Pneumonia is a major cause of death in the elderly. To investigate the role of silent aspiration in community-acquired pneumonia, we examined the occurrence of silent aspiration during sleep in 14 elderly patients with acute episode of pneumonia and 10 age-matched control subjects by a new technique using indium111 chloride. Scanning of the thorax demonstrated that 71% of patients aspirated, whereas aspiration was observed in only 10% of control subjects. The percentage of positive scans was significantly higher in patients with acute episode of pneumonia than in control subjects (p < 0.02). The results may indicate an important role of silent aspiration in the development of community-acquired pneumonia in the elderly.

Overexpression of an anti-apoptotic protein cIAP1 caused by its genetic amplification was reported in certain cancers, such as hepatocellular carcinoma, esophageal squamous cell carcinoma, cervical cancer, and lung cancer, which confers resistance to chemotherapy and radiotherapy. Here we report cIAP1 to be selectively down-regulated by a class of small molecules ((؊)-N-[(2S,3R)-3-amino-2-hydroxy-4-phenyl-butyryl]-L-leucine methyl ester (ME-BS)), resulting in a sensitization of cancer cells to apoptosis. ME-BS directly interacts with the BIR3 domain of cIAP1, promotes auto-ubiquitylation dependent on its RING domain, and facilitates proteasomal degradation of cIAP1. Other IAPs such as XIAP and cIAP2 were not affected by ME-BS. These results suggest targeted destabilization of cIAP1 by small molecules as a novel method to treat cancers expressing cIAP1, which interferes with treatment. Manipulation of the intrinsic ubiquitinligase activity could be a novel strategy to develop small molecules for therapeutic purposes.IAPs (inhibitor of apoptosis proteins) are a family of antiapoptotic proteins containing one to three baculoviral IAP repeat (BIR) 2 domains (1-3), some of which are frequently overexpressed in malignant cells. Certain IAPs such as XIAP/ hILP/BIRC4, cIAP1/MIHB/hiap-2/BIRC2, cIAP2/MIHC/hiap-1/BIRC3, ML-IAP/Livin/BIRC7 and Apollon/BRUCE/BIRC6 directly interact with and regulate caspases (4 -9). The BIR domain plays an important role in the interaction with caspases (8, 10, 11). These IAPs also contain a domain involved in ubiquitin conjugation (RING finger domain or UBC domain), and facilitate proteasomal degradation of caspases and IAPs (8, 12, 13). cIAP1 (cellular inhibitor of apoptosis protein 1) is overexpressed in human cancers such as esophageal squamous cell carcinoma, hepatocellular carcinoma, cervical cancer, and lung cancer, because of its genetic amplification and is regarded as an oncogene (14 -17). cIAP1 overexpression in cervical cancers correlates with resistance to radiotherapy. In addition, a comparative study of the expression of IAP family proteins and the sensitivity to chemotherapeutic drugs in 60 cell lines revealed the level of cIAP1 significantly correlates with resistance against anti-cancer drugs such as carboplatin, cisplatin, etoposide, and cytosine arabinoside (18). This evidence suggests cIAP1 to be a promising target for cancer therapy.Bestatin, an inhibitor of aminopeptidase N, has an immunomodulatory activity and is approved in Japan to treat patients with adult acute nonlymphatic leukemia (19 -21). In a clinical trial with stage I squamous cell lung carcinoma patients, bestatin significantly prolonged survival of these patients (22). Bestatin induces apoptosis in human leukemia cells (23) and augments death ligand-induced apoptosis in human solid tumor cell lines (24). In this paper, we describe selective down-regulation of cIAP1 by esterified analogs of bestatin represented by bestatin-methyl ester (ME-BS) (see Fig. 1A), resulting in a sensitization of cancer cells to ...

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Basal ganglia strokes might predispose these patients to develop pneumonia owing to frequent aspiration during sleep.

Formable high-strength low-alloy TRIP-aided sheet steels with annealed martensite matrix or "TRIP-aided annealed martensitic steel" were developed for automotive applications. The steels possessed a large amount of plate-like retained austenite along annealed martensite lath boundary, whose stability against the strain-induced transformation was higher than that of the conventional "TRIP-aided dual-phase steel" with polygonal ferrite matrix. In a tensile strength range between 600 and 1000 MPa, the TRIP-aided annealed martensite steels exhibited a superior large elongation and reduction of area. In addition, they possessed the same excellent stretch-flangeability and bendability as "TRIP-aided bainitic steel" with bainitic ferrite matrix. These properties were discussed by matrix structure, a strength ratio of second phase to matrix, retained austenite stability, internal stress and so on.

Summary• The Quaternary climatic changes resulted in range shifts of species, providing chances for hybridization. However, the genetic signatures of such ancient introgression have rarely been reported. To investigate such signatures, we performed a phylogeographical study on the perennial plant Veratrum album ssp. oxysepalum, which may have hybridized long ago with another congeneric species, V. stamineum.• Sequence variations in chloroplast DNA (cpDNA) were examined in 43 populations in Japan and adjacent areas. Phylogenetic analyses of different cpDNA haplotypes were conducted on the basis of cpDNA and nuclear ribosomal internal transcribed spacer (nrITS) variations.• In the Japanese archipelago, two major groups of haplotypes were detected, one of which was distributed in a disjunct pattern. The major haplotype, occupying the central part of the species' distribution, formed a monophyletic group with V. stamineum in phylogenetic trees on the basis of cpDNA variation, although the two species did not form a monophyletic group in phylogenetic trees on the basis of nrITS variation.• Historical hybridization between V. album ssp. oxysepalum and V. stamineum in refugia during the Quaternary climatic oscillations, and the resulting chloroplast capture of V. stamineum by V. album ssp. oxysepalum, are most probably responsible for the disjunct distribution of cpDNA in V. album ssp. oxysepalum.

The mechanism of photosensitized protein damage byphosphorus(V) tetraphenylporphyrin derivatives (P(V)TPPs) wasquantitatively clarified. P(V)TPPs bound to human serum albumin(HSA), a water-soluble protein, and damaged its tryptophan residueduring photoirradiation. P(V)TPPs photosensitized singlet oxygen ((1)O(2))generation, and the contribution of (1)O(2) to HSA damage was confirmedby the inhibitory effect of sodium azide, a (1)O(2) quencher. However,sodium azide could not completely inhibit HSA damage, suggesting thecontribution of an electron transfer mechanism to HSA damage. Thedecrement in the fluorescence lifetime of P(V)TPPs by HSA supportedthe electron transfer mechanism. The contribution of these processes could be determined by the kinetic analysis of the effect ofsodium azide on the photosensitized protein damage by P(V)TPPs.

Graft-versus-host disease (GVHD) and infection are major obstacles to successful allogeneic hematopoietic stem cell transplantation (HSCT). Intestinal goblet cells form the mucus layers, which spatially segregate gut microbiota from host tissues. Although it is well known that goblet cell loss is one of the histologic features of GVHD, effects of their loss in pathophysiology of GVHD remain to be elucidated. In mouse models of allogeneic HSCT, goblet cells in the colon were significantly reduced, resulting in disruption of the inner mucus layer of the colon and increased bacterial translocation into colonic mucosa. Pretransplant administration of interleukin-25 (IL-25), a growth factor for goblet cells, protected goblet cells against GVHD, prevented bacterial translocation, reduced plasma concentrations of interferon-γ (IFN-γ) and IL-6, and ameliorated GVHD. The protective role of IL-25 was dependent on Lypd8, an antimicrobial molecule produced by enterocytes in the colon that suppresses motility of flagellated bacteria. In clinical colon biopsies, low numbers of goblet cells were significantly associated with severe intestinal GVHD, increased transplant-related mortality, and poor survival after HSCT. Goblet cell loss is associated with poor transplant outcome, and administration of IL-25 represents an adjunct therapeutic strategy for GVHD by protecting goblet cells.