Clozapine-induced hepatotoxicity in rat hepatocytes by gel entrapment and monolayer culture.

Clozapine is limitedly used due to its adverse effect including agranulocytosis and hepatotoxicity. However, the mechanism of clozapine toxicity is still not clear. The previous in vitro studies on microsomes proposed a possible mediation of cytochrome P450 (CYP) in producing reactive metabolites. In this paper, clozapine toxicity was, respectively, examined in two cultures of rat hepatocytes. Gel entrapment culture of hepatocytes with higher expression on CYP activities showed higher sensitivity to clozapine treatment than hepatocyte monolayer, indicating the possible involvement of CYP in hepatotoxicity of clozapine. Moreover, in each culture, CYP inhibitors were used to confirm the possible mediation of CYP enzymes. Pretreatment of hepatocytes with CYP 3A inhibitor (ketoconazole), CYP 2E1 inhibitor (diethyldithiocarbamate, DDC) and non-specific inhibitor (cimetidine) significantly reduced the toxicity of clozapine. But the pretreatment with CYP 1A2 inhibitor (fluvoxamine) had no such protective effect indicative of non-function of CYP 1A2 in clozapine toxicity. In addition, glycyrrhizic acid (GA), a scavenger of reactive oxygen species (ROS), also inhibited the adverse response to clozapine, suggesting the positive involvement of oxidant pressure. Thus, it could be concluded that clozapine-induced toxicity was mediated by CYP, particularly CYP 3A and CYP 2E1, and oxidant pressure.

No Shot: US Vaccine Prices And Shortages.

In 2004 an Institute of Medicine report warned of vaccine shortages, raising concerns about disease outbreaks. More than a decade later, we looked for progress in reducing vaccine shortages. We analyzed data on vaccine sales and shortages reported by practitioners and patients to the Food and Drug Administration and the American Society of Health-System Pharmacists in the period 2004-13. We found that the number of annual vaccine shortages peaked in 2007, when there were shortages of seven vaccines; there were only two shortages in 2013. There were no shortages of vaccines with a mean price per dose greater than $75 during the study period. Furthermore, we found that a 10 percent increase in price was associated with a nearly 1 percent decrease in the probability of a shortage. Government payers should carefully consider the benefits of averting shortages when evaluating prices for vaccines, including older vaccines whose prices have been subject to congressional price caps.

Nicotianamine, a novel enhancer of rice iron bioavailability to humans.

BACKGROUND: Polished rice is a staple food for over 50% of the world's population, but contains little bioavailable iron (Fe) to meet human needs. Thus, biofortifying the rice grain with novel promoters or enhancers of Fe utilization would be one of the most effective strategies to prevent the high prevalence of Fe deficiency and iron deficiency anemia in the developing world. METHODOLOGY/PRINCIPAL FINDINGS: We transformed an elite rice line cultivated in Southern China with the rice nicotianamine synthase gene (OsNAS1) fused to a rice glutelin promoter. Endosperm overexpression of OsNAS1 resulted in a significant increase in nicotianamine (NA) concentrations in both unpolished and polished grain. Bioavailability of Fe from the high NA grain, as measured by ferritin synthesis in an in vitro Caco-2 cell model that simulates the human digestive system, was twice as much as that of the control line. When added at 1:1 molar ratio to ferrous Fe in the cell system, NA was twice as effective when compared to ascorbic acid (one of the most potent known enhancers of Fe bioavailability) in promoting more ferritin synthesis. CONCLUSIONS: Our data demonstrated that NA is a novel and effective promoter of iron utilization. Biofortifying polished rice with this compound has great potential in combating global human iron deficiency in people dependent on rice for their sustenance.

Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy.

Nephronophthisis-related ciliopathies (NPHP-RC) are recessive disorders that feature dysplasia or degeneration occurring preferentially in the kidney, retina and cerebellum. Here we combined homozygosity mapping with candidate gene analysis by performing 'ciliopathy candidate exome capture' followed by massively parallel sequencing. We identified 12 different truncating mutations of SDCCAG8 (serologically defined colon cancer antigen 8, also known as CCCAP) in 10 families affected by NPHP-RC. We show that SDCCAG8 is localized at both centrioles and interacts directly with OFD1 (oral-facial-digital syndrome 1), which is associated with NPHP-RC. Depletion of sdccag8 causes kidney cysts and a body axis defect in zebrafish and induces cell polarity defects in three-dimensional renal cell cultures. This work identifies loss of SDCCAG8 function as a cause of a retinal-renal ciliopathy and validates exome capture analysis for broadly heterogeneous single-gene disorders.