OBJECTIVE: To evaluating the efficacy of fresh frozen plasma (FFP) in comparison with conventional regimen in the treatment of organophosphate (OP) poisoning. METHODS: PubMed, ScopeMed, Cochrane, Scopus, and Google Scholar databases were searched. The search strategy used the following key words "organophosphate" and "poisoning or toxicity", "(atropine and oxime)", "fresh frozen plasma", "clinical trial", "outcome". The treatment with atropine or/and oxime was considered conventional therapy. The length of hospitalization, the length of ICU admission, need for mechanical ventilation and its duration, clinical recovery point, choline esterase level, mortality rate, and intermediate syndrome (IMS) occurrence were the key outcomes of interest. Databases were searched during the period of 2003-2019. Five studies were included in the analysis. RESULTS: Pooling of data showed that the relative risk (RR) of mortality in OP poisoning for five included trials comparing FFP-treated group with conventional regimen therapy was [0.563 (95% CI (0.252, 1.255)]. The summary of RR for IMS in two studies was [RR: 1.34, 95% CI (0.655, 2.742)]. In addition, there was a non-significant mean difference (MD) in hospital stay [MD: -0.106, 95% CI (-0.434, 0.223)] in three included trials. A significant MD was observed in the length of ICU admission in two trials between FFP-treated group compared to the conventional treatment group [MD: -2.672, 95% CI (-4.189, -1.154)], but after random effects meta-analysis, the changes were not significant [MD: -2.015, 95% CI (-6.308, 2.277)]. The summary of fixed-effect meta-analysis for choline esterase level in three trails was [MD: -0.117, 95% CI (-0.468, 0.234)]. The RR of ventilation requirement for two included trials in the FFP-treated group comparing to the conventional regimen therapy was [0.84, 95% CI (0.691, 1.022)] while for ventilation duration in two studies was [MD: -0.183, 95% CI (-0.567, 0.201)]. CONCLUSION: The addition of FFP to conventional therapy did not improve the outcomes of mortality, IMS, hospital length of stay, cholinesterase levels, need or duration of mechanical ventilation, and only the length of ICU stay could affect in the treated group.
        
Title: The inhibition of acetylcholinesterase by a brain-targeting polylysine-ApoE peptide: biochemical and structural characterizations Lu L, Michelena TM, Wong A, Zhang CJ, Meng Y Ref: Conf Proc IEEE Eng Med Biol Soc, 2018:155, 2018 : PubMed
The in-trans delivery of protein therapeutics across the blood-brain barrier by K16ApoE peptide carrier has been demonstrated to improve the neurological symptoms and increase the life-span of late-infantile neuronal ceroid lipofuscinosis (LINCL) mice. However, acute toxicity of K16ApoE was observed in LINCL mice resulting in a narrow therapeutic index, limiting the potential of translating the K16ApoE into a viable drug delivery system. This study aims to unravel the toxic mechanism of action. We hypothesized that the toxic response towards the peptide was induced by inhibition of acetylcholinesterase (AChE) activity at neuro-muscular junction. Here, results from the dose-response study suggested that AChE activity was inhibited by K16ApoE at either low or high doses but not at the mid-dose where a significant increase in AChE activity was observed. Meanwhile, molecular docking simulations showed that the N-terminus of K16ApoE is capable of binding to the active site gorge of AChE. In addition to a favorable spatial orientation, this docking pose also revealed strong surface charge interactions which may account for the observed inhibitory effect. While statistical analysis of the dose response and survival ratio suggested that AChE is not the primary mechanism of action for the acute toxicity of K16ApoE, both biochemical evidence and structural analysis have assigned indirect but critical roles for AChE in the overall toxicity mechanism of this peptide carrier.
The Asian tiger mosquito (Aedes albopictus) is an important vector for pathogens that affect human health, including the viruses that cause dengue and Chikungunya fevers. It is also one of the world's fastest-spreading invasive species. For these reasons, it is crucial to identify strategies for controlling the reproduction and spread of this mosquito. During mating, seminal fluid proteins (Sfps) are transferred from male mosquitoes to females, and these Sfps modulate female behavior and physiology in ways that influence reproduction. Despite the importance of Sfps on female reproductive behavior in mosquitoes and other insects, the identity of Sfps in Ae. albopictus has not previously been reported. We used transcriptomics and proteomics to identify 198 Sfps in Ae. albopictus. We discuss possible functions of these Sfps in relation to Ae. albopictus reproduction-related biology. We additionally compare the sequences of these Sfps with proteins (including reported Sfps) in several other species, including Ae. aegypti. While only 72 (36.4%) of Ae. albopictus Sfps have putative orthologs in Ae. aegypti, suggesting low conservation of the complement of Sfps in these species, we find no evidence for an elevated rate of evolution or positive selection in the Sfps that are shared between the two Aedes species, suggesting high sequence conservation of those shared Sfps. Our results provide a foundation for future studies to investigate the roles of individual Sfps on feeding and reproduction in this mosquito. Functional analysis of these Sfps could inform strategies for managing the rate of pathogen transmission by Ae. albopictus.
        
Title: Extensive Ace2 duplication and multiple mutations on Ace1 and Ace2 are related with high level of organophosphates resistance in Aphis gossypii Shang Q, Pan Y, Fang K, Xi J, Wong A, Brennan JA, Cao C Ref: Environ Toxicol, 29:526, 2014 : PubMed
Aphis gossypii (Glover) has been found to possess multiple mutations in the acetylcholinesterase (AChE) gene (Ace) that might involve target site insensitivity. In vitro functional expression of AChEs reveals that the resistant Ace1 (Ace1R) and Ace2 (Ace2R) were significantly less inhibited by eserine, omethoate, and malaoxon than the susceptible Ace1 (Ace1S) and Ace2 (Ace2S). Furthermore, in both the mutant and susceptible AChEs, Ace2 was significantly less sensitive to eserine, omethoate, and malaoxon than Ace1. These results suggested that both the mutant Ace1 and Ace2 were responsible for omethoate resistance, while the mutant Ace2 played a major role in insecticide resistance. The DNA copy number and transcription level of Ace2 were 1.52- and 1.88-fold higher in the ORR strain than in the OSS strain. Furthermore, the DNA copy number and transcription level of Ace2 were significantly higher than that of Ace1 in either OSS or ORR strains, demonstrating the involvement of Ace2 gene duplication in resistance. Thus, the authors conclude that omethoate resistance in cotton aphids appears to have evolved through a combination of multiple mutations and extensive Ace2R gene duplication. (c) 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 526-533, 2014.
Despite reports of high colonization rates of ST398 livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) among pigs and pig farmers, the incidence of LA-MRSA infection in the general population in Canada appears to be rare in comparison to that in some European countries. In this study, the complete genome sequence of a Canadian representative LA-MRSA isolate (08BA02176) from a human postoperative surgical site infection was acquired and compared to the sequenced genome of an LA-MRSA isolate (S0385) from Europe to identify genetic traits that may explain differences in the success of these particular strains in some locales.
        
Title: Spinal administration of the monoacylglycerol lipase inhibitor JZL184 produces robust inhibitory effects on nociceptive processing and the development of central sensitization in the rat Woodhams S, Wong A, Barrett D, Bennett A, Chapman V, Alexander S Ref: British Journal of Pharmacology, 167:1609, 2012 : PubMed
BACKGROUND AND PURPOSE: The cannabinoid receptor-mediated analgesic effects of 2-arachidonoylglycerol (2-AG) are limited by monoacylglycerol lipase (MAGL). 4-nitrophenyl 4-[bis (1,3-benzodioxol-5-yl) (hydroxy) methyl] piperidine-1-carboxylate (JZL184) is a potent inhibitor of MAGL in the mouse, though potency is reportedly reduced in the rat. Here we have assessed the effects of spinal inhibition of MAGL with JZL184 on nociceptive processing in rats. EXPERIMENTAL APPROACH: In vivo spinal electrophysiological assays in anaesthetized rats were used to determine the effects of spinal administration of JZL184 on spinal nociceptive processing in the presence and absence of hindpaw inflammation. Contributions of CB(1) receptors to these effects was assessed with AM251. Inhibition of 2-oleoylglycerol hydrolytic activity and alterations of 2-AG in the spinal cord after JZL 184 were also assessed. KEY RESULTS: Spinal JZL184 dose-dependently inhibited mechanically evoked responses of wide dynamic range (WDR) neurones in naive anaesthetized rats, in part via the CB(1) receptor. A single spinal administration of JZL184 abolished inflammation-induced expansion of the receptive fields of spinal WDR neurones. However, neither spinal nor systemic JZL184 altered levels of 2-AG, or 2-oleoylglycerol hydrolytic activity in the spinal cord, although JZL184 displayed robust inhibition of MAGL when incubated with spinal cord tissue in vitro. CONCLUSIONS AND IMPLICATIONS: JZL184 exerted robust anti-nociceptive effects at the level of the spinal cord in vivo and inhibited rat spinal cord MAGL activity in vitro. The discordance between in vivo and in vitro assays suggests that localized sites of action of JZL184 produce these profound functional inhibitory effects. LINKED ARTICLES: This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http:\/\/dx.doi.org/10.1111/bph.2012.167.issue-8.
        
Title: Exon sequencing and association analysis of EPHX1 genetic variants with maintenance warfarin dose in a multiethnic Asian population Chan SL, Thalamuthu A, Goh BC, Chia KS, Chuah B, Wong A, Lee SC Ref: Pharmacogenet Genomics, 21:35, 2011 : PubMed
BACKGROUND AND OBJECTIVES: Warfarin inhibits vitamin K epoxide reductase, of which microsomal epoxide hydrolase is a putative member. Several studies have found signals of association with warfarin maintenance dose in the EPHX1 gene. The aim of this study was to determine the effects of EPHX1 variants on warfarin maintenance dose in a multiethnic Asian population. METHODS: We sequenced the exons of EPHX1 using PCR and direct sequencing in 279 patients consisting of three major ethnic groups receiving maintenance warfarin with a stable international normalized ratio. The effects of EPHX1 variants were assessed using multiple linear regression. RESULTS: An association between an intronic SNP rs1877724 and warfarin maintenance dose was found, with homozygous variant carriers requiring approximately 0.5 mg/day lower than wild type and heterozygotes after adjustment for covariates. However, its contribution is small, explaining only an additional 0.8% of the dose variability. Rare variants were pooled but there was no association between their presence and warfarin maintenance dose. However, the presence of noncoding rare SNPs was significantly associated with warfarin maintenance dose. CONCLUSION: Despite a significant finding in rs1877724, which concurs with an earlier study, overall, genetic variants in EPHX1 do not have a clinically significant impact on warfarin dose requirements in our population.
Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.