Benzo[a]pyrene Toxicokinetics in Rainbow Trout (Oncorhynchus mykiss) Acclimated to Different Salinities

Abstract. The effects of environmental salinity on the distribution, metabolism, and elimination of benzo [a]pyrene (B[a]P) were examined in mature rainbow trout. Trout acclimated to either fresh water (0 ppt, FW) or sea water (20 ppt, SW) for 3 weeks received a single 10 mg/kg intra-arterial injection of [ 3 H]-benzo[a]pyrene (B[a]P) at their acclimation salinity or when subjected to an acute salinity change. Statistically significant differences in the percent body burden of B[a]P-derived radioactivity in various tissues were seen between fish in FW versus SW. Significant differences in the distribution of B[a]P and its metabolites were also noted when fish were subjected to an acute salinity change after chemical injection. Modulation of B[a]P metabolism by environmental salinity included: (1) significant differences in the proportions of Phase I metabolites in the bile of FW-(2.3%) versus SW-acclimated (14.1%) fish, and (2) alterations in the accumulations of specific metabolites (predominantly t-9, 10-dihydrodiol-B[a]P in FW fish, and 3-hydroxy-B[a]P in SW fish). The percentages of the [ 3 H]-B[a]P dose eliminated by 48 h was similar in FW and SW fish, but decreased in fish subjected to an acute salinity change (FW 98.8% eliminated, FW:SW 90.4%, SW 98.1%, and SW:FW 93.1%). Pharmacokinetic modeling confirmed that acute salinity changes can result in longer terminal half-lives and slower total body clearances of B[a]P

Tiger Sharks Eat Songbirds: Reply

In response to our recent paper (Drymon et al. 2019), Yosef (2019) questions the mechanism proposed to explain interactions between tiger sharks (Galeocerdo cuvier) and migratory songbirds, while offering an alternative mechanism based on a single observation. We appreciate the comments from Yosef and the opportunity to respond

Secreted Amyloid β-Proteins in a Cell Culture Model Include N-Terminally Extended Peptides That Impair Synaptic Plasticity

Evidence for a central role of amyloid β-protein (Aβ) in the genesis of Alzheimer’s disease (AD) has led to advanced human trials of Aβ-lowering agents. The “amyloid hypothesis” of AD postulates deleterious effects of small, soluble forms of Aβ on synaptic form and function. Because selectively targeting synaptotoxic forms of soluble Aβ could be therapeutically advantageous, it is important to understand the full range of soluble Aβ derivatives. We previously described a Chinese hamster ovary (CHO) cell line (7PA2 cells) that stably expresses mutant human amyloid precursor protein (APP). Here, we extend this work by purifying an sodium dodecyl sulfate (SDS)-stable, ∼8 kDa Aβ species from the 7PA2 medium. Mass spectrometry confirmed its identity as a noncovalently bonded Aβ40 homodimer that impaired hippocampal long-term potentiation (LTP) in vivo. We further report the detection of Aβ-containing fragments of APP in the 7PA2 medium that extend N-terminal from Asp1 of Aβ. These N-terminally extended Aβ-containing monomeric fragments are distinct from soluble Aβ oligomers formed from Aβ1-40/42 monomers and are bioactive synaptotoxins secreted by 7PA2 cells. Importantly, decreasing β-secretase processing of APP elevated these alternative synaptotoxic APP fragments. We conclude that certain synaptotoxic Aβ-containing species can arise from APP processing events N-terminal to the classical β-secretase cleavage site

Interventions to enhance effective communication during over-the-counter consultations in the community pharmacy setting : a systematic review

Background Easy access to effective over-the-counter (OTC) treatments allows self-management of some conditions, however inappropriate or incorrect supply or use of OTC medicines can cause harm. Pharmacy personnel should support consumers in their health-seeking behaviour by utilising effective communication skills underpinned by clinical knowledge. Objective To identify interventions targeted towards improving communication between consumers and pharmacy personnel during OTC consultations in the community pharmacy setting. Methods Systematic review and narrative analysis. Databases searched were MEDLINE, EMBASE, Psycinfo, Cochrane Central Register and Cochrane Database of Systematic Reviews for literature published between 2000 and 30 October 2014, as well as reference lists of included articles. The search was re-run on 18 January 2016 and 25 September 2017 to maximise the currency. Two reviewers independently screened retrieved articles for inclusion, assessed study quality and extracted data. Full publications of intervention studies were included. Participants were community pharmacy personnel and/or consumers involved in OTC consultations. Interventions which aimed to improve communication during OTC consultations in the community pharmacy setting were included if they involved a direct measurable communication outcome. Studies reporting attitudes and measures not quantifiable were excluded. The protocol was published on Prospero Database of Systematic Reviews. Results Of 4978 records identified, 11 studies met inclusion criteria. Interventions evaluated were: face-to-face training sessions (n = 10); role-plays (n = 9); a software decision making program (n = 1); and simulated patient (SP) visits followed by immediate feedback (n = 1). Outcomes were measured using: SP methodology (n = 10) and a survey (n = 1), with most (n = 10) reporting a level of improvement in some communication behaviours. Conclusion Empirical evaluation of interventions using active learning techniques such as face-to-face training with role-play can improve some communication skills. However interventions that are not fully described limit the ability for replication and/or generalisability. This review identified interventions targeting pharmacy personnel. Future interventions to improve communication should consider the consumer's role in OTC consultations

Assessing Implicit Odor Localization in Humans Using a Cross-Modal Spatial Cueing Paradigm

Navigation based on chemosensory information is one of the most important skills in the animal kingdom. Studies on odor localization suggest that humans have lost this ability. However, the experimental approaches used so far were limited to explicit judgements, which might ignore a residual ability for directional smelling on an implicit level without conscious appraisal.A novel cueing paradigm was developed in order to determine whether an implicit ability for directional smelling exists. Participants performed a visual two-alternative forced choice task in which the target was preceded either by a side-congruent or a side-incongruent olfactory spatial cue. An explicit odor localization task was implemented in a second experiment.No effect of cue congruency on mean reaction times could be found. However, a time by condition interaction emerged, with significantly slower responses to congruently compared to incongruently cued targets at the beginning of the experiment. This cueing effect gradually disappeared throughout the course of the experiment. In addition, participants performed at chance level in the explicit odor localization task, thus confirming the results of previous research.The implicit cueing task suggests the existence of spatial information processing in the olfactory system. Response slowing after a side-congruent olfactory cue is interpreted as a cross-modal attentional interference effect. In addition, habituation might have led to a gradual disappearance of the cueing effect. It is concluded that under immobile conditions with passive monorhinal stimulation, humans are unable to explicitly determine the location of a pure odorant. Implicitly, however, odor localization seems to exert an influence on human behaviour. To our knowledge, these data are the first to show implicit effects of odor localization on overt human behaviour and thus support the hypothesis of residual directional smelling in humans

TIGIT blockade repolarizes AML-associated TIGIT(+) M2 macrophages to an M1 phenotype and increases CD47-mediated phagocytosis

BACKGROUND: Leukemia-associated macrophages (LAMs) represent an important cell population within the tumor microenvironment, but little is known about the phenotype, function, and plasticity of these cells. The present study provides an extensive characterization of macrophages in patients with acute myeloid leukemia (AML). METHODS: The phenotype and expression of coregulatory markers were assessed on bone marrow (BM)-derived LAM populations, using multiparametric flow cytometry. BM and blood aspirates were obtained from patients with newly diagnosed acute myeloid leukemia (pAML, n=59), patients in long-term remission (lrAML, n=8), patients with relapsed acute myeloid leukemia (rAML, n=7) and monocyte-derived macrophages of the blood from healthy donors (HD, n=17). LAM subpopulations were correlated with clinical parameters. Using a blocking anti-T-cell immunoreceptor with Ig and ITIM domains (TIGIT) antibody or mouse IgG2a isotype control, we investigated polarization, secretion of cytokines, and phagocytosis on LAMs and healthy monocyte-derived macrophages in vitro. RESULTS: In pAML and rAML, M1 LAMs were reduced and the predominant macrophage population consisted of immunosuppressive M2 LAMs defined by expression of CD163, CD204, CD206, and CD86. M2 LAMs in active AML highly expressed inhibitory receptors such as TIGIT, T-cell immunoglobulin and mucin-domain containing-3 protein (TIM-3), and lymphocyte-activation gene 3 (LAG-3). High expression of CD163 was associated with a poor overall survival (OS). In addition, increased frequencies of TIGIT(+) M2 LAMs were associated with an intermediate or adverse risk according to the European Leukemia Network criteria and the FLT3 ITD mutation. In vitro blockade of TIGIT shifted the polarization of primary LAMs or peripheral blood-derived M2 macrophages toward the M1 phenotype and increased secretion of M1-associated cytokines and chemokines. Moreover, the blockade of TIGIT augmented the anti-CD47-mediated phagocytosis of AML cell lines and primary AML cells. CONCLUSION: Our findings suggest that immunosuppressive TIGIT(+) M2 LAMs can be redirected into an efficient effector population that may be of direct clinical relevance in the near future

Run-Off Replication of Host-Adaptability Genes Is Associated with Gene Transfer Agents in the Genome of Mouse-Infecting Bartonella grahamii

The genus Bartonella comprises facultative intracellular bacteria adapted to mammals, including previously recognized and emerging human pathogens. We report the 2,341,328 bp genome sequence of Bartonella grahamii, one of the most prevalent Bartonella species in wild rodents. Comparative genomics revealed that rodent-associated Bartonella species have higher copy numbers of genes for putative host-adaptability factors than the related human-specific pathogens. Many of these gene clusters are located in a highly dynamic region of 461 kb. Using hybridization to a microarray designed for the B. grahamii genome, we observed a massive, putatively phage-derived run-off replication of this region. We also identified a novel gene transfer agent, which packages the bacterial genome, with an over-representation of the amplified DNA, in 14 kb pieces. This is the first observation associating the products of run-off replication with a gene transfer agent. Because of the high concentration of gene clusters for host-adaptation proteins in the amplified region, and since the genes encoding the gene transfer agent and the phage origin are well conserved in Bartonella, we hypothesize that these systems are driven by selection. We propose that the coupling of run-off replication with gene transfer agents promotes diversification and rapid spread of host-adaptability factors, facilitating host shifts in Bartonella