Community-acquired pneumonia.

PURPOSE OF REVIEW: This review examines the epidemiology, diagnosis, prognosis, treatment and prevention of community-acquired pneumonia (CAP) in adults. RECENT FINDINGS: CAP is a significant cause of morbidity and mortality. Streptococcus pneumoniae is the most common CAP pathogen; however, microbial cause varies by geographic location and host factors. Identification of a microbial cause in CAP remains challenging - 30-65% of cases do not have a pathogen isolated. The use of molecular techniques in addition to culture, serology and urinary antigen testing has improved diagnostic yield. Scoring systems are useful for CAP prognostication and site of care decisions. Studies evaluating novel biomarkers including pro-B-type natriuretic peptide and procalcitonin suggest potential adjunctive roles in CAP prognosis. Guideline-based treatment for CAP has changed little in recent years. Effective and timely antimicrobial therapy is crucial in optimizing outcomes and should be based on local antimicrobial susceptibility patterns. Macrolides may have additional anti-inflammatory properties and a mortality benefit in severe CAP. Preventive strategies include immunization and modification of specific patient risk factors. SUMMARY: CAP is common and causes considerable morbidity and mortality. A comprehensive approach including advanced diagnostic testing, effective and timely antimicrobial therapy and prevention is required to optimize CAP outcomes.

Microglial recruitment, activation, and proliferation in response to primary demyelination.

We have characterized the cellular response to demyelination/remyelination in the central nervous system using the toxin cuprizone, which causes reproducible demyelination in the corpus callosum. Microglia were distinguished from macrophages by relative CD45 expression (CD45(dim)) using flow cytometry. Their expansion occurred rapidly and substantially outnumbered infiltrating macrophages and T cells throughout the course of cuprizone treatment. We used bromodeoxyuridine incorporation and bone marrow chimeras to show that both proliferation and immigration from blood accounted for increased microglial numbers. Microglia adopted an activated phenotype during demyelination, up-regulating major histocompatibility class I and B7.2/CD86. A subpopulation of CD45(dim-high) microglia that expressed reduced levels of CD11b emerged during demyelination. These microglia expressed CD11c and were potent antigen-presenting cells in vitro. T cells were recruited to the demyelinated corpus callosum but did not appear to be activated. Our study highlights the role of microglia as a heterogeneous population of cells in primary demyelination, with the capacity to present antigen, proliferate, and migrate into demyelinated areas.

Nogo-A is a reliable oligodendroglial marker in adult human and mouse CNS and in demyelinated lesions.

The unambiguous identification of oligodendrocytes in tissue sections, especially in myelinated tracts, is often difficult. Most of the antibodies used to identify oligodendrocytes label the myelin sheath as well. Originally described as an inhibitor of axonal outgrowth, Nogo-A is known to be strongly expressed in mature oligodendrocytes in vivo. In the present investigation we analyzed the expression patterns of Nogo-A in adult mouse and human CNS as well as in demyelinating animal models and multiple sclerosis lesions. Nogo-A expression was compared with that of other frequently used oligodendroglial markers such as CC1, CNP, and in situ hybridization for proteolipid protein mRNA. Nogo-A strongly and reliably labeled oligodendrocytes in the adult CNS as well as in demyelinating lesions and thus represents a valuable tool for the identification of oligodendrocytes in human and mouse CNS tissue.

Continued administration of ciliary neurotrophic factor protects mice from inflammatory pathology in experimental autoimmune encephalomyelitis.

Multiple sclerosis is an inflammatory disease of the central nervous system that leads to loss of myelin and oligodendrocytes and damage to axons. We show that daily administration (days 8 to 24) of murine ciliary neurotrophic factor (CNTF), a neurotrophic factor that has been described as a survival and differentiation factor for neurons and oligodendrocytes, significantly ameliorates the clinical course of a mouse model of multiple sclerosis. In the acute phase of experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein peptide 35-55, treatment with CNTF did not change the peripheral immune response but did reduce the number of perivascular infiltrates and T cells and the level of diffuse microglial activation in spinal cord. Blood brain barrier permeability was significantly reduced in CNTF-treated animals. Beneficial effects of CNTF did not persist after it was withdrawn. After cessation of CNTF treatment, inflammation and symptoms returned to control levels. However, slight but significantly higher numbers of oligodendrocytes, NG2-positive cells, axons, and neurons were observed in mice that had been treated with high concentrations of CNTF. Our results show that CNTF inhibits inflammation in the spinal cord, resulting in amelioration of the clinical course of experimental autoimmune encephalomyelitis during time of treatment.

Neutrophils that infiltrate the central nervous system regulate T cell responses.

Regulation of inflammatory responses is critical to progression of organ-specific autoimmune disease. Although many candidate cell types have been identified, immunoregulatory activity has rarely been directly assayed and never from the CNS. We have analyzed the regulatory capability of Gr-1high neutrophils isolated from the CNS of mice with experimental autoimmune encephalomyelitis. Proportions of neutrophils were markedly increased in the CNS of IFN-gamma-deficient mice. Strikingly, CNS-derived neutrophils, whether or not they derived from IFN-gamma-deficient mice, were potent suppressors of T cell responses to myelin or adjuvant Ags. Neutrophil suppressor activity was absolutely dependent on IFN-gamma production by target T cells, and suppression was abrogated by blocking NO synthase. These data identify an immunoregulatory capacity for neutrophils, and indicate that interplay between IFN-gamma, NO, and activated Gr-1high neutrophils within the target organ determines the outcome of inflammatory and potentially autoimmune T cell responses.