Spectral control of elastic dynamics in metallic nano-cavities.

We show how the elastic response of metallic nano-cavities can be tailored by tuning the interplay with an underlying phononic superlattice. In particular, we exploit ultrafast optical excitation in order to address a resonance mode in a tungsten thin film, grown on top of a periodic MgO/ZrO2 multilayer. Setting up a simple theoretical model, we can explain our findings by the coupling of the resonance in the tungsten to an evanescent surface mode of the superlattice. To demonstrate a second potential benefit of our findings besides characterization of elastic properties of multilayer samples, we show by micromagnetic simulation how a similar structure can be utilized for magneto-elastic excitation of exchange-dominated spin waves.

Identification of contaminant interferences which cause positive urine reagent test strip reactions in a cage setting for the laboratory-housed nonhuman primate, Beagle dog, and Sprague-Dawley rat.

BACKGROUND: A high incidence of unexplained positive urine reagent test strip reactions was observed in healthy, untreated laboratory-housed nonhuman primates, Beagle dogs, and Sprague-Dawley rats. Exposure of urine to cage pan contaminants was the suspected cause of the positive reactions. OBJECTIVES: The objective of this study was to identify cage pan contaminants which could cause positive reagent test strip reactions. METHODS: Contaminated urine was simulated by exposing water samples to cage pan contaminants, including cleaning solutions, feces from nonhuman primates, Beagle dogs, and Sprague-Dawley rats, certified laboratory animal diets, and dietary enrichments (vegetables, fruits, and food treats). Ten samples were prepared for each contaminant and analyzed for blood, glucose, bilirubin, ketones, pH, protein, urobilinogen, nitrite, and leukocyte esterase using commercially available urine reagent test strips and an automated urine chemistry analyzer. RESULTS: Positive reactions were common for all but one analyte and frequently associated with multiple contaminants. Blood, glucose, and protein reactions had the highest incidence and/or strongest positive reactions. Positive reactions for other reagent test strip analytes were observed, but generally of lower incidence and magnitude. CONCLUSIONS: We identified a high incidence of contaminant interferences in a water matrix causing positive reagent test strip reactions, primarily for the blood, glucose, and protein reactions. These findings highlight the potential limited value of urine reagent test strip assays as reliable biomarkers for detecting kidney toxicity in nonclinical studies, and imply that urine collection methods that minimize exposure to contaminants will likely improve the diagnostic validity of reagent test strip assays.

Best practices for veterinary toxicologic clinical pathology, with emphasis on the pharmaceutical and biotechnology industries.

The purpose of this paper by the Regulatory Affairs Committee (RAC) of the American Society for Veterinary Clinical Pathology (ASVCP) is to review the current regulatory guidances (eg, guidelines) and published recommendations for best practices in veterinary toxicologic clinical pathology, particularly in the pharmaceutical and biotechnology industries, and to utilize the combined experience of ASVCP RAC to provide updated recommendations. Discussion points include (1) instrumentation, validation, and sample collection, (2) routine laboratory variables, (3) cytologic laboratory variables, (4) data interpretation and reporting (including peer review, reference intervals and statistics), and (5) roles and responsibilities of clinical pathologists and laboratory personnel. Revision and improvement of current practices should be in alignment with evolving regulatory guidance documents, new technology, and expanding understanding and utility of clinical pathology. These recommendations provide a contemporary guide for the refinement of veterinary toxicologic clinical pathology best practices.

Safety assessment of 4'-thio-beta-D-arabinofuranosylcytosine in the beagle dog suggests a drug-induced centrally mediated effect on the hypothalamic-pituitary-adrenal axis.

4'-Thio-beta-D-arabinofuranosylcytosine (OSI-7836) is a nucleoside analogue with structural similarity to gemcitabine and cytarabine (ara-C). Myelosuppression, reversible transaminase elevations, and flu-like symptoms are common side effects associated with human use of gemcitabine and ara-C. Fatigue is also associated with the use of gemcitabine and OSI-7836 in humans. To better understand the toxicity of OSI-7836, subchronic studies were conducted in dogs. OSI-7836 was administered on days 1 and 8 or on days 1, 2, and 3 of a 21-day dose regimen. These schedules attempted to match clinical trial dosing regimens. Routine toxicity study end points demonstrated that OSI-7836 was primarily cytotoxic to the gastrointestinal tract, bone marrow, and testes; the myelotoxicity was mild and reversible. Plasma pharmacokinetics were dose-linear with an elimination half-life of 2.2 h. Follow-up single dose experiments in dogs assessed drug effects on lymphocyte subpopulations and on adrenal and thyroid function. Populations of T and B cells were equally reduced following OSI-7836 administration. There were no adverse effects on thyroid function, but there were marked reductions in circulating cortisol and adrenocorticotropic hormone concentrations suggesting a centrally mediated impairment of the hypothalamic-pituitary-adrenal axis. These findings show a toxicological profile with OSI-7836 similar to other nucleoside analogues and suggest that the beagle is a model for studying one possible cause of OSI-7836-related fatigue, impaired function of the hypothalamic-pituitary-adrenal axis.

Biological effects of short-term or prolonged administration of 9-[2-(phosphonomethoxy)propyl]adenine (tenofovir) to newborn and infant rhesus macaques.

The reverse transcriptase inhibitor 9-[2-(phosphonomethoxy)propyl]adenine (PMPA; tenofovir) was previously found to offer strong prophylactic and therapeutic benefits in an infant macaque model of pediatric human immunodeficiency virus (HIV) infection. We now summarize the toxicity and safety of PMPA in these studies. When a range of PMPA doses (4 to 30 mg/kg of body weight administered subcutaneously once daily) was administered to 39 infant macaques for a short period of time (range, 1 day to 12 weeks), no adverse effects on their health or growth were observed; this included a subset of 12 animals which were monitored for more than 2 years. In contrast, daily administration of a high dose of PMPA (30 mg/kg subcutaneously) for prolonged periods of time (>8 to 21 months) to 13 animals resulted in a Fanconi-like syndrome (proximal renal tubular disorder) with glucosuria, aminoaciduria, hypophosphatemia, growth restriction, bone pathology (osteomalacia), and reduced clearance of PMPA. The adverse effects were reversible or were alleviated following either complete withdrawal of PMPA treatment or reduction of the daily regimen from 30 mg/kg to 2.5 to 10 mg/kg subcutaneously. Finally, to evaluate the safety of a prolonged low-dose treatment regimen, two newborn macaques were started on a 10-mg/kg/day subcutaneous regimen; these animals are healthy and have normal bone density and growth after 5 years of daily treatment. In conclusion, our findings suggest that chronic daily administration of a high dose of PMPA results in adverse effects on kidney and bone, while short-term administration of relatively high doses and prolonged low-dose administration are safe.

Evaluation of mitochondrial DNA content and enzyme levels in tenofovir DF-treated rats, rhesus monkeys and woodchucks.

The antiviral compound tenofovir DF (Gilead Sciences) was evaluated for possible mitochondrial toxicity in rats, rhesus monkeys and woodchucks. Animals were treated by oral gavage with tenofovir DF, and the levels of mitochondrial enzymes cytochrome c oxidase and citrate synthase were assayed. In rats (6/group) treated daily for 28 days with 300 mg/kg tenofovir DF the enzyme levels were unchanged versus control in liver, kidney, and skeletal muscle. In a parallel study, rats (6/group) were treated with 40 mg/kg of the antiviral adefovir dipivoxil (Gilead Sciences) and enzyme levels were also unchanged versus control. In rhesus monkeys (6/group) treated daily with 30 mg/kg or 250 mg/kg tenofovir DF for 56 days, and in woodchucks (6/group) treated daily with 15 mg/kg or 50mg/kg tenofovir DF for 90 days, the enzyme levels were unchanged in liver, kidney, skeletal muscle and cardiac muscle. Mitochondrial DNA (mtDNA) content was determined in tissue from treated versus control animals by utilizing a quantitative real-time PCR (QPCR) technique, where the relative ratios of mitochondrial cytochrome b gene to the genomic actin gene were measured. The relative mtDNA content from rats, rhesus monkeys and woodchucks were unchanged in the various treatment groups. Variations in mtDNA content between animals in the same treatment group were noted. The actual species-dependent mitochondria/genomic ratios were estimated from the QPCR assay. In summary, treatment with tenofovir DF, or with adefovir dipivoxil, did not affect mtDNA content or level of mitochondrial enzymes, and no liver, muscle or renal microscopic abnormalities were observed in tenofovir-treated animals.