Associations between hair trace mineral concentrations and the occurrence of treponeme-associated hoof disease in elk (Cervus canadensis).

BACKGROUND: Trace minerals are important for animal health. Mineral deficiency or excess can negatively affect immune function, wound healing, and hoof health in domestic livestock, but normal concentrations and health impairment associated with mineral imbalances in wild animals are poorly understood. Treponeme-associated hoof disease (TAHD) is an emerging disease of free-ranging elk (Cervus canadensis) in the U.S. Pacific Northwest. Selenium and copper levels identified in a small number of elk from areas where TAHD is established (i.e., southwestern Washington) suggested a mineral deficiency may have increased susceptibility to TAHD. Our objectives were to determine trace mineral concentrations using hair from elk originating in TAHD affected areas of Washington, California, Idaho, and Oregon and assess their associations with the occurrence of the disease. RESULTS: We identified limited associations between TAHD occurrence and severity with hair mineral concentrations in 72 free-ranging elk, using Firth's logistic regression and multinomial regression models. We found consistent support for a priori hypotheses that selenium concentration, an important mineral for hoof health, is inversely associated with the occurrence of TAHD. Less consistent support was observed for effects of other minerals previously associated with hoof health (e.g., copper or zinc) or increased disease risk from potential toxicants. CONCLUSION: Trace mineral analysis of hair is a non-invasive sampling technique that offers feasibility in storage and collection from live animals and carcasses. For some minerals, levels in hair correlate with visceral organs that are challenging to obtain. Our study using hair collected opportunistically from elk feet submitted for diagnostic investigations provides a modest reference of hair mineral levels in elk from the U.S. Pacific Northwest that may be useful in future determination of reference ranges. Although our results revealed high variability in mineral concentrations between elk, consistent relationship of possibly low selenium levels and TAHD suggest that further investigations are warranted.

SURVEILLANCE FOR AN EMERGENT HOOF DISEASE IN ELK (CERVUS ELAPHUS) IN THE US PACIFIC WEST SUPPLEMENTED BY 16S RRNA GENE AMPLICON SEQUENCING.

A novel hoof disease of elk (Cervus elaphus) was described in southwestern Washington, US, in 2008 and was subsequently diagnosed in an adjacent area in northwestern Oregon in 2014. The disease, currently referred to as treponeme-associated hoof disease (TAHD), is characterized by lesions ranging from mild erosions, to severe ulcers with underrunning of the hoof capsule and heel-sole junction, to overgrown and avulsed hoof capsules. Histologically, lesions exhibit epithelial erosion or ulceration, suppurative inflammation, and the presence of argyrophilic spirochetes. We used data collected by the Washington Department of Fish and Wildlife and Oregon Department of Fish and Wildlife from 2008 to 2017 as reference for disease distribution. We then conducted enhanced surveillance in 2018-20 by obtaining 164 submissions from four US Pacific West states. We detected TAHD for the first time in Idaho and northern California, as well as in multiple counties in Washington and Oregon where it had not been previously reported. Given the unexpectedly broad disease distribution, continued surveillance is warranted to determine the full geographic extent of TAHD. From samples of 22 elk, we investigated 16S rRNA gene amplicon sequencing as a technique that could be used to supplement TAHD surveillance. Operational taxonomic units of the family Spirochaetaceae were identified in 10 of 12 histologically diagnosed TAHD-positive cases and two of 10 TAHD-negative cases. Phyla Spirochaetae (P<0.008), Fusobacteria (P<0.006), and Tenericutes (P<0.01) were overrepresented in samples from TAHD-positive feet when compared with TAHD-negative elk. A unique spirochete, PT19, was detected in hooves of 11 elk and from at least one elk in each state. Results support the use of 16S rRNA gene amplicon sequencing as a reliable and informative tool to supplement investigations into distribution and etiology of this presumed polybacterial disease.

A Landscape Epidemiological Approach for Predicting Chronic Wasting Disease: A Case Study in Virginia, US.

Many infectious diseases in wildlife occur under quantifiable landscape ecological patterns useful in facilitating epidemiological surveillance and management, though little is known about prion diseases. Chronic wasting disease (CWD), a fatal prion disease of the deer family Cervidae, currently affects white-tailed deer (Odocoileus virginianus) populations in the Mid-Atlantic United States (US) and challenges wildlife veterinarians and disease ecologists from its unclear mechanisms and associations within landscapes, particularly in early phases of an outbreak when CWD detections are sparse. We aimed to provide guidance for wildlife disease management by identifying the extent to which CWD-positive cases can be reliably predicted from landscape conditions. Using the CWD outbreak in Virginia, US from 2009 to early 2020 as a case study system, we used diverse algorithms (e.g., principal components analysis, support vector machines, kernel density estimation) and data partitioning methods to quantify remotely sensed landscape conditions associated with CWD cases. We used various model evaluation tools (e.g., AUC ratios, cumulative binomial testing, Jaccard similarity) to assess predictions of disease transmission risk using independent CWD data. We further examined model variation in the context of uncertainty. We provided significant support that vegetation phenology data representing landscape conditions can predict and map CWD transmission risk. Model predictions improved when incorporating inferred home ranges instead of raw hunter-reported coordinates. Different data availability scenarios identified variation among models. By showing that CWD could be predicted and mapped, our project adds to the available tools for understanding the landscape ecology of CWD transmission risk in free-ranging populations and natural conditions. Our modeling framework and use of widely available landscape data foster replicability for other wildlife diseases and study areas.

CHRONIC WASTING DISEASE MODELING: AN OVERVIEW.

Chronic wasting disease (CWD) is an infectious and fatal prion disease occurring in the family Cervidae. To update the research community regarding the status quo of CWD epidemic models, we conducted a meta-analysis on CWD research. We collected data from peer-reviewed articles published since 1980, when CWD was first diagnosed, until December 2018. We explored the analytical methods used historically to understand CWD. We used 14 standardized variables to assess overall analytical approaches of CWD research communities, data used, and the modeling methods used. We found that CWD modeling initiated in the early 2000s and has increased since then. Connectivity of the research community was heavily reliant on a cluster of CWD researchers. Studies focused primarily on regression and compartment-based models, population-level approaches, and host species of game management concern. Similarly, CWD research focused on single populations, species, and locations, neglecting modeling using community ecology and biogeographic approaches. Chronic wasting disease detection relied on classic diagnostic methods with limited sensitivity for most stages of infection. Overall, we found that past modeling efforts generated a solid baseline for understanding CWD in wildlife and increased our knowledge on infectious prion ecology. Future analytical efforts should consider more sensitive diagnostic methods to quantify uncertainty and broader scale studies to elucidate CWD transmission beyond population-level approaches. Considering that infectious prions may not follow biological rules of well-known wildlife pathogens (i.e., viruses, bacteria, fungi), assumptions used when modeling other infectious disease may not apply for CWD. Chronic wasting disease is a new challenge in wildlife epidemiology.

The ecology of chronic wasting disease in wildlife.

Prions are misfolded infectious proteins responsible for a group of fatal neurodegenerative diseases termed transmissible spongiform encephalopathy or prion diseases. Chronic Wasting Disease (CWD) is the prion disease with the highest spillover potential, affecting at least seven Cervidae (deer) species. The zoonotic potential of CWD is inconclusive and cannot be ruled out. A risk of infection for other domestic and wildlife species is also plausible. Here, we review the current status of the knowledge with respect to CWD ecology in wildlife. Our current understanding of the geographic distribution of CWD lacks spatial and temporal detail, does not consider the biogeography of infectious diseases, and is largely biased by sampling based on hunters' cooperation and funding available for each region. Limitations of the methods used for data collection suggest that the extent and prevalence of CWD in wildlife is underestimated. If the zoonotic potential of CWD is confirmed in the short term, as suggested by recent results obtained in experimental animal models, there will be limited accurate epidemiological data to inform public health. Research gaps in CWD prion ecology include the need to identify specific biological characteristics of potential CWD reservoir species that better explain susceptibility to spillover, landscape and climate configurations that are suitable for CWD transmission, and the magnitude of sampling bias in our current understanding of CWD distribution and risk. Addressing these research gaps will help anticipate novel areas and species where CWD spillover is expected, which will inform control strategies. From an ecological perspective, control strategies could include assessing restoration of natural predators of CWD reservoirs, ultrasensitive CWD detection in biotic and abiotic reservoirs, and deer density and landscape modification to reduce CWD spread and prevalence.

Effects of Load on Peak Power Output Fatigue During the Bench Throw.

Boffey, D, Sokmen, B, Sollanek, K, Boda, W, and Winter, S. Effects of load on peak power output fatigue during the bench throw. J Strength Cond Res 33(2): 355-359, 2019-The ability to create power is an important variable for athletic success. No study to date has compared peak power output (PPO) fatigue across multiple sets and with different loads with the bench throw. This study aimed to begin the process of establishing empirical upper-body power training guidelines for moderately strong athletes by determining how load (30, 45, and 60% 1 repetition maximum [1RM]) affects PPO (Watts) dropoff during 3 sets of 10 repetitions of the bench throw. Ten resistance-trained male volunteers ([mean ± SD]: age 20.58 ± 1.36 years, height 176.05 ± 9.09 cm, body mass 78.65 ± 9.93 kg, bench press 1RM 99.79 ± 18.52 kg) performed 3 sets of 10 repetitions of the bench throw with one of the 3 loads during 3 weekly sessions. A Humac 360 device collected concentric phase PPO data during each repetition. The data were analyzed using one-way (treatment) and 2-way (treatment × time) repeated-measures analysis of variance. A significant decrease in PPO was observed during repetitions 5-7 at 30%, 3-4 at 45%, and 2-3 at 60% 1RM. Based on the results of this study, coaches who want to maximize power should potentially keep sets of upper-body plyometrics within these repetition ranges. The authors recommend that moderately strong athletes perform the bench throw on a Smith machine at 45% or 60% 1RM to produce high PPO over multiple sets.

Effects of CP-532,623 and torcetrapib, cholesteryl ester transfer protein inhibitors, on arterial blood pressure.

ILLUMINATE, the phase 3 morbidity and mortality trial of the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib, plus atorvastatin terminated in 2006. The underlying morbidity and mortality cause remains undetermined. In addition to lipoprotein changes, off-target increases in blood pressure (BP), sodium, bicarbonate, and aldosterone and potassium decreases were described. We report nonclinical and clinical studies using torcetrapib and a closely related CETP inhibitor, CP-532,623, to further characterize this pharmacology. Pressor effects of torcetrapib and CP-532,623 were observed in monkeys and human subjects. CETP inhibition and high-density lipoprotein cholesterol elevation were demonstrated. In humans, high- versus low-dose CP-532,623 produced significantly greater pressor effects despite similar maximal CETP inhibition. Inhibition of CETP was seen 48 hours post dose, whereas BP elevation dissipated by 24 hours, temporally dissociating CETP inhibition from BP changes. These data, and structural similarities between the compounds, support the conclusion that the BP effects are related to chemotype. We also observed an acute aldosterone increase without changes in renin in monkeys. Continuous BP measurements showed persistent elevations, whereas aldosterone changes were transient, suggesting that increases in BP were not directly the result of renin-angiotensin-aldosterone system activation and may, in part, be due to direct effects on blood vessels or other nongenomic effects.

Discovery and pharmacologic characterization of CP-724,714, a selective ErbB2 tyrosine kinase inhibitor.

Amplification and overexpression of erbB2 (Her-2/neu) proto-oncogene has been linked to human malignancies including tumors of the breast, ovary, and stomach. It has been implicated in tumor growth, sensitivity to standard chemotherapy, prognosis of patients, and disease-free survival. Although the clinical use of trastuzumab (Herceptin) has prolonged the survival of breast cancer patients with erbB2-overexpressing tumors, there is an urgent need for more potent and orally bioavailable small-molecule inhibitors. CP-724,714 is a potent inhibitor of erbB2 receptor autophosphorylation in intact cells and is currently undergoing phase I clinical trials. Here, we describe the effects of CP-724,714 in vitro and in vivo in human breast cancer models. CP-724,714 is selective for inhibiting growth of HER2-driven cell lines. In addition, we show that it induces G1 cell cycle block in erbB2-overexpressing BT-474 human breast carcinoma cells and inhibits erbB2 autophosphorylation in xenografts when administered p.o. to athymic mice. It induces a marked reduction of extracellular signal-regulated kinase and Akt phosphorylation, tumor cell apoptosis, and release of caspase-3. P.o. administration (q.d. or b.i.d.) of CP-724,714 inhibits the growth of erbB2-overexpressing tumors in athymic mice without overt adverse effects.

The role of absorption, distribution, metabolism, excretion and toxicity in drug discovery.

Major reasons preventing many early candidates reaching market are the inappropriate ADME (absorption, distribution, metabolism and excretion) properties and drug-induced toxicity. From a commercial perspective, it is desirable that poorly behaved compounds are removed early in the discovery phase rather than during the more costly drug development phases. As a consequence, over the past decade, ADME and toxicity (ADMET) screening studies have been incorporated earlier in the drug discovery phase. The intent of this review is to introduce the desirable attributes of a new chemical entity (NCE) to the medicinal chemist from an ADMET perspective. Fundamental concepts, key tools, reagents and experimental approaches used by the drug metabolism scientist to aid a modern project team in predicting human pharmacokinetics and assessing the "drug-like" molecule are discussed.