Clonogenic analysis reveals reserve stem cells in postnatal mammals. II. Pluripotent epiblastic-like stem cells.

Undifferentiated cells have been identified in the prenatal blastocyst, inner cell mass, and gonadal ridges of rodents and primates, including humans. After isolation these cells express molecular and immunological markers for embryonic cells, capabilities for extended self-renewal, and telomerase activity. When allowed to differentiate, embryonic stem cells express phenotypic markers for tissues of ectodermal, mesodermal, and endodermal origin. When implanted in vivo, undifferentiated noninduced embryonic stem cells formed teratomas. In this report we describe a cell clone isolated from postnatal rat skeletal muscle and derived by repetitive single-cell clonogenic analysis. In the undifferentiated state it consists of very small cells having a high ratio of nucleus to cytoplasm. The clone expresses molecular and immunological markers for embryonic stem cells. It exhibits telomerase activity, which is consistent with its extended capability for self-renewal. When induced to differentiate, it expressed phenotypic markers for tissues of ectodermal, mesodermal, and endodermal origin. The clone was designated as a postnatal pluripotent epiblastic-like stem cell (PPELSC). The undifferentiated clone was transfected with a genomic marker and assayed for alterations in stem cell characteristics. No alterations were noted. The labeled clone, when implanted into heart after injury, incorporated into myocardial tissues undergoing repair. The labeled clone was subjected to directed lineage induction in vitro, resulting in the formation of islet-like structures (ILSs) that secreted insulin in response to a glucose challenge. This study suggests that embryonic-like stem cells are retained within postnatal mammals and have the potential for use in gene therapy and tissue engineering.

Long-term use of inhaled corticosteroids and the risk of pneumonia in chronic obstructive pulmonary disease: a meta-analysis.

BACKGROUND: Recent studies have suggested a possible association between pneumonia and the use of inhaled corticosteroids. We aimed to ascertain the risk of pneumonia with long-term inhaled corticosteroid use among patients with chronic obstructive pulmonary disease (COPD). METHODS: We performed systematic searches with no date restrictions through June 30, 2008, of MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, regulatory documents, and trial registries. We included randomized controlled trials of any inhaled corticosteroid vs a control treatment for COPD, with at least 24 weeks of follow-up and reporting of pneumonia as an adverse event. Outcomes evaluated included any pneumonia, serious pneumonia, pneumonia-related mortality, and overall mortality. RESULTS: Eighteen randomized controlled trials (n = 16 996) with 24 to 156 weeks of follow-up were included after a detailed screening of 97 articles. Inhaled corticosteroids were associated with a significantly increased risk of any pneumonia (relative risk [RR], 1.60; 95% confidence interval [CI], 1.33-1.92 [P < .001]; I(2) = 16%) and serious pneumonia (1.71; 1.46-1.99 [P < .001]; I(2) = 0%) but without a significantly increased risk of pneumonia-related mortality (1.27; 0.80-2.03 [P = .31]; I(2) = 0%) or overall mortality (0.96; 0.86-1.08 [P = .51]; I(2) = 0%). Inhaled corticosteroids were associated with a significantly increased risk of serious pneumonia when compared with placebo (RR, 1.81; 95% CI, 1.44-2.29 [P < .001]) or when the combination of inhaled corticosteroids and long-acting beta-agonists was compared with long-acting beta-agonists (1.68; 1.20-2.34 [P = .002]). CONCLUSION: Among patients with COPD, inhaled corticosteroid use for at least 24 weeks is associated with a significantly increased risk of serious pneumonia, without a significantly increased risk of death.