Ethanol inhibits dopamine uptake via organic cation transporter 3: Implications for ethanol and cocaine co-abuse.

Concurrent cocaine and alcohol use is among the most frequent drug combination, and among the most dangerous in terms of deleterious outcomes. Cocaine increases extracellular monoamines by blocking dopamine (DA), norepinephrine (NE) and serotonin (5-HT) transporters (DAT, NET and SERT, respectively). Likewise, ethanol also increases extracellular monoamines, however evidence suggests that ethanol does so independently of DAT, NET and SERT. Organic cation transporter 3 (OCT3) is an emergent key player in the regulation of monoamine signaling. Using a battery of in vitro, in vivo electrochemical, and behavioral approaches, as well as wild-type and constitutive OCT3 knockout mice, we show that ethanol's actions to inhibit monoamine uptake are dependent on OCT3. These findings provide a novel mechanistic basis whereby ethanol enhances the neurochemical and behavioral effects of cocaine and encourage further research into OCT3 as a target for therapeutic intervention in the treatment of ethanol and ethanol/cocaine use disorders.

A decline in the occurrence of extended-spectrum ß-lactamase-producing Escherichia coli in retail chicken meat in the UK between 2013 and 2018.

AIMS: The aim of this study was to report on the occurrence of antimicrobial resistant (AMR) Escherichia coli from retail chicken meat samples in the UK, with particular focus on AmpC and extended spectrum beta-lactamase (ESBL) production and carbapenem resistance. METHODS AND RESULTS: Methods from EU protocols were used for selective isolation of AmpC-/ESBL-producing E. coli, carbapenem-resistant E. coli and for performing minimum inhibitory concentrations. Additional work not part of EU protocols included viable counts, detection by PCR of blaCTX-M , blaOXA, blaSHV and blaTEM genes in ESBL-phenotype E. coli and screening for mcr plasmid-mediated colistin resistance. From the 313/309 retail chicken meat samples tested in 2016/2018, carbapenem or mcr plasmid-mediated colistin-resistant E. coli were not detected. For 2016/2018 chicken samples, 141/42 (45·0%/13·6%), 90/23 (28·8%/7·4%), 48/16 (15·3%/5·2%) and 3/3 (1·0%/1·0%) were positive for ESBL- and/or AmpC-, ESBL- alone AmpC- alone and AmpC+ESBL-phenotype E. coli respectively. ESBL-producing E. coli were predominantly blaCTX-M-1 . All AmpC and/or ESBL-phenotype E. coli were sensitive to colistin, ertapenem, imipenem, meropenem, temocillin and tigecycline, applying epidemiological cut-off values. CONCLUSIONS: A previous study in 2013/14 showed that 65·4% of retail chicken meat samples tested in the UK were positive for ESBL-producing (mainly CTX-M) E. coli. Since then the proportion of samples positive in the UK has dropped significantly to 7·4% in 2018. SIGNIFICANCE AND IMPACT OF THE STUDY: Significant reductions in antimicrobials used in the UK poultry meat sector between 2012 and 2016 may be linked to significant reductions in AmpC/ESBL-phenotype E. coli in retail chicken between 2013/14 and 2018.

Cryptic footprints of rare earth elements on natural resources and living organisms.

BACKGROUND: Rare earth elements (REEs) are gaining attention due to rapid rise of modern industries and technological developments in their usage and residual fingerprinting. Cryptic entry of REEs in the natural resources and environment is significant; therefore, life on earth is prone to their nasty effects. Scientific sectors have expressed concerns over the entry of REEs into food chains, which ultimately influences their intake and metabolism in the living organisms. OBJECTIVES: Extensive scientific collections and intensive look in to the latest explorations agglomerated in this document aim to depict the distribution of REEs in soil, sediments, surface waters and groundwater possibly around the globe. Furthermore, it draws attention towards potential risks of intensive industrialization and modern agriculture to the exposure of REEs, and their effects on living organisms. It also draws links of REEs usage and their footprints in natural resources with the major food chains involving plants, animals and humans. METHODS: Scientific literature preferably spanning over the last five years was obtained online from the MEDLINE and other sources publishing the latest studies on REEs distribution, properties, usage, cycling and intrusion in the environment and food-chains. Distribution of REEs in agricultural soils, sediments, surface and ground water was drawn on the global map, together with transport pathways of REEs and their cycling in the natural resources. RESULTS: Fourteen REEs (Ce, Dy, Er, Eu, Gd, Ho, La, Lu, Nd, Pr, Sm, Tb, Th and Yb) were plighted in this study. Wide range of their concentrations has been detected in agricultural soils (<15.9-249.1 µg g-1) and in groundwater (<3.1-146.2 µg L-1) at various sites worldwide. They have strong tendency to accumulate in the human body, and thus associated with kidney stones. The REEs could also perturb the animal physiology, especially affecting the reproductive development in both terrestrial and aquatic animals. In plants, REEs might affect the germination, root and shoot development and flowering at concentration ranging from 0.4 to 150 mg kg-1. CONCLUSIONS: This review article precisely narrates the current status, sources, and potential effects of REEs on plants, animals, humans health. There are also a few examples where REEs have been used to benefit human health. However, still there is scarce information about threshold levels of REEs in the soil, aquatic, and terrestrial resources as well as living entities. Therefore, an aggressive effort is required for global action to generate more data on REEs. This implies we prescribe an urgent need for inter-disciplinary studies about REEs in order to identify their toxic effects on both ecosystems and organisms.

Detection of extended-spectrum ß-lactam, AmpC and carbapenem resistance in Enterobacteriaceae in beef cattle in Great Britain in 2015.

AIMS: This study investigated the occurrence and genetic diversity of Enterobacteriaceae with extended-spectrum ß-lactamase (ESBL)-, AmpC- and carbapenemase-mediated resistance in British beef cattle, and related risk factors. METHODS AND RESULTS: Faecal samples (n = 776) were obtained from farms in England and Wales (n = 20) and Scotland (n = 20) in 2015. Isolates from selective agars were identified by MALDI ToF mass spectrometry. Selected isolates were characterized by multiplex PCR (blaCTX -M, blaOXA , blaSHV and blaTEM genes), whole-genome sequencing (WGS), minimum inhibitory concentrations and pulsed-field gel electrophoresis. None of the faecal samples yielded carbapenem-resistant Escherichia coli. Ten (25%) of the farms tested positive for ESBL-producing CTX-M Enterobacteriaceae, 15 (37·5%) of the farms were positive for AmpC phenotype E. coli and none were positive for carbapenem-resistant E. coli. WGS showed a total of 30 different resistance genes associated with E. coli, Citrobacter and Serratia from ESBL agars, and colocation of resistance genes with blaCTX -M1 . Buying bulls and bringing in fattening cattle from another farm were identified as significant risk factors for positive samples harbouring CTX-M Enterobacteriaceae or AmpC phenotype E. coli respectively. CONCLUSIONS: Beef cattle on a proportion of farms in GB carry ESBL-producing Enterobacteriaceae. Factors, such as operating as a closed herd, may have an important role in reducing introduction and transmission of resistant Enterobacteriaceae. The results indicate management factors may play an important role in impacting ESBL prevalence. In particular, further study would be valuable to understand the impact of maintaining a closed herd on reducing the introduction of resistant Enterobacteriaceae. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study showing the presence of ESBL-producing Enterobacteriaceae in British beef cattle.

Longitudinal study on the occurrence in pigs of colistin-resistant Escherichia coli carrying mcr-1 following the cessation of use of colistin.

AIMS: In 2015, colistin-resistant Escherichia coli and Salmonella with the mcr-1 gene were isolated from a pig farm in Great Britain. Pigs were subsequently monitored over a ~20-month period for the occurrence of mcr-1-mediated colistin resistance and the risk of mcr-1 E. coli entering the food chain was assessed. METHODS AND RESULTS: Pig faeces and slurry were cultured for colistin-resistant E. coli and Salmonella, tested for the mcr-1 gene by PCR and selected isolates were further analysed. Seventy-eight per cent of faecal samples (n = 275) from pigs yielded mcr-1 E. coli after selective culture, but in positive samples only 0·2-1·3% of the total E. coli carried mcr-1. Twenty months after the initial sampling, faecal samples (n = 59) were negative for E. coli carrying mcr-1. CONCLUSIONS: The risk to public health from porcine E. coli carrying mcr-1 was assessed as very low. Twenty months after cessation of colistin use, E. coli carrying mcr-1 was not detected in pig faeces on a farm where it was previously present. SIGNIFICANCE AND IMPACT OF THE STUDY: The results suggest that cessation of colistin use may help over time to reduce or possibly eliminate mcr-1 E. coli on pig farms where it occurs.

Understanding and mitigating hydrogen embrittlement of steels: a review of experimental, modelling and design progress from atomistic to continuum.

Hydrogen embrittlement is a complex phenomenon, involving several length- and timescales, that affects a large class of metals. It can significantly reduce the ductility and load-bearing capacity and cause cracking and catastrophic brittle failures at stresses below the yield stress of susceptible materials. Despite a large research effort in attempting to understand the mechanisms of failure and in developing potential mitigating solutions, hydrogen embrittlement mechanisms are still not completely understood. There are controversial opinions in the literature regarding the underlying mechanisms and related experimental evidence supporting each of these theories. The aim of this paper is to provide a detailed review up to the current state of the art on the effect of hydrogen on the degradation of metals, with a particular focus on steels. Here, we describe the effect of hydrogen in steels from the atomistic to the continuum scale by reporting theoretical evidence supported by quantum calculation and modern experimental characterisation methods, macroscopic effects that influence the mechanical properties of steels and established damaging mechanisms for the embrittlement of steels. Furthermore, we give an insight into current approaches and new mitigation strategies used to design new steels resistant to hydrogen embrittlement.

Longitudinal study of CTX-M ESBL-producing E. coli strains on a UK dairy farm.

The aim of this study was to investigate the bacterial strains and farm environment that may contribute to the persistence of ESBL-producing E. coli on a single UK dairy farm. A longitudinal study was conducted comprising 6 visits, between August and October 2010, followed by a further visit at approximately 69weeks after the initial visit. Faecal and environmental samples were collected from different parts of the farm. The persistence and extent of faecal shedding of ESBL E. coli by individual calves was also determined. Twenty two different PFGE types were identified. Four of these were persistent during the study period and were associated with serotypes: O98, O55, O141 and O33. The counts suggest that shedding in calf faeces was an important factor for the persistence of strains, and the data will be useful for parameterising mathematical models of the spread and persistence of ESBL strains within a dairy farm.

Differentiation of UK endemic strains of Salmonella enterica serovar Newport from epidemic North American strains by PCR detection of a truncated bapA chromosomal gene.

The aim of this study was to develop a PCR test to detect chromosomal differences between epidemic multidrug resistant (epi-MDR) strains of Salmonella enterica serovar Newport (S. Newport) and non-epi-MDR strains of S. Newport that are endemic to the United Kingdom (UK). Sequence analysis of the biofilm-associated protein A gene (bapA) showed that epi-MDR strains of S. Newport from the United States of America (USA) had a deletion of 309 bp, which was not present in non-epi-MDR strains of S. Newport from the UK. A PCR test was developed using primers designed to target this difference and was applied to a panel of S. Newport isolates comprising of strains from the UK (n=20, non-epi-MDR), from the USA (n=10, epi-MDR) and from Canada (n=7). A second panel of isolates (n=73) was used to assess the test specificity, and these isolates consisted of non-Newport Salmonella serovars (n=25), and other epidemic serovars (n=48). Epi-MDR S. Newport isolates produced a characteristic 505 bp amplicon, whereas non-epi-MDR S. Newport isolates produced an 814 bp amplicon. The bapA PCR has potential to discriminate between these S. Newport strains irrespective of their carrying resistance genes.

An assessment of evidence data gaps in the investigation of possible transmission routes of extended spectrum ß-lactamase producing Escherichia coli from livestock to humans in the UK.

Antimicrobial resistance (AMR) threatens the effective prevention and treatment of bacterial diseases in both humans and animals. Globally, there has been much research done regarding resistant bacteria in the livestock industry, but few published resources collate this information. This report discusses a risk assessment (RA) framework and subsequent analysis of data availability for AMR in bacteria from 4 livestock sectors: dairy cattle, beef cattle, pigs and poultry, with particular reference to ESBL-producing Escherichia coli (ESBL E. coli) prevalence in the dairy cattle sector within the United Kingdom. The aim of this assessment was to identify where quality data exist, for the purpose of parameterising a quantitative RA, and where it would be useful to direct future research to provide quality data to improve the current knowledge base. Such research is necessary to support risk modelling and forecasting capability regarding the relative contributions of factors that maintain the emergence and spread of AMR in bacteria. The review suggested that there are data gaps regarding ESBL E. coli occurrence in the following: beef cattle, bulk tank milk and dairy products, animal-by-products, the farm environment (including after flooding) as well as the effect of animal stress on shedding levels. Filling these data gaps prior to undertaking a full quantitative RA would make the assessment more robust and give greater confidence in the final outcome and consequently inform the targeting and prioritising of interventions to minimise spread of AMR in bacteria in farm animals.

Preclinical studies on the pharmacokinetics, safety, and toxicology of oxfendazole: toward first in human studies.

A 2-week study in rats identified target organs of oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased white blood cell levels, a class effect of benzimidazole anthelmintics, returned to normal during the recovery period. The no observed adverse effect level was determined to be >5 but <25 mg/kg/d and the maximum tolerated dose 100 mg/kg/d. The highest dose, 200 mg/kg/d, resulted in significant toxicity and mortality, leading to euthanization of the main study animals in this group after 7 days. Oxfendazole did not exhibit genetic toxicology signals in standard Ames bacterial, mouse lymphoma, or rat micronucleus assays nor did it provoke safety concerns when evaluated for behavioral effects in rats or cardiovascular safety effects in dogs. These results support the transition of oxfendazole to First in Human safety studies preliminary to its evaluation in human helminth diseases.

Traumatic brain injury imaging research roadmap.

The past decade has seen impressive advances in the types of neuroimaging information that can be acquired in patients with traumatic brain injury. However, despite this increase in information, understanding of the contribution of this information to prognostic accuracy and treatment pathways for patients is limited. Available techniques often allow us to infer the presence of microscopic changes indicative of alterations in physiology and function in brain tissue. However, because histologic confirmation is typically lacking, conclusions reached by using these techniques remain solely inferential in almost all cases. Hence, a need exists for validation of these techniques by using data from large population samples that are obtained in a uniform manner, analyzed according to well-accepted procedures, and correlated with closely monitored clinical outcomes. At present, many of these approaches remain confined to population-based research rather than diagnosis at an individual level, particularly with regard to traumatic brain injury that is mild or moderate in degree. A need and a priority exist for patient-centered tools that will allow advanced neuroimaging tools to be brought into clinical settings. One barrier to developing these tools is a lack of an age-, sex-, and comorbidities-stratified, sequence-specific, reference imaging data base that could provide a clear understanding of normal variations across populations. Such a data base would provide researchers and clinicians with the information necessary to develop computational tools for the patient-based interpretation of advanced neuroimaging studies in the clinical setting. The recent "Joint ASNR-ACR HII-ASFNR TBI Workshop: Bringing Advanced Neuroimaging for Traumatic Brain Injury into the Clinic" on May 23, 2014, in Montreal, Quebec, Canada, brought together neuroradiologists, neurologists, psychiatrists, neuropsychologists, neuroimaging scientists, members of the National Institute of Neurologic Disorders and Stroke, industry representatives, and other traumatic brain injury stakeholders to attempt to reach consensus on issues related to and develop consensus recommendations in terms of creating both a well-characterized normative data base of comprehensive imaging and ancillary data to serve as a reference for tools that will allow interpretation of advanced neuroimaging tests at an individual level of a patient with traumatic brain injury. The workshop involved discussions concerning the following: 1) designation of the policies and infrastructure needed for a normative data base, 2) principles for characterizing normal control subjects, and 3) standardizing research neuroimaging protocols for traumatic brain injury. The present article summarizes these recommendations and examines practical steps to achieve them.

Degradation of cefquinome in spiked milk as a model for bioremediation of dairy farm waste milk containing cephalosporin residues.

AIMS: The aims of this work were to develop a model of dairy farm waste milk and to investigate methods for the bioremediation of milk containing cefquinome residues. METHODS AND RESULTS: Unpasteurized milk and UHT milk that had both been spiked with cefquinome at a concentration of 2 µg ml(-1) were used as a model for waste milk containing cephalosporin residues. Adjustment of the spiked UHT milk to pH 10 or treatment with conditioned medium from bacterial growth producing cefotaximase, were the most effective methods for decreasing the cefquinome concentrations within 24 h. A large-scale experiment (10 l of cefquinome-spiked unpasteurized milk) suggested that fermentation for 22 h at 37°C followed by heating at 60°C for 2 h was sufficient to decrease cefquinome concentrations to below the limit of quantification (<125 µg kg(-1) ) and to kill the majority of the enriched bacterial population. CONCLUSIONS: One or a combination of the bioremediation methods described may have potential as a practical treatment for dairy farm waste milk. SIGNIFICANCE AND IMPACT OF THE STUDY: Treatment of waste milk to decrease cephalosporin residue concentrations and also to kill bacteria prior to feeding to dairy calves could decrease the risk of selection for ESBL bacteria on dairy farms.