Hypercapnia provided consistent and biologically plausible in vivo protection against VILI, but elevated lung tissue levels of nitro-tyrosine as previously described in sepsis. Clinicians and those designing clinical trials need to be aware of the potential for detrimental effects when using hypercapnia in order to balance benefits versus harm with this approach.

The PECARN rules were less sensitive for physically abused children, although the rules showed excellent applicability for the cohort without physical abuse. Thoughtful consideration may be needed for cases of nonaccidental trauma. Further prospective studies are required to verify the applicability of the PECARN rules for children with minor head trauma in Japan.

We report the discovery of an osmosensitive transcriptional control of human CYP3A4, CYP3A7, and CYP3A5. Ambient hypertonicity (350 -450 mOsmol/kg) increased mRNA expressions of the CYP3A by ϳ10-to 20-fold in human-intestinal C 2 bbe1 cells, followed by an increase of CYP3A protein. Hypotonicity, on the other hand, suppressed CYP3A mRNA levels, indicating that physiological isotonic conditions may regulate the basal expression of CYP3A. Similar responses to ambient tonicity were observed in other human-derived cell lines (intestinal LS180 and hepatic HepG2) and human primary colonic cells. The 11-base pair tonicity-responsive enhancer (TonE) is an osmosensitive regulator that is activated by the transcription factor, the nuclear factor of activated T-cells 5 (NFAT5). Luciferase-based reporter assays of 13 consensus TonE motifs within Ϯ10 kilobases (kb) from the transcription start sites of CYP3A showed that only the CYP3A7 intron 2 region (ϳ5 kb downstream from the transcription start site), which contains two TonE motifs (ϩ5076/ϩ5086 and ϩ 5417/ ϩ5427), was responsive to hypertonicity stimuli. This observation was confirmed upon cotransfection with an NFAT5 expression vector, small interfering RNA, or dominant-negative NFAT5. Deletion and mutation analyses suggested that the TonE (ϩ5417/ ϩ5427) is indispensable for the enhancer activity. NFAT5 binding to the CYP3A7 intron 2 TonE motif was demonstrated with electrophoretic mobility shift assay and in a native cell context by chromatin immunoprecipitation. We conclude that transcription of human CYP3A is influenced by ambient tonicity. The physiological significance of the tonic regulation of CYP3A enzymes remains to be determined.The human cytochrome P450 3A (CYP3A) subfamily represents the most abundant cytochrome P450 drug-metabolizing enzymes in the liver and intestine. Together with membrane-bound transporters, they constitute a crucial component for drug elimination and excretion. Of the three major isoforms (CYP3A4, CYP3A5, and CYP3A7), CYP3A4 is the most abundant adult form, whereas CYP3A7 is the main fetal form. These isozymes collectively metabolize nearly half of all currently used medications.The human CYP3A genes reside in a cluster on chromosome 7 (Nelson et al., 2004), and their expression is characterized by wide interindividual variations. Significant coex-