CD4(+) and CD8(+) T cells make discrete contributions to demyelination and neurologic disease in a viral model of multiple sclerosis

Following intracerebral infection with Theiler's murine encephalomyelitis virus (TMEV), susceptible strains of mice (SJL and PLJ) develop virus persistence and demyelination similar to that found in human multiple sclerosis. Resistant strains of mice (C57BL/6) clear virus and do not develop demyelination. To resolve the controversy about the role of CD4(+) and CD8(+) T cells in the development of demyelination and neurologic deficits in diseases of the central nervous system, we analyzed TMEV infection in CD4- and CD8-deficient B6, PLJ, and SJL mice. Genetic deletion of either CD4 or CD8 from resistant B6 mice resulted in viral persistence and demyelination during the chronic stage of disease. Viral persistence and demyelination were detected in all strains of susceptible background. Although genetic deletion of CD8 had no effect on the extent of demyelination in susceptible strains, deletion of CD4 dramatically increased the degree of demyelination observed. Whereas strains with deletions of CD4 showed severe neurologic deficits, mice with deletions of CD8 showed minimal or no deficits despite demyelination. In all strains, deletion of CD4 but not CD8 resulted in a decreased delayed-type hypersensitivity response to viral antigen. We conclude that each T-cell subset makes a discrete and nonredundant contribution to protection from viral persistence and demyelination in resistant strains. In contrast, in susceptible strains, CD8(+) T cells do not provide protection against chronic demyelinating disease. Furthermore, in persistent TMEV infection of the central nervous system, neurologic deficits appear to result either from the absence of a protective class II-restricted immune response or from the presence of a pathogenic class I-restricted response.     

Coordinated actions of RuvABC in Holliday junction processing

The objective of this article is to describe the creation and operation of a multidisciplinary group to examine the Oklahoma City (OKC) bombing. The OKC bombing presented an opportunity to study a major disaster within 2 days of the incident. The Disaster Health Studies Group (DHSG) was created to facilitate this effort. The creation, organization, and operation of the DHSG is outlined. In addition the mission statement, participants, communications, political empowerment, data preservation and collection, data ownership, patient rights, threats to the DHSG, media interactions, funding, the institutional review board process, and results reporting will be detailed. The 22 projects of the DHSG are listed. In conclusion, four main findings are examined: 1) A multidisciplinary disaster study group is feasible and can be rapidly organized; 2) certain organizations and institutions form a core group for facilitation of the research effort; 3) specific issues must be addressed in order for the group to succeed; and 4) the group leader should have disaster expertise and be committed to the multidisciplinary process.     

An antagonist peptide-EPO receptor complex suggests that receptor dimerization is not sufficient for activation

Dimerization of the erythropoietin (EPO) receptor (EPOR), in the presence of either natural (EPO) or synthetic (EPO-mimetic peptides, EMPs) ligands is the principal extracellular event that leads to receptor activation. The crystal structure of the extracellular domain of EPOR bound to an inactive (antagonist) peptide at 2.7 A resolution has unexpectedly revealed that dimerization still occurs, but the orientation between receptor molecules is altered relative to active (agonist) peptide complexes. Comparison of the biological properties of agonist and antagonist EMPs with EPO suggests that the extracellular domain orientation is tightly coupled to the cytoplasmic signaling events and, hence, provides valuable new insights into the design of synthetic ligands for EPOR and other cytokine receptors.     

Oxygen isotopic abundances in calcium- aluminum-rich inclusions from ordinary chondrites: implications for nebular heterogeneity

The oxygen isotopic compositions of two calcium-aluminum-rich inclusions (CAIs) from the unequilibrated ordinary chondrite meteorites Quinyambie and Semarkona are enriched in 16O by an amount similar to that in CAIs from carbonaceous chondrites. This may indicate that most CAIs formed in a restricted region of the solar nebula and were then unevenly distributed throughout the various chondrite accretion regions. The Semarkona CAI is isotopically homogeneous and contains highly 16O-enriched melilite, supporting the hypothesis that all CAI minerals were originally 16O-rich, but that in most carbonaceous chondrite inclusions some minerals exchanged oxygen isotopes with an external reservoir following crystallization.     

Comparing change readiness, quality improvement, and cost management among Veterans Administration, for-profit, and nonprofit hospitals

To elucidate the conditions of atrophy in the sternocleidomastoid muscle (SCM) after modified neck dissection (MND), we tried to scrutinize the atrophic regions in the SCM and determine the cause of atrophy, by electromyography in 40 patients with SCM atrophy following MND. We also examined the detailed anatomy of the SCM in 40 cadavers. Atrophy was observed in the caudal portion in the SCM in 90% of the patients. Electromyographic examination revealed neurogenic atrophy in 24 patients, ischemic atrophy in 11, and a mixing of both types in 5. The SCM was found to be innervated by the spinal accessory nerve (SAN) and the SCM branch of the cervical nerve. The main artery feeding the cranial half of the SCM was a branch of the occipital artery (Oc) or the external carotid artery (Ex), and the auxiliary artery was a branch of the posterior auricular artery (Ap). The main artery feeding the caudal half of the SCM was a branch of the superior thyroidal artery (St), and the auxiliary artery was a branch of the subclavian artery (Sc). Postoperative SCM atrophy is attributed to damage of the feeding artery in the SCM caudal portion and local damage in the nerve fibers running through the SCM. To prevent this type of atrophy, it is important to carefully handle this muscle itself and protect the nerve fibers running through it, as well as to conserve the SCM branches of the St and Sc.     

Solution structure of murine macrophage inflammatory protein-2

The solution structure of murine macrophage inflammatory protein-2 (MIP-2), a heparin-binding chemokine that is secreted in response to inflammatory stimuli, has been determined using two-dimensional homonuclear and heteronuclear NMR spectroscopy. Structure calculations were carried out by means of torsion-angle molecular dynamics using the program X-PLOR. The structure is based on a total of 2390 experimental restraints, comprising 2246 NOE-derived distance restraints, 44 distance restraints for 22 hydrogen bonds, and 100 torsion angle restraints. The structure is well-defined, with the backbone (N, Calpha, C) and heavy atom atomic rms distribution about the mean coordinates for residues 9-69 of the dimer being 0.57 +/- 0.16 A and 0.96 +/- 0.12 A, respectively. The N- and C-terminal residues (1-8 and 70-73, respectively) are disordered. The overall structure of the MIP-2 dimer is similar to that reported previously for the NMR structures of MGSA and IL-8 and consists of a six-stranded antiparallel beta-sheet (residue 25-29, 39-44, and 48-52) packed against two C-terminal antiparallel alpha-helices. A best fit superposition of the NMR structure of MIP-2 on the structures of MGSA, NAP-2, and the NMR and X-ray structures of IL-8 are 1.11, 1.02, 1.27, and 1.19 A, respectively, for the monomers, and 1.28, 1.10, 1.55, and 1.36 A, respectively, for the dimers (IL-8 residues 7-14 and 16-67, NAP-2 residues 25-84). At the tertiary level, the main differences between the MIP-2 solution structure and the IL-8, MGSA, and NAP-2 structures involve the N-terminal loop between residues 9-23 and the loops formed by residues 30-38 and residues 53-58. At the quaternary level, the difference between MIP-2 and IL-8, MGSA, or NAP-2 results from differing interhelical angles and separations.     

Synthesis and action of the cyclic AMP antagonist, prostaglandylinositol cyclic phosphate (cyclic PIP), in Dictyostelium discoideum

PURPOSE: To examine the incidence of and risk factors for retinal detachment during a 10-year follow-up on intracapsular cataract extraction (ICCE). METHODS: Retrospective analysis of medical records of 1041 eyes operated on with ICCE in the years 1984-86. A complete follow-up was achieved, and actuarial methods were used in the risk assessment. The risk time averaged 82 months. RESULTS: Twenty-two (2.1%) eyes developed retinal detachment; half of the cases occurred during the first postoperative year, but new cases emerged throughout the period. The cumulative incidence of RD amounted to 2.8%; 95% confidence interval: 1.5-4.2%. Multivariate Cox regression analysis identified younger age at surgery (relative risk for each 10-year increase in age=0.6; 95% confidence interval: 0.39-0.95) and male gender (relative risk=2.5; 95% confidence interval 1.04-6.04) as significant risk factors for RD. Eleven eyes, 50% of eyes with RD and 1% of the total number of eyes, lost useful vision in spite of retinal surgery. CONCLUSION: Even though the risk for both RD and an unfavourable result following retinal surgery may be smaller using contemporary surgical techniques, the present study indicates a substantial morbidity following cataract surgery, when a sufficiently long observation period is considered.     

Overexpression of the cardiac Na+/Ca2+ exchanger increases susceptibility to ischemia/reperfusion injury in male, but not female, transgenic mice

Influx of Ca2+ into myocytes via Na+/Ca2+ exchange may be stimulated by the high levels of intracellular Na+ and the changes in membrane potential known to occur during ischemia/reperfusion. This increased influx could, in turn, lead to Ca2+ overload and injury. Overexpression of the cardiac Na+/Ca2+ exchanger therefore may increase susceptibility to ischemia/reperfusion injury. To test this hypothesis, the hearts of male and female transgenic mice, overexpressing the Na+/Ca2+ exchange protein, and hearts of their wild-type littermates, were perfused with Krebs-Henseleit buffer and subjected to 20 minutes of ischemia and 40 minutes of reperfusion. Preischemic left ventricular developed pressures and +dP/dtmax, as well as -dP/dtmin, were higher in the male transgenic hearts compared with wild-type, implying a role for Na+/Ca2+ exchange in the contraction, as well as the relaxation, phases of the cardiac beat. Postischemic function was lower in male transgenic than in male wild-type hearts (7+/-2% versus 32+/-6% of preischemic function), but there was no difference between female transgenic and female wild-type hearts, both at approximately 30% of preischemic function. To assess whether this male/female difference was due to female-specific hormones such as estrogen, the hearts of bilaterally ovariectomized and sham-operated transgenic females were subjected to the same protocol. The functional recoveries of ovariectomized female transgenic hearts were lower (17+/-3% of preischemic function) than those of wild-type and sham-operated transgenic females. The lower postischemic functional recovery in the male transgenic and female ovariectomized transgenic hearts correlated with lower recoveries of the energy metabolites, ATP and phosphocreatine, as measured by 31P nuclear magnetic resonance spectroscopy. Alternans were observed during reperfusion in male transgenic and female ovariectomized transgenic hearts only, consistent with intracellular Ca2+ overload. Western analyses showed that alterations in the expression of the Na+/Ca2+ exchange or L-type Ca2+ channel proteins were not responsible for the protection observed in the female transgenic hearts. In conclusion, in males, overexpression of the Na+/Ca2+ exchanger reduced postischemic recovery of both contractile function and energy metabolites, indicating that the Na+/Ca2+ exchanger may play a role in ischemia/reperfusion injury. From the studies of females, however, it appears that this exacerbation of ischemia/reperfusion injury by overexpression of the Na+/Ca2+ exchanger can be overcome partially by female-specific hormones such as estrogen.     

Is canine hepatocerebellar degeneration syndrome an animal model for carbohydrate-deficient glycoprotein syndrome in humans? An example of sequencing glycoprotein glycans with mass spectrometry

TNF genes determine strength, effectiveness, and duration of local and systemic inflammatory reactions, as well as repair and recovery from infectious and toxic agents. Multiple pro- and anti-inflammatory activities of TNF factors are conditioned by their profound effects on metabolism of many cell types, their activation state, cell survival and others. TNF genes show strong linkage disequilibrium with HLA class I and class II genes and with other genes in the MHC region relevant to immuneregulation. Structural or regulatory defects in TNF genes may contribute to pathogenesis of MHC associated diseases especially those with inflammatory and autoimmune components.