A case of NDM-1-producing Acinetobacter baumannii transferred from India to Japan.

A 52-year-old male Japanese businessman with massive cerebral bleeding was transferred from India to Japan and was admitted to our hospital. Multidrug-resistant Acinetobacter baumannii was isolated from his sputum. The minimum inhibitory concentrations for this strain were as follows: imipenem, 64 µg/ml; meropenem, 32 µg/ml; ciprofloxacin, 16 µg/ml; amikacin, 16 µg/ml; aztreonam, 16 µg/ml; colistin, <1 µg/ml. This A. baumannii strain had both bla NDM-1 and bla OXA-23 by polymerase chain reaction analysis. In Japan, NDM-1-producing bacteria are extremely rare in clinical specimens. To date, three NDM-1-positive cases have been detected in Japan, and this is the first case of A. baumannii-producing NDM-1 in Japan. Our case suggests that NDM-1-producing bacteria could be introduced into our country easily. There is concern that various resistant bacteria may be transferred from epidemic countries as a result of international medical care.

A novel approach for a toxicity prediction model of environmental pollutants by using a quantitative structure-activity relationship method based on toxicogenomics.

The development of automobile emission reduction technologies has decreased dramatically the particle concentration in emissions; however, there is a possibility that unexpected harmful chemicals are formed in emissions due to new technologies and fuels. Therefore, we attempted to develop new and efficient toxicity prediction models for the myriad environmental pollutants including those in automobile emissions. We chose 54 compounds related to engine exhaust and, by use of the DNA microarray, examined their effect on gene expression in human lung cells. We focused on IL-8 as a proinflammatory cytokine and developed a prediction model with quantitative structure-activity relationship (QSAR) for the IL-8 gene expression by using an in silico system. Our results demonstrate that this model showed high accuracy in predicting upregulation of the IL-8 gene. These results suggest that the prediction model with QSAR based on the gene expression from toxicogenomics may have great potential in predictive toxicology of environmental pollutants.

Examination of mRNA expression in rat hearts and lungs for analysis of effects of exposure to concentrated ambient particles on cardiovascular function.

Epidemiological studies have suggested that fine particulate matter (f-PM) is associated with adverse effects on cardiovascular health. However, these effects on the cardiovascular system have not yet been fully elucidated. Using mRNA expression and correlation analyses, we designed the present study to elucidate (1) translocation of chemicals in inhaled f-PM to the heart, (2) induction of oxidative stress, one of the causes of cardiovascular diseases (CVDs), (3) mRNA expression related to CVDs, and (4) correlations among mRNA expression of various molecules and cardiovascular function. Wistar Kyoto male rats were exposed to concentrated ambient particles (CAPs, 0.6-1.5mg/m3) in Yokohama for 4 days (4.5h/day) or to filtered air for 3 days and CAPs for 1 day or to filtered air for 4 days. Messenger RNA expression and cardiovascular function were measured after the 4-day exposure. In samples of heart tissue, the mRNAs of cytochrome P450 (CYP) 1B1, a biomarker of exposure to chemicals; heme oxygenase-1 (HO-1), a marker of oxidative stress; and endothelin A (ET A) receptor, a receptor of vasoconstrictors, were up-regulated by CAPs; their levels were significantly correlated with the cumulative weight of CAPs in the exposure chamber. The up-regulation of ET A receptor mRNA was significantly correlated with the increase in HO-1 mRNA and weakly with the increase in mean blood pressure (Delta MBP). These results suggest the possibility that chemicals in CAPs might be translocated to the heart, where they induce oxidative stress and activate endothelin signaling, resulting in an increase in the blood pressure. The exposure to f-PM might thus affect cardiovascular function through activation of endothelin signaling.

The role of the Ah receptor and p38 in benzo[a]pyrene-7,8-dihydrodiol and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide-induced apoptosis.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous contaminants in the environment. Benzo[a]pyrene (B[a]P), a prototypical member of this class of chemicals, affects cellular signal transduction pathways and induces apoptosis. In this study, the proximate carcinogen of B[a]P metabolism, trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (B[a]P-7,8-dihydrodiol) and the ultimate carcinogen, B[a]P-r-7,t-8-dihydrodiol-t-9,10-epoxide(+/-) (BPDE-2) were found to induce apoptosis in human HepG2 cells. Apoptosis initiated by B[a]P-7,8-dihydrodiol was linked to activation of the Ah receptor and induction of CYP1A1, an event that can lead to the formation of BPDE-2. With both B[a]P-7,8-dihydrodiol and BPDE-2 treatment, changes in anti- and pro-apoptotic events in the Bcl-2 family of proteins correlated with the release of mitochondrial cytochrome c and caspase activation. The onset of apoptosis as monitored by caspase activation was linked to mitogen-activated protein (MAP) kinases. Utilizing mouse hepa1c1c7 cells and the Arnt-deficient BPRc1 cells, activation of MAP kinase p38 by B[a]P-7,8-dihydrodiol was shown to be Ah receptor-dependent, indicating that metabolic activation by CYP1A1 was required. This was in contrast to p38 activation by BPDE-2, an event that was independent of Ah receptor function. Confirmation that MAP kinases play a critical role in BPDE-2-induced apoptosis was shown by inhibiting caspase activation of poly(ADP-ribose)polymerase 1 (PARP-1) by chemical inhibitors of p38 and ERK1/2. Furthermore, mouse embryo p38-/- fibroblasts were shown to be resistant to the actions of BPDE-2-induced apoptosis as determined by annexin V analysis, cytochrome c release, and cleavage of PARP-1. These results confirm that the Ah receptor plays a critical role in B[a]P-7,8-dihydrodiol-induced apoptosis while p38 MAP kinase links the actions of an electrophilic metabolite like BPDE-2 to the regulation of programmed cell death.