FORTY FIVE YEARS OF ANTICOAGULANT RODENTICIDES — PAST, PRESENT AND FUTURE TRENDS

The anticoagulant rodenticides were discovered in the 1940s and their advantages of efficacy and safety quickly resulted in their use dominating the practice of rodent control in temperate countries. However, the development of resistance to the early compounds within a decade stimulated research culminating in the invention of anew class of anticoagulant, the second generation compounds, active against resistant strains but also overall far more potent than those previously available. A novel baiting strategy, pulsed baiting, was developed to make full use of this valuable characteristic. Pulsed baiting has enabled the use of second generation anticoagulants in situations where early products were of limited value, particularly in tropical agriculture. The future of this highly-successful group of compounds is reviewed in relation to resistance and the difficulty and cost of developing further rodenticides

Anticoagulant rodenticide uptake in resistant rat populations

The use of potent anticogulant rodenticide ‘resistance-breakers’ is avoided due to their higher toxicity and potential to be more hazardous in the environment [6]. However, in areas where practitioners seek to control resistant rodent infestations, their use may pose less of a risk than applications of ineffective baits. Compounds to which rodents are resistant to, do not provide effective control and create a long-term source of AR in the environment. The higher quantities of anticoagulant rodenticide used show that using ineffective compounds may extend both the period and severity of exposure to non-target animals to anticoagulant rodenticides. Conversely the effective use of resistance-breakers to control anticoagulant rodenticide-resistant rat populations results in lower environmental exposure of anticoagulant rodenticides for non-targets. Of course, the relative toxicity of the different anticoagulant rodenticides will also play an important part in overall risk assessments. However, this can be outweighed by the relative exposure to different anticoagulant rodenticides in such situations

Chapter 11 An International Perspective on the Regulation of Rodenticides

In the late 1940s, anticoagulant active ingredients were introduced into the global rodenticide market. They were rapidly favored over existing rodenticides, such as red squill, zinc phosphide, strychnine and inorganic compounds, because they were comparatively inexpensive and did not appear to have any unpalatable taste, odor or cause any immediate post-ingestive reaction that could lead to bait shyness in rodents (Wardrop and Keeling 2008). The number of products registered in the United States (US) under Section 3 of the Federal Fungicide, Insecticide and Rodenticide Act (FIFRA), which was passed in 1947 and was the first US law to require product registration, illustrates the rapid dominance of anticoagulants in the US rodenticide market (Fig. 11.1). It is striking that the number of anticoagulant-based rodenticide products (ARs) registered under FIFRA was more than two times greater than the other categories of rodenticide active ingredients 40 years after the enactment of FIFRA. The greatest number of rodenticide products registered in a single year under Section 3 of FIFRA (750) was in 1985, and ARs accounted for 547 (73%) o

PFD: a database for the investigation of protein folding kinetics and stability

We have developed a new database that collects all protein folding data into a single, easily accessible public resource. The Protein Folding Database (PFD) contains annotated structural, methodological, kinetic and thermodynamic data for more than 50 proteins, from 39 families. A user-friendly web interface has been developed that allows powerful searching, browsing and information retrieval, whilst providing links to other protein databases. The database structure allows visualization of folding data in a useful and novel way, with a long-term aim of facilitating data mining and bioinformatics approaches. PFD can be accessed freely at http://pfd.med.monash.edu.au

The Hampshire-Berkshire focus of L120Q anticoagulant resistance in the Norway rat (Rattus norvegicus) and field trials of bromadiolone, difenacoum and brodifacoum

Anticoagulant resistance has been present in Norway rats (Rattus norvegicus) in Hampshire and Berkshire for forty years. All first-generation anticoagulants and two of the second generation, bromadiolone and difenacoum, are resisted by rats carrying the L120Q single nucleotide polymorphism (SNP). A regulatory restriction on the use of resistance-breakers brodifacoum, difethialone and flocoumafen in the UK effectively prevented their use against Norway rats for more than 30 years. During this time, L120Q spread from original localised foci eventually to cover most of central-southern England; with other more dispersed foci elsewhere in the UK. We summarise research on L120Q Norway rats and the field performance of anticoagulant baits against them. Bromadiolone (50 ppm), difenacoum (50 ppm) and brodifacoum (23 ppm) baits were each applied on two farmsteads where it had been established that Norway rats carried the L120Q SNP. Preliminary DNA resistance tests conducted at the farms found only one of 107 rats to be susceptible and 86.9% to be homozygous resistant. The bromadiolone and difenacoum applications were either partially or wholly ineffective; brodifacoum treatments were fully effective. Quantities of active substances used varied between farms and substances; but more bromadiolone and difenacoum baits were applied than brodifacoum baits during the treatments. Results confirm the high incidence of resistance and support advice that bromadiolone and difenacoum should not be used against the L120Q SNP. Prolonged use of resisted anticoagulants has resulted in a high prevalence of homozygosity and resistance spread. Failed treatments result in prolonged feeding on anticoagulant bait and leave Norway rats alive carrying, presumably, high residues. It remains to be seen whether the use of now-permitted effective substances, and the introduction of a rodenticide stewardship regime, will curtail the spread of resistance and reduce anticoagulant residues in wildlife

Chaperone activity and structure of monomeric polypeptide binding domains of GroEL

The chaperonin GroEL is a large complex composed of 14 identical 57-kDa subunits that requires ATP and GroES for some of its activities. We find that a monomeric polypeptide corresponding to residues 191 to 345 has the activity of the tetradecamer both in facilitating the refolding of rhodanese and cyclophilin A in the absence of ATP and in catalyzing the unfolding of native barnase. Its crystal structure, solved at 2.5 A resolution, shows a well-ordered domain with the same fold as in intact GroEL. We have thus isolated the active site of the complex allosteric molecular chaperone, which functions as a "minichaperone." This has mechanistic implications: the presence of a central cavity in the GroEL complex is not essential for those representative activities in vitro, and neither are the allosteric properties. The function of the allosteric behavior on the binding of GroES and ATP must be to regulate the affinity of the protein for its various substrates in vivo, where the cavity may also be required for special functions

VEZF1 elements mediate protection from DNA methylation

There is growing consensus that genome organization and long-range gene regulation involves partitioning of the genome into domains of distinct epigenetic chromatin states. Chromatin insulator or barrier elements are key components of these processes as they can establish boundaries between chromatin states. The ability of elements such as the paradigm β-globin HS4 insulator to block the range of enhancers or the spread of repressive histone modifications is well established. Here we have addressed the hypothesis that a barrier element in vertebrates should be capable of defending a gene from silencing by DNA methylation. Using an established stable reporter gene system, we find that HS4 acts specifically to protect a gene promoter from de novo DNA methylation. Notably, protection from methylation can occur in the absence of histone acetylation or transcription. There is a division of labor at HS4; the sequences that mediate protection from methylation are separable from those that mediate CTCF-dependent enhancer blocking and USF-dependent histone modification recruitment. The zinc finger protein VEZF1 was purified as the factor that specifically interacts with the methylation protection elements. VEZF1 is a candidate CpG island protection factor as the G-rich sequences bound by VEZF1 are frequently found at CpG island promoters. Indeed, we show that VEZF1 elements are sufficient to mediate demethylation and protection of the APRT CpG island promoter from DNA methylation. We propose that many barrier elements in vertebrates will prevent DNA methylation in addition to blocking the propagation of repressive histone modifications, as either process is sufficient to direct the establishment of an epigenetically stable silent chromatin stat

Trends in use of intraosseous and intravenous access in out-of-hospital cardiac arrest across English ambulance services : a registry-based, cohort study

Introduction: The optimum route for drug administration in cardiac arrest is unclear. Recent data suggest that use of the intraosseous route may be increasing. This study aimed to explore changes over time in use of the intraosseous and intravenous drug routes in out-of-hospital cardiac arrest in England. Methods: We extracted data from the UK Out-of-Hospital Cardiac Arrest Outcomes registry. We included adult out-of-hospital cardiac arrest patients between 2015–2020 who were treated by an English Emergency Medical Service that submitted vascular access route data to the registry. The primary outcome was any use of the intraosseous route during cardiac arrest. We used logistic regression models to describe the association between time (calendar month) and intraosseous use. Results: We identified 75,343 adults in cardiac arrest treated by seven Emergency Medical Service systems between January 2015 and December 2020. The median age was 72 years, 64% were male and 23% presented in a shockable rhythm. Over the study period, the percentage of patients receiving intraosseous access increased from 22.8% in 2015 to 42.5% in 2020. For each study-month, the odds of receiving any intraosseous access increased by 1.019 (95% confidence interval 1.019 to 1.020, p < 0.001). This observed effect was consistent across sensitivity analyses. We observed a corresponding decrease in use of intravenous access. Conclusion: In England, the use of intraosseous access in out-of-hospital cardiac arrest has progressively increased over time. There is an urgent need for randomised controlled trials to evaluate the clinical effectiveness of the different vascular access routes in cardiac arrest

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead