The risk of fragment penetrating injury to the heart.

Injury due to the penetration of fragments into parts of the body has been the major cause of morbidity and mortality after an explosion. Penetrating injuries into the heart present very high mortality, yet the risk associated with such injuries has not been quantified. Quantifying this risk is key in the design of personal protection and the design of infrastructure. This study is the first quantitative assessment of cardiac penetrating injuries from energised fragments. Typical fragments (5-mm sphere, 0.78-g right-circular cylinder and 1.1-g chisel-nosed cylinder) were accelerated to a range of target striking velocities using a bespoke gas-gun system and impacted ventricular and atrial walls of lamb hearts. The severity of injury was shown to not depend on location (ventricular or atrial wall). The striking velocity with 50% probability of critical injury (Abbreviated Injury Scale (AIS) 5 score) ranged between 31 and 36 m/s across all 3 fragments used. These findings can help directly in reducing morbidity and mortality from explosive events as they can be implemented readily into models that aim to predict casualties in an explosive event, inform protocols for first responders, and improve design of infrastructure and personal protective equipment.

Inhibition of epidermal growth factor-induced cell transformation by tannins.

The mouse epidermal JB6 cell system is a well developed model for studying tumor promotion, and the JB6 Cl 41 promotion sensitive (P+) cell line, in which transformed colonies are induced by epidermal growth factor (EGF), was used to test the anti-tumor promoting effect of seven tannins and two triterpenoids. We found that six tannins, ellagitannins (compounds 1, 2, 3 and 4) and chromone gallates (compounds 6 and 7), significantly blocked EGF-induced cell transformation in a concentration-dependent manner. The inhibition of cell transformation by the tannins was not due to growth inhibition. The ellagitannins, but not the chromone gallates, significantly attenuated EGF-induced activator protein 1 (AP-1) activation, a transcription factor. Compounds 1 and 3, among the ellagitannins analysed, inhibited the EGF-induced phosphorylation of extracellular-signal regulated protein kinases and p38 kinases, which regulate AP-1 activation. On the other hand, compounds 3 and 4 suppressed EGF-induced phosphatidylinositol 3-kinase (PI3K) activation. In addition, all tannins that blocked cell transformation markedly inhibited EGF-induced activation of Akt, a downstream effector of PI3K. Because signal-transduction pathways, including AP-1 and PI3K pathways, have been focused as prime targets for chemopreventive phytochemicals, our results suggest that inhibition by tannins of EGF-induced neoplastic transformation in JB6 cells is related to blocking of Akt activation, and also attenuation of AP-1 activation for ellagitannins.

Conjugated bilirubin induces multidrug resistance-associated protein 2 mRNA expression and in vivo cisplatin resistance in rat hepatoma AH66 cells.

In vivo cisplatin resistance of rat ascites hepatoma AH66 cells is suggested to result from the induction of multidrug resistance-associated protein 2 (MRP2) expression by ascites fluid (ASF) in the peritoneal cavity. The in vitro cisplatin sensitivity of AH66 cells grown in assay medium containing 5% fetal bovine serum in Dulbecco's modified Eagle's medium (5% FBS DMEM) did not change when the cells were treated with probenecid, an inhibitor of anion transporters, while the decreased cisplatin sensitivity of AH66 cells cultured in an assay medium containing 5% ASF (5% ASF DMEM) was restored by probenecid. Furthermore, in an in vivo study, the survival span (%ILS) of AH66-bearing rats was markedly extended by combination therapy with cisplatin and probenecid, compared with either agent alone. The expression of MRP2 mRNA was increased when AH66 cells were cultured in medium containing 5% ASF or 5% bile for 24 h. The induction of MRP2 mRNA expression in AH66 cells was also observed in the presence of heat-denatured ASF. The bilirubin content in ASF was characteristically higher than that in FBS, normal rat serum or AH66-bearing rat serum. Unconjugated bilirubin did not change the expression of MRP2 mRNA, whereas conjugated bilirubin markedly increased it. The cisplatin uptake in AH66 cells after culture in 5% FBS DMEM containing conjugated bilirubin was about half that of the cells cultured in 5% FBS DMEM alone (p < 0.01). In addition, the cisplatin sensitivity of the cells was significantly lowered by the addition of conjugated bilirubin. The expression of MRP2 mRNA in rat normal hepatocytes was also increased after culture in medium containing 5% ASF or 5% bile. These results indicated that conjugated bilirubin, a component of ASF, induces the mRNA expression of MRP2, which is a determinant of the in vivo cisplatin resistance of AH66 cells.

Influence of chronic hepatic failure on disposition kinetics of valproate excretion through a phase II reaction in rats treated with carbon tetrachloride.

The influence of chronic hepatic failure on the disposition kinetics of valproate (VPA) excretion via a phase II reaction was examined in rats treated with carbon tetrachloride (1.0 mg/kg, s.c., 3 times a week) for 2 or 3 months. There was no significant difference in the plasma concentration-time courses of VPA among the control and two treated groups up to 120 min after i.v. administration of VPA (75 mg/kg), but subsequently the plasma concentrations of the treated groups declined significantly below the control levels. Expression of Mrp2 mRNA in the liver of the treated groups was significantly lower than in the control group; conversely that in the kidney was significantly higher. The enzyme activity of UGTs in the liver of the treated groups decreased significantly, but UGT1A8 mRNA expression in the duodenum was increased about 3-fold. Cumulative excretion of VPA glucuronide (VPA-G) in bile of the treated groups was reduced significantly, while that in urine was markedly increased. In conclusion, the area under the VPA plasma concentration-time curve was decreased significantly in rats with chronic hepatic failure owing to increased excretion of VPA-G via the kidney as a result of induction of Mrp2, and inhibition of enterohepatic circulation of VPA-G.

Development of dosage design of hepatic metabolizing drugs using serum albumin level in chronic hepatic failure.

We have previously reported good correlations among serum aminotransferase (AST) activity, metabolic enzyme activity of CYPs, and total clearance (CL(tot)) of probe drugs in rats with acute hepatic failure induced by CCl4. In this study, we searched for new biochemical indicators that correlate with hepatic function and tried to simulate appropriate drug dosage in chronic hepatic failure. Model rats were prepared by administration of CCl4 (1 ml/kg, s.c., 3 times/week) and used at 48 h after the last administration. Serum albumin concentration was time-dependently decreased and correlated well with 3 major biologic determinants of drug clearance, hepatic blood flow (HBF), intrinsic clearance (CL(int)), and the unbound fraction of drugs in plasma (fp) after intravenous administration of cyclophosphamide, tolbutamide, zonisamide, and chlorzoxazone (as probe drugs for low hepatic extraction) and propranolol and lidocaine (as high-hepatic extraction drugs). By calculating these parameters based on prediction equations by the level of albumin, CL(tot) was obtained. As a result of having evaluated this model using administration of cyclosporin, there was a statistically significant relationship between predicted CL(tot) and observed CL(tot). In conclusion, the value of serum albumin level is a useful parameter that correlates well with chronic hepatic function. We have shown that this quantitative administering design using serum albumin level can predict appropriate dosages of hepatic metabolizing drugs in chronic hepatic failure.