Clinical Features of Reported Ethylene Glycol Exposures in the United States

Background

Ethylene glycol is highly toxic and represents an important cause of poisonings worldwide. Toxicity can result in central nervous system dysfunction, cardiovascular compromise, elevated anion gap metabolic acidosis and acute kidney injury. Many states have passed laws requiring addition of the bittering agent, denatonium benzoate, to ethylene glycol solutions to reduce severity of exposures. The objectives of this study were to identify differences between unintentional and intentional exposures and to evaluate the utility of denatonium benzoate as a deterrent.

Methods and Findings

Using the National Poison Data System, we performed a retrospective analysis of reported cases of ethylene glycol exposures from January 2006 to December 2013. Outcome classification was summed for intentionality and used as a basis for comparison of effect groups. There were 45,097 cases of ethylene glycol exposures resulting in 154 deaths. Individuals more likely to experience major effects or death were older, male, and presented with more severe symptoms requiring higher levels of care. Latitude and season did not correlate with increased exposures; however, there were more exposures in rural areas. Denatonium benzoate use appeared to have no effect on exposure severity or number.

Conclusion

Deaths due to ethylene glycol exposure were uncommon; however, there were major clinical effects and more exposures in rural areas. Addition of denatonium benzoate was not associated with a reduction in exposures. Alternative means to deter ingestion are needed. These findings suggest the need to consider replacing ethylene glycol with alternative and less toxic agents.     

Immunocytochemical localization of water-soluble glycoproteins, including Group 1 allergen, in pollen of ryegrass,Lolium perenne, using ferritin-labelled antibody

Summary The cellular sites of the glycoproteins Group 1 allergen (glycoprotein 1) and Antigen A (glycoprotein 2) in mature ryegrass pollen have been investigated by immunoelectron microscopy. Radioimmunoassays confirm previous findings of cross-reactivity between the purified glycoprotein antigens at the high immunoglobulin G (IgG) concentrations used for localization.Freeze-drying of anthers followed by anhydrous processing has been employed because of the water solubility and mobility of the glycoproteins. A double-embedding technique has been developed. This involves, first, embedding anthers in the water-soluble plastic resin JB-4, sectioning and incubating in ferritin-labelled antisera by the indirect method. The sections are then embedded in Spurr's resin for ultra-thin sectioning. Both glycoproteins are found in the following sites: (1) exine and intine wall layers; (2) pollen cytoplasm; (3) the orbicules and anther loculus; and (4) the anther cuticle. In the exine arcades and surface and in the anther loculus, the ferritin label is bound to pollenkitt. The finding that the glycoproteins are in similar sites is predictable in view of the cross-specificity of the antisera. The extent of antibody penetration of the plastic sections has been examined; labelling is confined to cut grains and absent from intact grains.     

Mitochondrial whims: metabolic rate,longevity and the rate of molecular evolution

The evolutionary rate of mitochondrial DNA (mtDNA) is highly variable across lineages in animals, and particularly in mammals. This variation has been interpreted as reflecting variations in metabolic rate: mitochondrial respiratory activity would tend to generate mutagenic agents, thus increasing the mutation rate. Here we review recent evidence suggesting that a direct, mechanical effect of species metabolic rate on mtDNA evolutionary rate is unlikely. We suggest that natural selection could act to reduce the (somatic) mtDNA mutation rate in long-lived species, in agreement with the mitochondrial theory of ageing.     

Exome sequencing identifies a nonsense mutation in <Emphasis Type="Italic">Fam46a</Emphasis> associated with bone abnormalities in a new mouse model for skeletal dysplasia

We performed exome sequencing for mutation discovery of an ENU (N-ethyl-N-nitrosourea)-derived mouse model characterized by significant elevated plasma alkaline phosphatase (ALP) activities in female and male mutant mice, originally named BAP014 (bone screen alkaline phosphatase #14). We identified a novel loss-of-function mutation within the Fam46a (family with sequence similarity 46, member A) gene (NM_001160378.1:c.469G>T, NP_001153850.1:p.Glu157*). Heterozygous mice of this mouse line (renamed Fam46a ^E157*Mhda) had significantly high ALP activities and apparently no other differences in morphology compared to wild-type mice. In contrast, homozygous Fam46a ^E157*Mhda mice showed severe morphological and skeletal abnormalities including short stature along with limb, rib, pelvis, and skull deformities with minimal trabecular bone and reduced cortical bone thickness in long bones. ALP activities of homozygous mutants were almost two-fold higher than in heterozygous mice. Fam46a is weakly expressed in most adult and embryonic tissues with a strong expression in mineralized tissues as calvaria and femur. The FAM46A protein is computationally predicted as a new member of the superfamily of nucleotidyltransferase fold proteins, but little is known about its function. Fam46a ^E157*Mhda mice are the first mouse model for a mutation within the Fam46a gene.     

Root, shoot tissues of Brassica juncea and Cereal secale promote potato health

Brassica species are increasingly being used as cover crops to suppress soil-borne diseases in potato cropping systems. Experiments were conducted in controlled environments and in the field to evaluate the effects of cover crop root or shoot or a combination of root and shoot tissues on potato root and tuber health. In a lab assay we examined the extent to which volatile compounds released from tissues of two cover crop species, rye (Cereale secale L.) and oriental mustard (Brassica juncea L.), could inhibit mycelium growth of two important potato diseases, Rhizoctonia solani and Pythium ultimum. Twenty-four hours into the lab assay, volatile compounds from all residues suppressed fungal growth. After 48 h, marked suppression of hyphal growth continued in the presence of mustard residues but not in the presence of rye tissues or the control without tissues. A 75 L volume container experiment evaluated the effect of incorporating different quantities of mustard shoot and root tissues (none, comparable to field level and fourfold field level) into R. solani and P. ultimum infested soil on potato growth, root health and tuber disease. In the container study, incorporating mustard shoots at the highest dose increased potato yield by 54% and reduced disease rating to 2.3 compared to a severe rating of 4.4 in the control. In the field trial, potato growth, root health and tuber disease levels were evaluated in plots where disease management involved either incorporation of mustard or rye cover crop roots, shoots and whole plants (roots plus shoots) or standard farmer practice of a fumigated fallow as a control. White root tissue was used as a health indicator, and averaged 58 and 78% in the fumigated control and mustard cover crop treatments, respectively. The highest healthy root tissue status (91%) was recorded where whole plants of mustard were incorporated. In contrast to the visual assessment of root and tuber health, tuber yield in the field was not influenced by cover crop treatment. Across experiments, the incorporation of or exposure to whole mustard plants was consistently effective at suppressing soil-borne fungi and promoting healthy roots and tubers, especially at higher rates of biomass. Mustard should be managed so as to maximize incorporated biomass for effective biofumigation. Multipurpose management requiring removal of mustard shoots is incompatible with promoting potato rhizosphere health.     

Structural characterization of inhibitor complexes with checkpoint kinase 2 (Chk2), a drug target for cancer therapy

Chk2 (checkpoint kinase 2) is a serine/threonine kinase that participates in a series of signaling networks responsible for maintaining genomic integrity and responding to DNA damage. The development of selective Chk2 inhibitors has recently attracted much interest as a means of sensitizing cancer cells to current DNA-damaging agents used in the treatment of cancer. Additionally, selective Chk2 inhibitors may reduce p53-mediated apoptosis in normal tissues, thereby helping to mitigate adverse side effects from chemotherapy and radiation. Thus far, relatively few selective inhibitors of Chk2 have been described and none have yet progressed into clinical trials. Here, we report crystal structures of the catalytic domain of Chk2 in complex with a novel series of potent and selective small molecule inhibitors. These compounds exhibit nanomolar potencies and are selective for Chk2 over Chk1. The structures reported here elucidate the binding modes of these inhibitors to Chk2 and provide information that can be exploited for the structure-assisted design of novel chemotherapeutics.     

Relipidated tissue factor linked to collagen surfaces potentiates platelet adhesion and fibrin formation in a microfluidic model of vessel injury

Microfluidic devices allow for the controlled perfusion of human or mouse blood over defined prothrombotic surfaces at venous and arterial shear rates. To mimic in vivo injuries such a plaque rupture, the need exists to link lipidated tissue factor (TF) to surface-bound collagen fibers. Recombinant TF was relipidated in liposomes of phosphatidylserine/phosphatidylcholine/biotin-linked phosphatidylethanolamine (20:79:1 PS/PC/bPE molar ratio). Collagen was patterned in a 250-μm-wide stripe and labeled with biotinylated anticollagen antibody which was then bound with streptavidin, allowing the subsequent capture of the TF liposomes. To verify and detect the TF liposome-collagen assembly, individual molecular complexes of TF-factor VIIa on collagen were visualized using the proximity ligation assay (PLA) to produce discretely localized fluorescent events that were strictly dependent on the presence of factor VIIa and primary antibodies against TF or factor VIIa. Perfusion for 450 s (wall shear rate, 200 s(-1)) of corn trypsin inhibitor (CTI, a factor XIIa inhibitor) treated whole blood over the stripe of TF-collagen enhanced platelet adhesion by 30 ± 8% (p < 0.001) and produced measurable fibrin (>50-fold increase) as compared to surfaces lacking TF. PS/PC/bPE liposomes lacking TF resulted in no enhancement of platelet deposition. Essentially no fibrin was formed during perfusion over collagen surfaces or collagen surfaces with liposomes lacking TF despite the robust platelet deposition, indicating a lack of kinetically significant platelet-borne tissue factor in healthy donor blood. This study demonstrates a reliable approach to link functionally active TF to collagen for microfluidic thrombosis studies.