Impact of a computerized intervention for high distress intolerance on cannabis use outcomes: A randomized controlled trial.

OBJECTIVE: Prevalence of regular cannabis use and cannabis use disorder (CUD) have increased in the past two decades, but treatment-seeking is low and extant brief interventions do not target causal risk factors implicated in etiological models of addiction. Elevated distress intolerance (DI) is one risk factor that has been empirically linked with greater CUD severity and maintenance in regular users, but, to our knowledge, research has never targeted it in a brief intervention among cannabis users with CUD or at high risk. The current RCT evaluated the impact of a DI intervention (i.e., Distress Tolerance Intervention [DTI]) compared to a healthy habits control intervention (i.e., Healthy Video Control [HVC]) on DI and cannabis use outcomes. METHOD: We randomized cannabis users with high DI (N = 60) to the DTI or HVC condition and they received two computerized intervention sessions. We assessed relief cannabis craving at pre- and post-treatment; and we assessed DI, cannabis use coping motives, use-related problems, and use frequency at pre- and post-treatment as well as one- and four-month follow-ups. We assessed CUD symptoms via interviews at pre-treatment and four-month follow-up. RESULTS: Significant, durable reductions in DI and all cannabis use outcomes occurred in both conditions. Compared to the HVC condition, the DTI led to greater reductions in use frequency during the treatment period. Reductions in self-reported DI were correlated with reductions in coping motives and CUD symptoms. CONCLUSION: The DTI's impact on all outcomes was largely comparable to the control condition, though it may have utility as an adjunctive intervention.

Development and validation of a cannabis cue stimulus set.

Regular cannabis use and cannabis use disorder (CUD) have become increasingly prevalent in the United States over the past two decades. Theory and empirical data suggest that the incentive salience of cannabis cues is important to the development and chronicity of CUD. Cannabis cue incentive salience is often assessed with a cannabis cue reactivity paradigm wherein cannabis-related and neutral images are presented. However, prior cannabis cue reactivity studies have been limited by the use of heterogeneous stimuli that were not properly characterized across motivational/affective characteristics, physical image attributes, or non-cannabis-related salient image features (e.g., human presence, face visibility). In order to increase standardization and flexibility of future cannabis cue reactivity tasks, the aim of the present study was to develop and validate a cannabis cue and matched neutral image database comprised of motivational/affective ratings as well as physical image attributes. 234 regular cannabis users varying in primary use method (i.e., bowl, blunt/joint, bong, vaporizer) made motivational (i.e., urge to smoke cannabis) and affective (i.e., arousal, valence) ratings of cannabis-related and neutral images matched on salient, non-cannabis-related features. Physical features (hue, saturation, value) of each image were also analyzed. Motivational/affective ratings of cannabis-related and neutral images differed as expected, and cannabis use frequency and cannabis craving correlations with cannabis image ratings generally supported stimulus validity. Motivational/affective ratings did not significantly differ across cannabis use method-specific images. This database may be a useful tool for future behavioral and neuroscience research on cannabis cue reactivity.

Impacts of Varying Dam Outflow Elevations on Water Temperature, Dissolved Oxygen, and Nutrient Distributions in a Large Prairie Reservoir.

Dam operations are known to have significant impacts on reservoir hydrodynamics and solute transport processes. The Gardiner Dam, one of the structures that forms the Lake Diefenbaker reservoir located in the Canadian Prairies, is managed for hydropower generation and agricultural irrigation and is known to have widely altering temperature regimes and nutrient circulations. This study applies the hydrodynamic and nutrient CE-QUAL-W2 model to explore how various withdrawal depths (5, 15, 25, 35, 45, and 55 m) influence the concentrations and distribution of nutrients, temperature, and dissolved oxygen (DO) within the Lake Diefenbaker reservoir. As expected, the highest dissolved nutrient (phosphate, P O 4 3 - - P and nitrate, N O 3 - - N ) concentrations were associated with hypoxic depth horizons in both studied years. During summer high flow period spillway operations impact the distribution of nutrients, water temperatures, and DO as increased epilimnion flow velocities route the incoming water through the surface of the reservoir and reduce mixing and surface warming. This reduces reservoir concentrations but can lead to increased outflow nitrogen (N) and phosphorus (P) concentrations. Lower withdrawal elevations pull warmer surface water deeper within the reservoir and decrease reservoir DO during summer stratification. During fall turnover low outflow elevations increase water column mixing and draws warmer water deeper, leading to slightly higher temperatures and nutrient concentrations than shallow withdrawal elevations. The 15 m depth (540 m above sea level) outflow generally provided the best compromise for overall reservoir and outflow nutrient reduction.

CE-QUAL-W2 model of dam outflow elevation impact on temperature, dissolved oxygen and nutrients in a reservoir.

Dams are typically designed to serve as flood protection, provide water for irrigation, human and animal consumption, and harness hydropower. Despite these benefits, dam operations can have adverse effects on in-reservoir and downstream water temperature regimes, biogeochemical cycling and aquatic ecosystems. We present a water quality dataset of water withdrawal scenarios generated after implementing the 2D hydrodynamic and water quality model, CE-QUAL-W2. The scenarios explore how six water extraction scenarios, starting at 5 m above the reservoir bottom at the dam and increasing upward at 10 m intervals to 55 m, influence water quality in Lake Diefenbaker reservoir, Saskatchewan, Canada. The model simulates daily water temperature, dissolved oxygen, total phosphorus, phosphate as phosphorus, labile phosphorus, total nitrogen, nitrate as nitrogen, labile nitrogen, and ammonium at 87 horizontal segments and at 60 water depths during the 2011-2013 period. This dataset intends to facilitate a broader investigation of in-reservoir nutrient dynamics under dam operations, and to extend the understanding of reservoir nutrient dynamics globally.

Vanadium and thallium exhibit biodilution in a northern river food web.

Trophic transfer of contaminants dictates concentrations and potential toxic effects in top predators, yet biomagnification behaviour of many trace elements is poorly understood. We examined concentrations of vanadium and thallium, two globally-distributed and anthropogenically-enriched elements, in a food web of the Slave River, Northwest Territories, Canada. We found that tissue concentrations of both elements declined with increasing trophic position as measured by δ15N. Slopes of log [element] versus δ15N regressions were both negative, with a steeper slope for V (-0.369) compared with Tl (-0.099). These slopes correspond to declines of 94% with each step in the food chain for V and 54% with each step in the food chain for Tl. This biodilution behaviour for both elements meant that concentrations in fish were well below values considered to be of concern for the health of fish-eating consumers. Further study of these elements in food webs is needed to allow a fuller understanding of biomagnification patterns across a range of species and systems.

Colony Stimulating Factor-1 Receptor Expressing Cells Infiltrating the Cornea Control Corneal Nerve Degeneration in Response to HSV-1 Infection.

Purpose: Herpes simplex virus type-1 (HSV-1) is a leading cause of neurotrophic keratitis, characterized by decreased or absent corneal sensation due to damage to the sensory corneal innervation. We previously reported the elicited immune response to infection contributes to the mechanism of corneal nerve regression/damage during acute HSV-1 infection. Our aim is to further establish the involvement of infiltrated macrophages in the mechanism of nerve loss upon infection. Methods: Macrophage Fas-Induced Apoptosis (MAFIA) transgenic C57BL/6 mice were systemically treated with AP20187 dimerizer or vehicle (VEH), and their corneas, lymph nodes, and blood were assessed for CD45+CD11b+GFP+ cell depletion by flow cytometry (FC). Mice were ocularly infected with HSV-1 or left uninfected. At 2, 4, and/or 6 days post infection (PI), corneas were assessed for sensitivity and harvested for FC, nerve structure by immunohistochemistry, viral content by plaque assay, soluble factor content by suspension array, and activation of signaling pathways by Western blot analysis. C57BL6 mice were used to compare to the MAFIA mouse model. Results: MAFIA mice treated with AP20187 had efficient depletion of CD45+CD11b+GFP+ cells in the tissues analyzed. The reduction of CD45+CD11b+GFP+ cells recruited to the infected corneas of AP20187-treated mice correlated with preservation of corneal nerve structure and function, decreased protein concentration of inflammatory cytokines, and decreased STAT3 activation despite no changes in viral content in the cornea compared to VEH-treated animals. Conclusions: Our results suggest infiltrated macrophages are early effectors in the nerve regression following HSV-1 infection. We propose the neurodegeneration mechanism involves macrophages, local up-regulation of IL-6, and activation of STAT3.

The Neonatal Fc Receptor and Complement Fixation Facilitate Prophylactic Vaccine-Mediated Humoral Protection against Viral Infection in the Ocular Mucosa.

The capacity of licensed vaccines to protect the ocular surface against infection is limited. Common ocular pathogens, such as HSV-1, are increasingly recognized as major contributors to visual morbidity worldwide. Humoral immunity is an essential correlate of protection against HSV-1 pathogenesis and ocular pathology, yet the ability of Ab to protect against HSV-1 is deemed limited due to the slow IgG diffusion rate in the healthy cornea. We show that a live-attenuated HSV-1 vaccine elicits humoral immune responses that are unparalleled by a glycoprotein subunit vaccine vis-à-vis Ab persistence and host protection. The live-attenuated vaccine was used to assess the impact of the immunization route on vaccine efficacy. The hierarchical rankings of primary immunization route with respect to efficacy were s.c. ≥ mucosal > i.m. Prime-boost vaccination via sequential s.c. and i.m. administration yielded greater efficacy than any other primary immunization route alone. Moreover, our data support a role for complement in prophylactic protection, as evidenced by intracellular deposition of C3d in the corneal epithelium of vaccinated animals following challenge and delayed viral clearance in C3-deficient mice. We also identify that the neonatal Fc receptor (FcRn) is upregulated in the cornea following infection or injury concomitant with increased Ab perfusion. Lastly, selective small interfering RNA-mediated knockdown of FcRn in the cornea impeded protection against ocular HSV-1 challenge in vaccinated mice. Collectively, these findings establish a novel mechanism of humoral protection in the eye involving FcRn and may facilitate vaccine and therapeutic development for other ocular surface diseases.

Open-water and under-ice seasonal variations in trace element content and physicochemical associations in fluvial bed sediment.

Across the circumpolar world, intensive anthropogenic activities in the southern reaches of many large, northward-flowing rivers can cause sediment contamination in the downstream depositional environment. The influence of ice cover on concentrations of inorganic contaminants in bed sediment (i.e., sediment quality) is unknown in these rivers, where winter is the dominant season. A geomorphic response unit approach was used to select hydraulically diverse sampling sites across a northern test-case system, the Slave River and delta (Northwest Territories, Canada). Surface sediment samples (top 1 cm) were collected from 6 predefined geomorphic response units (12 sites) to assess the relationships between bed sediment physicochemistry (particle size distribution and total organic carbon content) and trace element content (mercury and 18 other trace elements) during open-water conditions. A subset of sites was resampled under-ice to assess the influence of season on these relationships and on total trace element content. Concentrations of the majority of trace elements were strongly correlated with percent fines and proxies for grain size (aluminum and iron), with similar trace element grain size/grain size proxy relationships between seasons. However, finer materials were deposited under ice with associated increases in sediment total organic carbon content and the concentrations of most trace elements investigated. The geomorphic response unit approach was effective at identifying diverse hydrological environments for sampling prior to field operations. Our data demonstrate the need for under-ice sampling to confirm year-round consistency in trace element-geochemical relationships in fluvial systems and to define the upper extremes of these relationships. Whether contaminated or not, under-ice bed sediment can represent a "worst-case" scenario in terms of trace element concentrations and exposure for sediment-associated organisms in northern fluvial systems. Environ Toxicol Chem 2017;36:2916-2924. © 2017 SETAC.

Stable sulfur isotopes identify habitat-specific foraging and mercury exposure in a highly mobile fish community.

Tracking the uptake and transfer of toxic chemicals, such as mercury (Hg), in aquatic systems is challenging when many top predators are highly mobile and may therefore be exposed to chemicals in areas other than their location of capture, confounding interpretation of bioaccumulation trends. Here we show how the application of a less commonly used ecological tracer, stable sulfur isotope ratios (34S/32S, or δ34S), in a large river-delta-lake complex in northern Canada allows differentiation of resident from migrant fishes, beyond what was possible with more conventional 13C/12C and 15N/14N measurements. Though all large fishes (n=105) were captured in the river, the majority (76%) had δ34S values that were indicative of the fish having been reared in the lake. These migrant fishes were connected to a food chain with greater Hg trophic magnification relative to the resident fish of the river and delta. Yet, despite a shallower overall trophic magnification slope, large river-resident fish had higher Hg concentrations owing to a greater biomagnification of Hg between small and large fishes. These findings reveal how S isotopes can trace fish feeding habitats in large freshwater systems and better account for fish movement in complex landscapes with differential exposure pathways and conditions.

Impact of Type I Interferon on the Safety and Immunogenicity of an Experimental Live-Attenuated Herpes Simplex Virus 1 Vaccine in Mice.

Viral fitness dictates virulence and capacity to evade host immune defenses. Understanding the biological underpinnings of such features is essential for rational vaccine development. We have previously shown that the live-attenuated herpes simplex virus 1 (HSV-1) mutant lacking the nuclear localization signal (NLS) on the ICP0 gene (0ΔNLS) is sensitive to inhibition by interferon beta (IFN-ß) in vitro and functions as a highly efficacious experimental vaccine. Here, we characterize the host immune response and in vivo pathogenesis of HSV-1 0ΔNLS relative to its fully virulent parental strain in C57BL/6 mice. Additionally, we explore the role of type 1 interferon (IFN-α/ß) signaling on virulence and immunogenicity of HSV-1 0ΔNLS and uncover a probable sex bias in the induction of IFN-α/ß in the cornea during HSV-1 infection. Our data show that HSV-1 0ΔNLS lacks neurovirulence even in highly immunocompromised mice lacking the IFN-α/ß receptor. These studies support the translational viability of the HSV-1 0ΔNLS vaccine strain by demonstrating that, while it is comparable to a virulent parental strain in terms of immunogenicity, HSV-1 0ΔNLS does not induce significant tissue pathology.IMPORTANCE HSV-1 is a common human pathogen associated with a variety of clinical presentations ranging in severity from periodic "cold sores" to lethal encephalitis. Despite the consistent failures of HSV subunit vaccines in clinical trials spanning the past 28 years, opposition to live-attenuated HSV vaccines predicated on unfounded safety concerns currently limits their widespread acceptance. Here, we demonstrate that a live-attenuated HSV-1 vaccine has great translational potential.

Long-term consequences of topical dexamethasone treatment during acute corneal HSV-1 infection on the immune system.

Herpes simplex virus type 1 (HSV-1) is a leading cause of neurotrophic keratitis (NTK). NTK is characterized by decreased corneal sensation from damage to the corneal sensory fibers. We have reported on the regression of corneal nerves and their function during acute HSV-1 infection. That nerve loss is followed by an aberrant process of nerve regeneration during the latent phase of infection that lacks functional recovery. We recently showed the elicited immune response in the infected cornea, and not viral replication itself, is part of the mechanism responsible for the nerve degeneration process after infection. Specifically, we showed infected corneas topically treated with dexamethasone (DEX) significantly retained both structure and sensitivity of the corneal nerve network in comparison to mice treated with control eye drops, consistent with decreased levels of proinflammatory cytokines and reduced influx of macrophages and CD8+ T cells into the cornea. This study was undertaken to analyze the long-term effect of such a localized, immunosuppressive paradigm (DEX drops on the cornea surface during the first 8 d of HSV-1 infection) on the immune system and on corneal pathology. We found the profound immunosuppressive effect of DEX on lymphoid tissue was sustained in surviving mice for up to 30 d postinfection (p.i.). DEX treatment had prolonged effects, preserving corneal innervation and its function and blunting neovascularization, as analyzed at 30 d p.i. Our data support previously reported observations of an association between the persistent presence of inflammatory components in the latently infected cornea and structural and functional nerve defects in NTK.

Cornea lymphatics drive the CD8+ T-cell response to herpes simplex virus-1.

Herpes simplex virus-1 (HSV-1) infection of the cornea induces vascular endothelial growth factor A (VEGF-A)-dependent lymphangiogenesis. However, the extent to which HSV-1-induced corneal lymphangiogenesis impacts the adaptive immune response has not been characterized. Here, we used floxed VEGF-A mice to study the importance of newly created corneal lymphatic vessels in the host adaptive immune response to infection. Whereas the mice infected with the parental virus (strain SC16) exhibited robust corneal lymphangiogenesis, mice that received the recombinant virus (SC16 ICP0-Cre) that expresses Cre recombinase under the control of infected cell protein 0 (ICP0), an HSV-1 immediate-early gene, showed a significant reduction in lymphangiogenesis. There was no difference in virus recovered from the cornea of mice infected with SC16 vs SC16 ICP0-Cre. However, viral loads were significantly elevated in the trigeminal ganglia (TG) of mice with reduced corneal lymphangiogenesis. The increase in viral titer correlated with a significant loss of HSV-1-specific CD8+ T cells that traffic to the TG of mice infected with the recombinant virus. Intrastromal delivery of size-exclusion dye (fluorescein isothiocyanate-dextran) revealed a time-dependent defect in the ability of the lymphatic vessels in SC16 ICP0-Cre-infected mice to transport soluble antigen from the cornea to the draining lymph nodes. We interpret these results to suggest that the newly created lymphatic vessels in the cornea driven by HSV-1 infection are critical in the delivery of soluble viral antigen to the draining lymph node and subsequent development of the CD8+ T-cell response to HSV-1.

IL-6 Contributes to Corneal Nerve Degeneration after Herpes Simplex Virus Type I Infection.

Herpes simplex virus type 1 (HSV-1) is a leading cause of neurotrophic keratitis characterized by decreased corneal sensation because of damage to the corneal sensory fibers. We and others have reported regression of corneal nerves during acute HSV-1 infection. To determine whether denervation is caused directly by the virus or indirectly by the elicited immune response, mice were infected with HSV-1 and topically treated with dexamethasone (DEX) or control eye drops. Corneal sensitivity was measured using a Cochet-Bonnet esthesiometer and nerve network structure via immunohistochemistry. Corneas were assessed for viral content by plaque assay, leukocyte influx by flow cytometry, and content of chemokines and inflammatory cytokines by suspension array. DEX significantly preserved corneal nerve structure and sensitivity on infection. DEX reduced myeloid and T-cell populations in the cornea and did not affect viral contents at 4 and 8 days post infection. The elevated protein contents of chemokines and inflammatory cytokines on infection were greatly suppressed by DEX. Subconjunctival delivery of neutralizing antibody against IL-6 to infected mice resulted in partial preservation of corneal nerve structure and sensitivity. Our study supports a role for the immune response, but not local virus replication in the development of HSV-1-induced neurotrophic keratitis. IL-6 is one of the factors produced by the elicited inflammatory response to HSV-1 infection contributing to nerve regression.

A comparison of human chorionic gonadotropin and luteinizing hormone releasing hormone on the induction of spermiation and amplexus in the American toad (Anaxyrus americanus).

BACKGROUND: Captive breeding programs for endangered amphibian species often utilize exogenous hormones for species that are difficult to breed. The purpose of our study was to compare the efficacy of two different hormones at various concentrations on sperm production, quantity and quality over time in order to optimize assisted breeding. METHODS: Male American toads (Anaxyrus americanus) were divided into three separate treatment groups, with animals in each group rotated through different concentrations of luteinizing hormone releasing hormone analog (LHRH; 0.1, 1.0, 4.0 and 32 micrograms/toad), human chorionic gonadotropin (hCG; 50, 100, 200, and 300 IU), or the control over 24 hours. We evaluated the number of males that respond by producing spermic urine, the sperm concentration, percent motility, and quality of forward progression. We also evaluated the effects of hCG and LHRH on reproductive behavior as assessed by amplexus. Data were analyzed using the Generalized Estimating Equations incorporating repeated measures over time and including the main effects of treatment and time, and the treatment by time interaction. RESULTS: The hormone hCG was significantly more effective at stimulating spermiation in male Anaxyrus americanus than LHRH and showed a dose-dependent response in the number of animals producing sperm. At the most effective hCG dose (300 IU), 100% of the male toads produced sperm, compared to only 35% for the best LHRH dose tested (4.0 micrograms). In addition to having a greater number of responders (P < 0.05), the 300 IU hCG treatment group had a much higher average sperm concentration (P < 0.05) than the treatment group receiving 4.0 micrograms LHRH. In contrast, these two treatments did not result in significant differences in sperm motility or quality of forward progressive motility. However, more males went into amplexus when treated with LHRH vs. hCG (90% vs. 75%) by nine hours post-administration. CONCLUSION: There is a clear dichotomy between the two hormones' physiological responses on gamete production and stimulation of amplexus. Understanding how these two hormones influence physiology and reproductive behaviors in amphibians will have direct bearing on establishing similar breeding protocols for endangered species.

Seasonal shifts in giant panda feeding behavior: relationships to bamboo plant part consumption.

The giant panda (Ailuropoda melanoleuca) is classified as a carnivore, yet subsists on a diet comprised almost exclusively of bamboo. Wild and captive giant pandas use highly selective foraging behaviors for processing and consuming bamboo. These behaviors are for the first time quantified in captive giant pandas over a 5-year period of time showing highly specific seasonal trends. Giant panda feeding behavior was recorded using live video observations of two giant pandas housed at the Memphis Zoo from November 2003 to June 2008. Leaf was the primary plant part consumed from June to December, whereas culm was consumed primarily from February to May, with both bears displaying similar seasonal shifts in plant part consumption. From May to June, leaf consumption increased significantly (P-values<0.001); from June to August, leaf consumption remained high and stable. From December to March, leaf consumption decreased significantly (P-values<0.001). Specific behaviors for bamboo leaf and culm consumption were also observed. Both bears formed wads of leaves before ingestion while feeding on leaf, but the male employed this feeding behavior more often than the female (54 and 33%, respectively). Both bears used similar culm-stripping behavior (26 and 25%), used to remove the outer layer and isolate the pith for consumption. This study indicates that unique seasonal foraging behaviors observed in wild pandas are also apparent in captive animals in relation to plant part selectivity and feeding behaviors.