class I molecules required for clearance of infected cells. Previously, we showed that HLA class I is induced by measles virus (MV) on glial cells, which is primarily mediated by IFN-beta. In contrast, MV was unable to induce HLA class I or IFN-beta in neuronal cells. This failure was associated with lack of NF-kappa B binding to the positive regulatory domain II element of the IFN-beta promoter, which is essential for virus-induced IFN-beta gene activity. In this study, we demonstrate that the failure to activate NF-kappa B in neuronal cells is due to the inability of MV to induce phosphorylation and degradation of I kappa B, the inhibitor of NF-kappa B. In contrast, TNF-alpha induced degradation of I kappa B alpha in the neuronal cells, suggesting that failure to induce I kappa B alpha degradation is likely due to a defect in virus-mediated signaling rather than to a defect involving neuronal I kappa B alpha. Like MV, mumps virus and dsRNA failed to induce I kappa B alpha degradation in the neuronal cells, suggesting that this defect may be specific to viruses. Autophosphorylation of the dsRNA-dependent protein kinase, a kinase possibly involved in virus-mediated I kappa B alpha phosphorylation, was intact in both cell types. The failure of virus to induce I kappa B alpha phosphorylation and consequently to activate NF-kappa B in neuronal cells could explain the repression of IFN-beta and class I gene expression in virus-infected cells. These findings provide a potential mechanism for the ability of virus to persist in neurons and to escape immune surveillance. (+info)
The mumps virus neurovirulence safety test in Rhesus monkeys: a comparison of mumps virus strains.
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Wild type mumps viruses are highly neurotropic and a frequent cause of aseptic meningitis in unvaccinated humans. To test whether attenuated mumps viruses used in the manufacture of mumps vaccines have neurovirulent properties, a monkey neurovirulence safety test (MNVT) is performed. However, results with several mumps virus MNVTs have raised questions as to whether the test can reliably discriminate neurovirulent from nonneurovirulent mumps virus strains. Here, various mumps virus strains representing a wide range of neuropathogenicity were tested in a standardized MNVT. A trend of higher neurovirulence scores was observed in monkeys inoculated with wild type mumps virus versus vaccine strains, although differences were not statistically significant. Results indicated the need for further examination and refinement of the MNVT or for development of alternative MNVTs. (+info)
Genetic heterogeneity of mumps virus in the United Kingdom: identification of two new genotypes.
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A reverse transcriptase nested polymerase chain reaction (PCR) was developed to detect the small hydrophobic (SH) gene of mumps virus (MuV). Phylogenetic analysis was performed on the entire SH gene sequence (318 nucleotides) and the putative SH protein (57 amino acids). At least 4 MuV genotypes were identified in the United Kingdom between 1995 and 1998 by direct sequencing of 26 PCR amplicons from a variety of specimens. Comparison of these and GenBank sequences identified 2 new genotypes in the United Kingdom. The results suggest that, after the introduction of universal mumps vaccination in the United Kingdom in 1988, there appears to have been a switch from a predominant genotype to a heterogeneous group of strains. (+info)
Kawasaki disease: a maturational defect in immune responsiveness.
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Kawasaki disease (KD), an acute febrile disease in children of unknown etiology, is characterized by a vasculitis that may result in coronary artery aneurysms (CAAs). In new patients with KD, a selective and prolonged T cell unresponsiveness to activation via the T cell antigen receptor CD3 was observed, whereas proliferation to other stimuli was intact. This "split T cell anergy" delineated KD from other pediatric infections and autoimmune diseases and correlated with CAA formation (P<.001). A transient immune dysfunction was also suggested by an incomplete responsiveness to measles-mumps-rubella (MMR) vaccination in patients with KD versus controls (P<.0001; odds ratio, 15.6; 95% confidence interval, 4.8-51.1), which was overcome by revaccination(s). The reduced responsiveness to MMR in patients with KD suggests a subtle and predetermining immune dysfunction. An inherent immaturity to clear certain antigens may be an important cause that precipitates KD and the immune dysregulation during acute disease. (+info)
Immune reconstitution in the first year of potent antiretroviral therapy and its relationship to virologic response.
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The effects of 1 year of zidovudine, lamivudine, and ritonavir treatment on immune reconstitution were evaluated in 34 human immunodeficiency virus (HIV)-infected individuals. After 48 weeks of therapy, 20 (59%) subjects had <100 copies HIV RNA/mL. CD4+ T cells increased from a median of 192/mm3 at baseline to 362/mm3 at week 48. Lymphocyte proliferative responses to Candida normalized within 12 weeks, but responses to HIV and tetanus remained depressed throughout therapy. Alloantigen responses increased within 12 weeks and then declined to baseline levels. Recovery of delayed-type hypersensitivity responses occurred after 12 weeks for Candida and after 48 weeks for mumps. The magnitude of virologic suppression was correlated with numeric increases in CD4+ T cells, but not with measures of functional immune reconstitution. Plasma virus suppression <100 copies/mL was not significantly correlated with increases in CD4+ T cells or functional immune reconstitution. (+info)
Nested PCR for rapid detection of mumps virus in cerebrospinal fluid from patients with neurological diseases.
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In this study, we have developed a reverse transcription (RT)-nested polymerase chain reaction (n-PCR) for the detection of mumps virus RNA in cerebrospinal fluid (CSF) from patients with neurological infections. A specific 112-bp fragment was amplified by this method with primers from the nucleoprotein of the mumps virus genome. The mumps virus RT-n-PCR was capable of detecting 0.001 PFU/ml and 0.005 50% tissue culture infective dose/ml. This method was found to be specific, since no PCR product was detected in each of the CSF samples from patients with proven non-mumps virus-related meningitis or encephalitis. Mumps virus RNA was detected in all 18 CSF samples confirmed by culture to be infected with mumps virus. Positive PCR results were obtained for the CSF of 26 of 28 patients that were positive for signs of mumps virus infection (i.e., cultivable virus from urine or oropharyngeal samples or positivity for anti-mumps virus immunoglobulin M) but without cultivable virus in their CSF. Overall, mumps virus RNA was detected in CSF of 96% of the patients with a clinical diagnosis of viral central nervous system (CNS) disease and confirmed mumps virus infection, while mumps virus was isolated in CSF of only 39% of the patients. Furthermore, in a retrospective study, we were able to detect mumps virus RNA in 25 of 55 (46%) CSF samples from patients with a clinical diagnosis of viral CNS disease and negative laboratory evidence of viral infection including mumps virus infection. The 25 patients represent 12% of the 236 patients who had a clinical diagnosis of viral CNS infections and whose CSF was examined at our laboratory for a 2-year period. The findings confirm the importance of mumps virus as a causative agent of CNS infections in countries with low vaccine coverage rates. In summary, our study demonstrates the usefulness of the mumps virus RT-n-PCR for the diagnosis of mumps virus CNS disease and suggests that this assay may soon become the "gold standard" test for the diagnosis of mumps virus CNS infection. (+info)
Outbreak of aseptic meningitis associated with mass vaccination with a urabe-containing measles-mumps-rubella vaccine: implications for immunization programs.
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A mass immunization campaign with a Urabe-containing measles-mumps-rubella vaccine was carried out in 1997 in the city of Salvador, northeastern Brazil, with a target population of children aged 1-11 years. There was an outbreak of aseptic meningitis following the mass campaign. Cases of aseptic meningitis were ascertained through data collected from the records of children admitted to the local referral hospital for infectious diseases between March and October of 1997, using previously defined eligibility criteria. Vaccination histories were obtained through home visits or telephone calls. Eighty-seven cases fulfilled the study criteria. Of those, 58 cases were diagnosed after the vaccination campaign. An elevated risk of aseptic meningitis was observed 3 weeks after Brazil's national vaccination day compared with the risk in the prevaccination period (relative risk = 14.3; 95% confidence interval: 7.9, 25.7). This result was confirmed by a case series analysis (relative risk = 30.4; 95% confidence interval: 11.5, 80.8). The estimated risk of aseptic meningitis was 1 in 14,000 doses. This study confirms a link between measles-mumps-rubella vaccination and aseptic meningitis. The authors discuss the implications of this for the organization and planning of mass immunization campaigns. (+info)