Response of diademed sifaka (Propithecus diadema) to fosa (Cryptoprocta ferox) predation in the Betampona Strict Nature Reserve, Madagascar.

Large-bodied mammals living in fragmented habitats are at higher risk of extinction, and such risk can be influenced by ecological factors such as predator-prey system dynamics. These dynamics can be particularly complex for conservation management when one endangered species preys on another endangered species in an isolated or poor-quality habitat. Here we describe predation events observed over 19 months that involved two threatened species: the largest carnivore in Madagascar, the fosa (Cryptoprocta ferox), and three groups of diademed sifaka (Propithecus diadema) in the Betampona Strict Nature Reserve. This site is a 22 km2 low-altitude rainforest that is surrounded by agricultural land and isolated from larger forest corridors. We aim to (1) assess the behavioral changes of P. diadema in response to fosa attacks and identify any antipredator strategies that they adopted, and (2) quantify the frequency of fosa attacks and the predation impact on the sifaka population. We report five direct observations of fosa predation attempts (one successful), the discovery of a dead sifaka with evidence of fosa predation, and the disappearance of three individuals. We describe the observed attacks and compare the sifaka activity budgets and movement patterns before and after the events. To escape the predator, sifakas fled short distances, hid, and remained vigilant. The impact of predation, combined with low reproductive rates and potentially high inbreeding of this isolated diademed sifaka population, could affect the survival of this species in Betampona. Given the compounding effects of habitat isolation and high hunting pressure, community-specific conservation strategies should incorporate predator-prey dynamics via longitudinal monitoring of predator and prey population densities and quantifying the predation pressure between them.

Repeat patient testing-quality control compared to commercial quality control material for the Sysmex XT-2000iV hematology analyzer in a multi-site veterinary laboratory.

BACKGROUND: Quality control material (QCM) for hematology in veterinary laboratories is limited, and repeat patient testing quality control (RPT-QC) is an alternative method using excess matrix-specific samples. OBJECTIVES: This study aimed to determine if median differences between RPT-QC analyses for each time interval for RBC, HGB, HCT, and WBC were the same, determine if unified RPT-QC limits can be applied to a network of veterinary laboratories, compare the performance of RPT-QC to commercial QCM for the reference analyzer and evaluate the experience over a 4 month period and design, improve and implement an automated spreadsheet for RPT-QC data management. METHODS: The potential to unify individual analyzer RPT-QC limits for red blood cells (RBC), hematocrit (HCT), hemoglobin (HGB), and white blood cells (WBC) on multi-site Sysmex XT-2000-iV analyzers was explored by a difference of means test and confidence interval determination for the median difference for each network analyzer in comparison to the network reference analyzer. User experience of an automated RPT-QC data management Excel spreadsheet was collected by user feedback during monthly meetings. Numbers of out-of-control results and the root causes for these for RPT-QC were compared against those of a commercial QCM over a 4-month period. RESULTS: Differences between individual analyzer RPT-QC limits were too large to allow for unification of network limits. The automated spreadsheet successfully highlighted out-of-control events for RPT-QC. Trends or shifts were more frequent for commercial QCM based on observed performance and a 1-2.5 s QC rule than for RPT-QC. Following routine troubleshooting, RPT-QC out-of-control events were resolved with an alternative RPT-QC sample indicating random error associated with excessive deterioration. Use of an automated spreadsheet for recording RPT-QC, documentation and troubleshooting of out-of-control events, and collating monthly summary calculations were considered an asset in laboratory quality management. CONCLUSIONS: RPT-QC can be successfully implemented and integrated into a multi-site veterinary laboratory. Individual analyzer RPT-QC limit generation is recommended. The deterioration of commercial QCM caused shifts or trends in QC results, which initiated more repeat analyses and investigations than did RPT-QC.

Choice between food and cocaine or fentanyl reinforcers under fixed and variable schedules in female and male rhesus monkeys.

RATIONALE: Illicit drugs may be unpredictable in terms of the time and effort required to obtain them, and this can be modeled with variable- (VR) vs. fixed-ratio (FR) schedules. In a recent experiment (Zamarripa et al. 2023), the potency of cocaine to maintain choice was greatest under a VR (compared with a FR) when food was available under a FR schedule. OBJECTIVES: The goal of the current study was to extend prior choice results with VR vs. FR schedules to a more efficient procedure with cocaine or fentanyl vs. food. Furthermore, the FR schedule of food delivery was manipulated to determine whether increased drug choice under a VR (compared with a FR) schedule depends on the size of the schedule of nondrug reinforcement. METHODS: Adult female (n = 2) and male (n = 4) monkeys chose between cocaine (0-30 µg/kg/injection) or fentanyl (0-1.0 µg/kg/injection) and food (2 pellets/delivery) under a 5-component procedure. In different conditions, food was available under a FR 25, 50, or 100 and cocaine or fentanyl were available under FR or VR 100 schedules. RESULTS: Cocaine's potency to maintain choice was greatest under a VR 100 (compared with FR 100) when food was available under a FR 50 or 100, and fentanyl's potency to maintain choice was generally greatest under a VR 100 (compared with FR 100) when food was available under a FR 25 or 100. However, outcomes between FR and VR schedules with fentanyl were less robust compared with cocaine. CONCLUSION: Variability in the time and effort required to obtain illicit drugs could contribute to excessive allocation of behavior toward drug use at the expense of more predictable nondrug alternatives, supporting treatment or policies aimed at making drug access more predictable through agonist medications or a safe supply. The impact of variable requirements on drug choice may be reduced if nondrug reinforcers are relatively less costly, supporting the use of low-cost reinforcers in behavioral therapies like contingency management.

Analytical performance evaluation of two automated urine chemistry analysers using two levels of commercially available quality control material.

OBJECTIVE: Evaluate two point-of-care urine chemistry analysers, VetScan SA and VetLab UA using assayed, bilevel (two concentrations) urine quality control material to determine if performance is acceptable for semiquantitative clinical urine chemistry analysis. MATERIALS AND METHODS: Normal and abnormal urine quality control material sent to 23 veterinary practices was evaluated three times by each clinic on in-clinic automated urinalysis instruments. Accuracy, precision and clinical utility were evaluated. RESULTS: Normal urine quality control material: Results for blood, glucose, ketones and bilirubin were 100% accurate and precise for both analysers, and pH values were accurately acidic to neutral. However, pH from VetScan SA had clinically significant negative bias. Abnormal urine quality control material: VetScan SA: blood, microalbumin and bilirubin were 100% accurate; glucose, ketones, and protein demonstrated ≤10% inaccuracy; pH demonstrated 34% inaccuracy. VetLab UA: blood, ketones and bilirubin were 100% accurate; glucose and protein demonstrated ≤10% inaccuracy; pH was 100% accurately neutral to alkaline. CLINICAL SIGNIFICANCE: VetScan SA had marked negative pH bias versus VetLab UA resulting in clinically significant, overly acidic results. Specific gravity, nitrite, and leukocyte test pads should not be used. Both instruments had excellent performance in normal quality control material. While blood, glucose, protein and bilirubin are correctly identified as present in abnormal quality control material, exact concentrations cannot be interpreted due to imprecision. Only semiquantitative results, not numerical values implying quantification, should be reported from urine test strips.

Analytical performance evaluation of two automated urine sediment analysers using two levels of commercially available quality control material.

OBJECTIVES: Evaluate the in-clinic performance of point-of-care sediment analysers, Analyzer V (Vetscan SA, Abaxis) and Analyzer S (SediVue DX, IDEXX), using assayed, bilevel (2 concentrations) urine quality control material to determine if instrument specifications are acceptable for semi-quantitative clinical urine sediment analysis. MATERIALS AND METHODS: Accuracy, precision and clinical utility of Analyzer V and Analyzer S measurements were evaluated using a bilevel, assayed quality control material in 23 veterinary practices. RESULTS: Photomicrographs taken by the instruments facilitated manual review and quality assessment. Analyzer V and Analyzer S under-identified the presence of cystine crystals with 83 and 13% inaccuracy in the positive quality control material, respectively. Analyzer V and Analyzer S over-reported bacteria in the sterile quality control material with 82 and 94% specificity, respectively. Analyzer V and Analyzer S reported RBCs and WBCs within manufacturer specifications with excellent sensitivity (93 to 100%) and specificity (100%). CLINICAL SIGNIFICANCE: Additional improvement is needed to better classify crystal types and reduce false positives for bacteria before clinical use. While normal samples can generally be trusted, a manual review of abnormal samples is required to ensure that clinically important urine components are correctly evaluated. Future studies should evaluate the performance of these instruments with species-specific urine sediment.

Cross-Sectional Survey of Graduate Clinical Nutrition Students Describing Dietary Choices and Recommendations.

Objectives: Little data exists describing the dietary habits of nutrition students, including whether students' personal dietary choices influence their clinical recommendations. Study objectives were to: (1) Identify common dietary choices made by nutrition students, (2) determine students' rationale for choosing or avoiding specific diets, (3) identify key factors used to make dietary recommendations.Methods: An anonymous online survey was distributed to graduate-level clinical nutrition students who were attending five American universities. Data collected included demographics, current diet, reasons for following the current diet, reasons for recommending diets, and degree completion status. Percentage of diets chosen and rationale for dietary decisions were compared. Diets chosen and recommended were stratified and compared by degree completion status via chi-square test.Results: 208 participants completed the survey. The top diets students reported following were Whole Foods/Unprocessed (49%) and Gluten-Free (16%), followed by Vegan/Vegetarian (13%) and Paleo (12.5%). The top reasons identified for choosing a personal diet were health optimization and food allergy/intolerance/sensitivity. The top factors used to make dietary recommendations were clients' preferences/resources and results of laboratory testing. A Whole Foods/Unprocessed diet was also selected by the largest proportion of students as one they would recommend to clients-97% of students early in their program and 98.3% of students late in their program would recommend it to a client.Conclusion: A Whole Foods/Unprocessed diet was the most followed diet and the one most likely to be recommended to future clients, irrespective of students' degree completion progress.

Acute Responses of Core Muscle Activity during Bridge Exercises on the Floor vs. the Suspension System.

This study aimed to compare the neuromuscular activation of selected core musculature in supine and prone bridge exercises under stable versus suspended conditions. Forty-three healthy male participants were recruited to measure the electromyographic activities of the rectus abdominis (RA), lumbar multifidus (LM), thoracic erector spinae (TES), rectus femoris (RF), gluteus maximus (GM), and biceps femoris (BF) during supine and prone bridge exercises under six conditions: control, both arms and feet on the floor (Pronecon and Supinecon); arms on the floor and feet on the suspension system (Prone-Feetsuspension and Supine-Feetsuspension); and arms on the suspension system and feet on the floor (Prone-Armsuspension and Supine-Armsuspension). Prone-Armsuspension yielded significantly higher activities in the RA, RF, TES, and LM than Prone-Feetsuspension (p < 0.01) and Pronecon (p < 0.001). Moreover, Supine-Feetsuspension elicited significantly higher activities in the RA, RF, TES, LM, and BF than Supine-Armsuspension (p < 0.01) and Supinecon (p < 0.001). Furthermore, Supine-Feetsuspension elicited significantly higher activities in the RF, TES, and BF than Supinecon (p < 0.01). Therefore, if the RA and/or RF were the target training muscles, then Prone-Armsuspension was recommended. However, if the TES, LM, and/or BF were the target training muscles, then Supine-Feetsuspension was recommended.

Quantification of observable behaviors induced by typical and atypical kappa-opioid receptor agonists in male rhesus monkeys.

RATIONALE: Kappa-opioid receptor (KOR) agonists are antinociceptive but have side effects that limit their therapeutic utility. New KOR agonists have been developed that are fully efficacious at the KOR but may produce fewer or reduced side effects that are typical of KOR agonists. OBJECTIVES: We determined behavioral profiles for typical and atypical KOR agonists purported to differ in intracellular-signaling profiles as well as a mu-opioid receptor (MOR) agonist, oxycodone, using a behavioral scoring system based on Novak et al. (Am J Primatol 28:124-138, 1992, Am J Primatol 46:213-227, 1998) and modified to quantify drug-induced effects (e.g., Duke et al. J Pharmacol Exp Ther 366:145-157, 2018). METHODS: Six adult male rhesus monkeys were administered a range of doses of the typical KOR agonists, U50-488H (0.0032-0.1 mg/kg) and salvinorin A (0.00032-0.01 mg/kg); the atypical KOR agonists, nalfurafine (0.0001-0.001 mg/kg) and triazole 1.1 (0.01-0.32 mg/kg); the MOR agonist, oxycodone (0.0032-0.32 mg/kg); and as controls, cocaine (0.032-0.32 mg/kg) and ketamine (0.32-10 mg/kg). For time-course determinations, the largest dose of each KOR agonist or MOR agonist was administered across timepoints (10-320 min). In mixture conditions, oxycodone (0.1 mg/kg) was followed by KOR-agonist administration. RESULTS: Typical KOR agonists produced sedative-like and motor-impairing effects. Nalfurafine was similar to typical KOR agonists on most outcomes, and triazole 1.1 produced no effects on its own except for reducing scratch during time-course determinations. In the mixture, all KOR agonists reduced oxycodone-induced scratching, U50-488H and nalfurafine reduced species-typical activity, and U50-488H increased rest/sleep posture. CONCLUSIONS: Atypical "biased" KOR agonists produce side-effect profiles that are relatively benign (triazole 1.1) or reduced (nalfurafine) compared to typical KOR agonists.

Self-administration of benzodiazepine and cocaine combinations by male and female rhesus monkeys in a choice procedure: role of α1 subunit-containing GABAA receptors.

RATIONALE: Compounds lacking efficacy at the α1 subunit-containing GABAA (α1GABAA) receptor appear to have reduced abuse potential compared with those having measurable efficacy at this receptor, though their self-administration in nonhuman primates is dependent upon past drug experience. OBJECTIVES: We used a drug vs. drug choice procedure to evaluate the hypothesis that L-838,417, a compound lacking efficacy at αGABAA receptors, would not enhance cocaine choice in monkeys trained to self-administer cocaine. We also hypothesized that zolpidem, a compound with preferential modulation of ⍺1GABAA receptors and midazolam, a nonselective benzodiazepine, would enhance cocaine choice in this procedure. METHODS: One female and three male rhesus monkeys chose between cocaine alone (0.1 mg/kg/injection) vs. the same dose of cocaine combined with midazolam (0.003-0.1 mg/kg/injection), zolpidem (0.003-0.3 mg/kg/injection), or L-838-417 (0.01-0.1 mg/kg/injection). In addition, we evaluated choice between saline and L-838,417 at select doses to determine whether L-838,417 would function as a reinforcer on its own. RESULTS: Consistent with our hypotheses, midazolam- and zolpidem-cocaine mixtures were chosen over cocaine alone at sufficiently high doses. However, L-838,417-cocaine mixtures also were chosen over cocaine alone in three of four subjects with at least one dose. When available alone vs. saline, L-838,417 did not function as a reinforcer in any subject. CONCLUSION: Compounds that lack efficacy at α1GABAA receptors may have low abuse potential compared to classic benzodiazepines, but self-administration of these compounds is context-dependent.

The α2,3-selective potentiator of GABAA receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats.

Clinical evidence indicates that positive allosteric modulators (PAMs) of GABAA receptors have analgesic benefit in addition to efficacy in anxiety disorders. However, the utility of GABAA receptor PAMs as analgesics is compromised by the central nervous system side effects of non-selective potentiators. A selective potentiator of GABAA receptors associated with α2/3 subunits, KRM-II-81(5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole), has demonstrated anxiolytic, anticonvulsant, and antinociceptive effects in rodents with reduced motoric side effects. The present study evaluated the potential of KRM-II-81 as a novel analgesic. Oral administration of KRM-II-81 attenuated formalin-induced flinching; in contrast, diazepam was not active. KRM-II-81 attenuated nociceptive-associated behaviors engendered by chronic spinal nerve ligation (L5/L6). Diazepam decreased locomotion of rats at the dose tested in the formalin assay (10 mg/kg) whereas KRM-II-81 produced small decreases that were not dose-dependent (10-100 mg/kg). Plasma and brain levels of KRM-II-81 were used to demonstrate selectivity for α2/3- over α1-associated GABAA receptors and to define the degree of engagement of these receptors. Plasma and brain concentrations of KRM-II-81 were positively-associated with analgesic efficacy. GABA currents from isolated rat dorsal-root ganglion cultures were potentiated by KRM-II-81 with an ED50 of 32 nM. Measures of respiratory depression were reduced by alprazolam whereas KRM-II-81 was either inactive or produced effects with lower potency and efficacy. These findings add to the growing body of data supporting the idea that α2/3-selective GABAA receptor PAMs will have efficacy and tolerability as pain medications including those for neuropathic pain. Given their predicted anxiolytic effects, α2/3-selective GABAA receptor PAMs offer an additional inroad into the management of pain.

Biological variation of routine haematology and biochemistry measurands in the horse.

BACKGROUND: Clinical pathology results are typically interpreted by referring to population-based reference intervals. The use of individualised (subject-based) reference intervals is more appropriate for measurands with a high degree of variation between individuals. OBJECTIVES: To determine the biological variation of routinely analysed equine haematology and biochemistry measurands and calculate indices of individuality and reference change values which enable production of individualised reference intervals, in a group of healthy, privately owned horses. STUDY DESIGN: In a prospective cohort study, thirty-nine privately owned horses were sampled by jugular venipuncture for analysis of haematology and biochemistry measurands at weekly intervals for 6 weeks. METHODS: Haematology was analysed on the day of collection. Serum was frozen and biochemistry analyses performed on thawed samples. Duplicate results were obtained and the coefficient of variation was calculated for analytical variation, within-subject variation and between-subject variation. The index of individuality and reference change value were derived for each measurand. RESULTS: Haematology (red blood cell count, mean corpuscular haemoglobin and mean cell volume) and biochemistry measurands (total protein, globulins, albumin, gamma-glutamyl transferase, aspartate aminotransferase) demonstrated high individuality, indicating that individualised reference intervals are more appropriate for evaluation of these measurands. Two haematology (mean corpuscular haemoglobin concentration and platelets) and three biochemistry measurands (chloride, glucose and sodium) had low individuality, indicating that the use of traditional population-based reference intervals is appropriate for these measurands. Remaining measurands had intermediate individuality suggesting interpretation of the reference change value should occur with consideration of the population-based reference interval. MAIN LIMITATIONS: The use of privately owned horses, variable management and environmental factors. CONCLUSIONS: The use of individualised reference intervals is justified for many measurands in horses, supporting the use of serial sampling, consideration of biological variation and application of reference change values for improved clinical decision making and patient management in equine practice.

Pigment carbon and nitrogen isotopic signatures in euxinic basins.

The carbon and nitrogen isotopic signatures of chloropigments and porphyrins from the sediments of redox-stratified lakes and marine basins reveal details of past biogeochemical nutrient cycling. Such interpretations are strengthened by modern calibration studies, and here, we report on the C and N isotopic composition of pigments and nutrients in the water column and surface sediment of redox-stratified Fayetteville Green Lake (FGL; New York). We also report δ13 C and δ15 N values for pyropheophytin a (Pphe a) and bacteriochlorophyll e (Bchl e) deposited in the Black Sea during its transition to a redox-stratified basin ca. 7.8 ka. We propose a model for evolving nutrient cycling in the Black Sea from 7.8 to 6.4 ka, informed by the new pigment data from FGL. The seasonal study of water column nutrients and pigments at FGL revealed population dynamics in surface and deep waters that were also captured in the sediments. Biomass was greatest near the chemocline, where cyanobacteria, purple sulfur bacteria (PSB), and green sulfur bacteria (GSB) had seasonally variable populations. Bulk organic matter in the surface sediment, however, was derived mainly from the oxygenated surface waters. Surface sediment pigment δ13 C and δ15 N values indicate intact chlorophyll a (Chl a) was derived from near the chemocline, but its degradation product pheophytin a (Phe a) was derived primarily from surface waters. Bacteriopheophytin a (Bphe a) and Bchl e in the sediments came from chemocline populations of PSB and GSB, respectively. The distinctive δ13 C and δ15 N values for Chl a, Phe a, and Bphe a in the surface sediment are inputs to an isotopic mixing model that shows their decomposition to a common porphyrin derivative can produce non-specific sedimentary isotope signatures. This model serves as a caveat for paleobiogeochemical interpretations in basins that had diverse populations near a shallow chemocline.

Clinical application of biological variation data to facilitate interpretation of canine and feline laboratory results.

Interpretation of laboratory results is based on comparison of the patient's own results against established decision thresholds or reference intervals in the context of the clinical presentation and history. Blood measurand analysis has pre-analytical, analytical and physiological sources of variation, which may complicate interpretation of results. Biological variation describes the physiological random fluctuation of blood measurands around a homeostatic set point, which varies within and between individuals. This article reviews the practical applications of biological variation in the everyday clinical setting. Examples are offered to highlight how biological variation can be used to: (1) assess the usefulness of subject-based reference intervals, (2) determine measurand homeostatic set points, (3) interpret single or serial results for diagnosis of disease and (4) evaluate changes in serial results during monitoring.

Microbial communities and organic biomarkers in a Proterozoic-analog sinkhole.

Little Salt Spring (Sarasota County, FL, USA) is a sinkhole with groundwater vents at ~77 m depth. The entire water column experiences sulfidic (~50 µM) conditions seasonally, resulting in a system poised between oxic and sulfidic conditions. Red pinnacle mats occupy the sediment-water interface in the sunlit upper basin of the sinkhole, and yielded 16S rRNA gene clones affiliated with Cyanobacteria, Chlorobi, and sulfate-reducing clades of Deltaproteobacteria. Nine bacteriochlorophyll e homologues and isorenieratene indicate contributions from Chlorobi, and abundant chlorophyll a and pheophytin a are consistent with the presence of Cyanobacteria. The red pinnacle mat contains hopanoids, including 2-methyl structures that have been interpreted as biomarkers for Cyanobacteria. A single sequence of hpnP, the gene required for methylation of hopanoids at the C-2 position, was recovered in both DNA and cDNA libraries from the red pinnacle mat. The hpnP sequence was most closely related to cyanobacterial hpnP sequences, implying that Cyanobacteria are a source of 2-methyl hopanoids present in the mat. The mats are capable of light-dependent primary productivity as evidenced by 13 C-bicarbonate photoassimilation. We also observed 13 C-bicarbonate photoassimilation in the presence of DCMU, an inhibitor of electron transfer to Photosystem II. Our results indicate that the mats carry out light-driven primary production in the absence of oxygen production-a mechanism that may have delayed the oxygenation of the Earth's oceans and atmosphere during the Proterozoic Eon. Furthermore, our observations of the production of 2-methyl hopanoids by Cyanobacteria under conditions of low oxygen and low light are consistent with the recovery of these structures from ancient black shales as well as their paucity in modern marine environments.

Longitudinal study on the use of dried blood spots for home monitoring in children after kidney transplantation.

The use of DBSs for home monitoring has been limited due to unsatisfactory blood sampling and analytical difficulties. The aim of this longitudinal feasibility trial was to assess the utility of DBS to monitor TAC and Cr at home in transplant recipients. A total of 30 participants (2-21 years, mean±SD, 13.6±5.4 year) were enrolled over 12 months. Eighteen were males. Monthly DBS samples were obtained at home and mailed to the central laboratory for analysis of TAC and Cr. Nineteen patients completed the study, and 216 cards were received in the laboratory from a total of 279 cards expected, with 416/519 (80%) blood spots being suitable for analysis. We found a high correlation between blood TAC and Cr levels by DBS and the clinical laboratory, R2 =.81 and .95, respectively. Fifteen parents and 15 youth completed measures of satisfaction with and preference for DBS testing. All but one parent/caregiver and youth reported satisfaction and preference for this method of testing over laboratory blood draws. We conclude that home DBS monitoring is a feasible method to monitor TAC and Cr in pediatric transplant recipients.

Choice between variable and fixed cocaine injections in male rhesus monkeys.

RATIONALE: The schedule of drug availability may enhance choice of a drug. In non-human subjects, reinforcers are chosen more often when available under variable schedules of reinforcement relative to fixed schedules. OBJECTIVE: To determine whether variable-drug access is an important determinant of cocaine choice by manipulating the schedule, drug dose, and combination of schedule + dose. METHOD: Four male rhesus monkeys chose between cocaine doses (0.025-0.4 mg/kg/injection). In control conditions, the schedule and dose of each drug delivery were fixed. In other conditions, the reinforcement schedule (i.e., variable-ratio schedule), dose of each cocaine delivery, or both were variable on one lever while all aspects on the other lever remained fixed. RESULTS: When cocaine dose was equal on average (0.1 mg/kg/injection), 2 of 4 subjects chose cocaine associated with the variable schedule more than the fixed schedule. All subjects chose the variable dose that was equal on average to the fixed dose, and this difference was statistically significant. Three of 4 subjects chose cocaine associated with the variable combination over the fixed option (when the dose was equal on average). During dose-response determinations (when dose on the variable and fixed options were not equal), making the schedule, dose, or both variable generally did not alter cocaine's potency as a reinforcer. CONCLUSION: While many factors contribute to drug choice, unpredictable drug access is a feature that may be common in the natural environment and could play a key role in the allocation of behavior to drug alternatives by patients with substance-use disorders.

MYCN induces neuroblastoma in primary neural crest cells.

Neuroblastoma (NBL) is an embryonal cancer of the sympathetic nervous system (SNS), which causes 15% of pediatric cancer deaths. High-risk NBL is characterized by N-Myc amplification and segmental chromosomal gains and losses. Owing to limited disease models, the etiology of NBL is largely unknown, including both the cell of origin and the majority of oncogenic drivers. We have established a novel system for studying NBL based on the transformation of neural crest cells (NCCs), the progenitor cells of the SNS, isolated from mouse embryonic day 9.5 trunk neural tube explants. Based on pathology and gene expression analysis, we report the first successful transformation of wild-type NCCs into NBL by enforced expression of N-Myc, to generate phenotypically and molecularly accurate tumors that closely model human MYCN-amplified NBL. Using comparative genomic hybridization, we found that NCC-derived NBL tumors acquired copy number gains and losses that are syntenic to those observed in human MYCN-amplified NBL including 17q gain, 2p gain and loss of 1p36. When p53-compromised NCCs were transformed with N-Myc, we generated primitive neuroectodermal tumors with divergent differentiation including osteosarcoma. These subcutaneous tumors were metastatic to regional lymph nodes, liver and lung. Our novel experimental approach accurately models human NBL and establishes a new system with potential to study early stages of NBL oncogenesis, to functionally assess NBL oncogenic drivers and to characterize NBL metastasis.

Canine Cutaneous Plasmacytosis: 21 Cases (2005-2015).

BACKGROUND: Cutaneous plasmacytosis (CP) is a syndrome of multiple cutaneous plasma cell tumors, in the absence of multiple myeloma. Although rare in both humans and dogs, treatment recommendations are usually extrapolated from multiple myeloma protocols. To date, no case series of CP have been described in the veterinary literature. HYPOTHESIS/OBJECTIVES: To describe clinical presentation, determine treatment response rates and duration, and report overall survival of dogs with CP. ANIMALS: Twenty-one client-owned dogs with CP. METHODS: Medical records of 21 dogs with CP were reviewed. Diagnosis was based on histopathologic evaluation of at least 1 representative cutaneous or subcutaneous lesion in dogs with ≥3 lesions. Dogs with suspicion of multiple myeloma were excluded. RESULTS: The most commonly affected breeds were the golden (5/21) and Labrador retriever (3/21). Fourteen of 21 dogs had >10 lesions, with some having >100. Lesions commonly were described as round, raised, pink-to-red, and variably alopecic or ulcerated. The most commonly used drug protocol was combined melphalan and prednisone, with an overall response rate (ORR) of 73.7% (14/19 dogs). Single-agent lomustine was associated with a similar ORR of 71.4% (5/7 dogs). For all treatments combined, the median progression-free interval after the first treatment was 153 days. The median survival time from the first treatment was 542 days. CONCLUSIONS AND CLINICAL IMPORTANCE: Alkylating agents were effective in inducing remission of CP; corticosteroids, melphalan, and lomustine were the most commonly used drugs. Survival times were similar to those reported in dogs with multiple myeloma treated with alkylating agents.

Reformulations of well-known active ingredients in the topical treatment of psoriasis vulgaris can improve clinical outcomes for patients.

Although the majority of patients with psoriasis vulgaris are treated exclusively with topical therapies, research to develop more effective topical therapies that are associated with higher patient satisfaction has lagged behind the development of systemic agents. The aim of this literature review was to determine whether there is documented evidence that applying an innovative approach to improving the formulation of active ingredients commonly used in the topical treatment of psoriasis can have a positive effect on clinical outcomes and patient-reported outcomes (PROs). The Embase and PubMed databases were searched for articles published between 2001 and 2016 that made direct head-to-head comparisons of different formulations of an active pharmaceutical ingredient (API), focusing on clinical outcomes and PROs. In total, 22 publications on APIs or API combinations met the eligibility criteria (19 head-to-head clinical trials, one pooled analysis, one health-economic modelling study and one systematic review). Significant clinical benefit associated with the use of a reformulated API over an older formulation was reported in three trials of clobetasol propionate, one trial of calcipotriol, three trials of betamethasone and five trials/pooled analyses of calcipotriol/calcipotriene + betamethasone dipropionate (Cal/BD) formulations. Significantly improved PROs associated with the use of a reformulated API over an older formulation were reported in three trials of clobetasol propionate, one trial of betamethasone valerate and two trials of Cal/BD formulations. These results demonstrate that the innovative reformulation of APIs used in the treatment of psoriasis can produce therapies that attain significantly improved clinical outcomes and PROs. This suggests that improvement in topical therapy for psoriasis need not only to be achieved by the identification of new targets and the development of new APIs, but that improvement in the vehicle used to deliver existing APIs has the potential to result in significant clinical and patient benefits.