Differential gene expression during early development in brains of wildtype and biotinidase-deficient mice

Biotinidase deficiency is an autosomal recessively inherited disorder characterized by neurological and cutaneous abnormalities. Untreated individuals with biotinidase deficiency cannot recycle biotin from biocytin (N-biotinyl-ϵ-lysine), the proteolytic digestion product of protein-bound biotin. Biotin therapy can markedly resolve symptoms, or can prevent the development of symptoms if initiated early. To understand better the pathogenesis of the neurological problems in the disorder in humans, we have compared gene transcription changes during the first week post-birth in the brains of biotinidase-deficient, transgenic, knock-out mice at days 1 and 8 and compared to changes in wildtype mice at the same times. The knockout pups that were not supplemented with unconjugated biotin became symptomatic by day 8 and exhibiting failure to thrive. Wildtype pups remained asymptomatic under the same experimental conditions. We compared all four possible combinations and noted the most significant up- and down-regulated genes in the knockout animals at Day 8 compared to those at Day 1, reflecting the changes in gene expression over the first week of development. These alterations involved neurological development and immunological function pathways and provide some clues to avenues for further research. At this time, these preliminary analyses provide us with limited, but new information. However, with the development of new algorithms and programs examining various mechanisms and pathways in the central nervous system, these analyses may help us to understand better the role of biotinidase and the pathogenesis of biotinidase deficiency

Does Adherence to World Health Organization Hand Hygiene Protocols in the Operating Room Have the Potential to Produce Irritant Contact Dermatitis in Anesthesia Providers?

Anesthesia providers have the burden of constant hand hygiene during task dense periods. The requirement for hand hygiene often demands frequent application of alcohol-based hand rub. To assess whether frequent alcohol-based hand rub use leads to skin changes or irritant contact dermatitis, volunteers cleaned their hands with alcohol-based hand rub every 15 minutes for 8 hours for 5 sequential days. They were examined by a dermatologist before and after and asked about subjective skin changes. Results suggest an increase in irritant contact dermatitis scores and subjective complaints

ATM Inhibition Potentiates Death of Androgen Receptor-inactivated Prostate Cancer Cells with Telomere Dysfunction.

Androgen receptor (AR) plays a role in maintaining telomere stability in prostate cancer cells, as AR inactivation induces telomere dysfunction within 3 h. Since telomere dysfunction in other systems is known to activate ATM (ataxia telangiectasia mutated)-mediated DNA damage response (DDR) signaling pathways, we investigated the role of ATM-mediated DDR signaling in AR-inactivated prostate cancer cells. Indeed, the induction of telomere dysfunction in cells treated with AR-antagonists (Casodex or MDV3100) or AR-siRNA was associated with a dramatic increase in phosphorylation (activation) of ATM and its downstream effector Chk2 and the presenceof phosphorylated ATM at telomeres, indicating activation of DDR signaling at telomeres. Moreover, Casodex washout led to the reversal of telomere dysfunction, indicating repair of damaged telomeres. ATM inhibitor blocked ATM phosphorylation, induced PARP cleavage, abrogated cell cycle checkpoint activation and attenuated the formation of γH2AX foci at telomeres in AR-inactivated cells, suggesting that ATM inhibitor induces apoptosis in AR-inactivated cells by blocking the repair of damaged DNA at telomeres. Finally, colony formation assay revealed a dramatic decrease in the survival of cells co-treated with Casodex and ATM inhibitor as compared with those treated with either Casodex or ATM inhibitor alone. These observations indicate that inhibitors of DDR signaling pathways may offer a unique opportunity to enhance the potency of AR-targeted therapies for the treatment of androgen-sensitive as well as castration-resistant prostate cancer

Targeted Use of Alcohol-Based Hand Rub on Gloves During Task Dense Periods: One Step Closer to Pathogen Containment by Anesthesia Providers in the Operating Room

Anesthesia providers' hand hygiene practices in the operating room may contribute to the transmission of bacteria. There is a debate, however, over the best approaches for pathogen containment during task dense periods (induction and extubation) of anesthesia care. A novel approach to reducing pathogen spread during these task dense periods is the use of alcohol-based hand rub on gloves when it may be difficult to either change gloves or clean hands. To evaluate the impact of alcohol-based hand rub on gloves, we estimated perforation rates of 50 gloves that were worn as pairs by volunteers for 2 hours at a time applying alcohol-based hand rub every 15 minutes (total of 8 alcohol-based hand rub applications per pair of gloves). We also identified perforation rates of 50 new, unused gloves. To evaluate the ability to perform routine anesthesia functions, volunteers were asked to pick up a coin from a table top and document whether the gloves felt normal or sticky at each 15-minute period. Fifty new gloves (not exposed to alcohol-based hand rub) were tested for integrity using the Food and Drug Administration-approved process, and one was found to have a microperforation. Of the 50 gloves that had been applied with alcohol-based hand rub 8 times, no microperforations were identified. All volunteers demonstrated tactile competence by picking up a coin from a table top after 8 alcohol-based hand rub applications; in addition, as the number of alcohol-based hand rub applications progressed, the volunteers reported increased stickiness. This study suggests that the use of alcohol-based hand rub on commonly used nitrile examination gloves does not compromise glove integrity or hamper the ability to safely perform routine anesthesia functions

Nuclear imaging of the fuel assembly in ignition experiments

First results from the analysis of neutron image data collected on implosions of cryogenically layered deuterium-tritium capsules during the 2011-2012 National Ignition Campaign are reported. The data span a variety of experimental designs aimed at increasing the stagnation pressure of the central hotspot and areal density of the surrounding fuel assembly. Images of neutrons produced by deuterium-tritium fusion reactions in the hotspot are presented, as well as images of neutrons that scatter in the surrounding dense fuel assembly. The image data are compared with 1D and 2D model predictions, and consistency checked using other diagnostic data. The results indicate that the size of the fusing hotspot is consistent with the model predictions, as well as other imaging data, while the overall size of the fuel assembly, inferred from the scattered neutron images, is systematically smaller than models' prediction. Preliminary studies indicate these differences are consistent with a significant fraction (20%-25%) of the initial deuterium-tritium fuel mass outside the compact fuel assembly, due either to low mode mass asymmetry or high mode 3D mix effects at the ablator-ice interface