Numerous reports describe the successful use of nitrous oxide for analgesia in children undergoing painful procedures. Although shown to be safe, effective, and economical, nitrous oxide use is not yet common in pediatric oncology clinics and few reports detail its effectiveness for children undergoing repeated lumbar punctures. We developed a nitrous oxide clinic, and undertook a review of pediatric oncology lumbar puncture records for those patients receiving nitrous oxide in 2011. No major complications were noted. Minor complications were noted in 2% of the procedures. We offer guidelines for establishing such a clinic.

Bisphenol-A (BPA) is a ubiquitous precursor of polycarbonate plastics that is found in the blood and serum of >92% of Americans. While BPA has been well documented to act as a weak estrogen receptor (ER) agonist, its effects on cellular stress are unclear. Here, we demonstrate that high-dose BPA causes stress granules (SGs) in human cells. A common estrogen derivative, β-estradiol, does not trigger SGs, indicating the mechanism of SG induction is not via the ER pathway. We also tested other structurally related environmental contaminants including the common BPA substitutes BPS and BPF, the industrial chemical 4-nonylphenol (4-NP) and structurally related compounds 4-EP and 4-VP, as well as the pesticide 2,4-dichlorophenoxyacetic acid (2,4-D). The variable results from these related compounds suggest that structural homology is not a reliable predictor of the capacity of a compound to cause SGs. Also, we demonstrate that BPA acts primarily through the PERK pathway to generate canonical SGs. Finally, we show that chronic exposure to a low physiologically relevant dose of BPA suppresses SG assembly upon subsequent acute stress. Interestingly, this SG inhibition does not affect phosphorylation of eIF2α or translation inhibition, thus uncoupling the physical assembly of SGs from translational control. Our work identifies additional effects of BPA beyond endocrine disruption that may have consequences for human health.

29Bisphenol-A (BPA) is a ubiquitous precursor of polycarbonate plastics that is found in the blood 30 and serum of >92% of Americans. While BPA has been well documented to act as a weak 31 estrogen receptor (ER) agonist, its effects on cellular stress are unclear. Here, we demonstrate 32 that high-dose BPA causes stress granules (SGs) in human cells. A common estrogen 33 derivative, β-estradiol, does not trigger SGs, indicating the mechanism of SG induction is not via 34 the ER pathway. We also tested other structurally related environmental contaminants including 35 the common BPA substitutes BPS and BPF, the industrial chemical 4-nonylphenol (4-NP) and 36 structurally related compounds 4-EP and 4-VP, and the pesticide 2,4-dichlorophenoxyacetic 37 acid (2,4-D). The variable results from these related compounds suggest that structural 38 homology is not a reliable predictor of the capacity of a compound to cause SGs. Also, we 39 demonstrate that BPA acts primarily through the PERK pathway to generate canonical SGs. 40Finally, we show that chronic exposure to a low physiologically relevant dose of BPA disrupts 41 SG assembly by inhibiting SGs upon additional acute stress. Our work identifies additional 42 effects of BPA beyond endocrine disruption that may have consequences for human health. 43 2006). These kinases once activated all target the same mechanism, the phosphorylation of 96 serine 51 of the alpha-subunit of eIF2, which blocks the formation of initiation ternary complex 97 (eIF2-GTP-tRNA MET ) and thereby results in translational arrest. Often, the phosphorylation of 98 eIF2α-Ser51 triggers the assembly of SGs (Kedersha et al., 2002), though SGs can also form 99 through eIF2-independent mechanisms (Aulas et al., 2017, Farny et al., 2009. Whether BPA 100 activates any of these kinase pathways was previously unknown. 101Here, we investigated the link between the endocrine disrupting compound BPA and 102SGs. We determined that high doses of BPA cause canonical, phospho-eIF2α-dependent SG 103 assembly via activation of PERK, one of four eIF2α kinases that mediate the integrated stress 104 response. The common estrogen supplement β-estradiol does not trigger SG assembly, 105indicating that it is unlikely that BPA induced SG assembly in our cells is related to its reported 106 endocrine disrupting activity. While BPA induces robust SG assembly, closely related BPA 107 substitutes BPF and BPS cause lower or no SG response, respectively. Similarly, we find that 108 the industrial chemical 4-nonylphenol (4-NP), but not highly related structural compounds 4-EP 109 and 4-VP, trigger SG assembly. These results indicate that structural homology may not be a 110 good predictor for environmental contaminant to promote SG assembly. Finally, we show that 111 long term, low-dose BPA exposure within the physiologically relevant range can alter SG 112 dynamics by reducing SG assembly upon later acute stress exposures, suggesting that real 113 world chronic BPA exposures may compromise the ability of human cells to cope wit...