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Medical devices are a product class encompassing many materials and intended uses. While adversity determination is a key part of nonclinical safety assessments, relatively little has been published about the unique challenges encountered when determining adversity for implantable medical devices. The current paper uses the Society of Toxicologic Pathology (STP)’s “Scientific and Regulatory Policy Committee Recommended (‘Best’) Practices for Determining, Communicating, and Using Adverse Effect Data from Nonclinical Studies,” which were crafted for conventional bio/pharmaceutical products (small and large molecules, cell and gene therapies, etc), as a framework for making adversity decisions for medical devices. Some best principles are directly translatable to medical devices: (1) adversity indicates harm to the animal; (2) effects should be assessed on their merits without speculation regarding future or unmeasured implications; (3) adversity decisions apply only to the test species under the specific conditions of the nonclinical study; and (4) adversity decisions and supporting evidence should be clearly stated in reports. However, unique considerations also apply for evaluating implanted medical devices, including testing of multiple articles in the same animal and the unavoidable tissue trauma during device implantation. This opinion piece offers suggestions for applying previously published STP best practice recommendations for assigning adversity to implantable medical devices. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder characterized by synovitis that leads to cartilage and bone erosion by invading fibrovascular tissue. Mouse models of RA recapitulate many features of the human disease. Despite the availability of medicines that are highly effective in many patient populations, autoimmune diseases (including RA) remain an area of active biomedical research, and consequently mouse models of RA are still extensively used for mechanistic studies and validation of therapeutic targets. This review aims to integrate morphologic features with model biology and cover the key characteristics of the most commonly used induced and spontaneous mouse models of RA. Induced models emphasized in this review include collagen-induced arthritis and antibody-induced arthritis. Collagen-induced arthritis is an example of an active immunization strategy, whereas antibody- induced arthritis models, such as collagen antibody–induced arthritis and K/BxN antibody transfer arthritis, represent examples of passive immunization strategies. The coverage of spontaneous models in this review is focused on the TNFΔARE mouse, in which arthritis results from overexpression of TNF-α, a master proinflammatory cytokine that drives disease in many patients. [ABSTRACT FROM AUTHOR]

Bone structure is modulated by the interaction between receptor activator of nuclear factor–κB (RANK) and RANK ligand (RANKL). Osteoprotegerin (OPG), a decoy receptor for RANKL, modifies osteoclast-mediated bone resorption directly and spares articular cartilage indirectly in rodents with immune-mediated arthritis by preventing subchondral bone destruction. The OPG/RANKL balance also seems to be critical in maintaining joint integrity in osteoarthritis, a condition featuring articular bone and cartilage damage in the absence of profound inflammation. The current study explored the role of OPG in sparing articular cartilage by evaluating joint lesions in adult C57BL/6J mice lacking osteoprotegerin (Opg−/−). At 3, 5, 7, 9, and 12 months of age, both sexes of Opg−/− mice developed severe degenerative joint disease (DJD) characterized by progressive loss of cartilage matrix and eventually articular cartilage. Lesions developed earlier and more severely in Opg−/− mice relative to age-matched, wild-type (Opg+/+), or heterozygous (Opg+/−) littermates (P ≤ .05). The femorotibial joint was affected bilaterally at 3 months, while other key weight-bearing diarthrodial joints (eg, coxofemoral, scapulohumeral, humeroradioulnar) were affected later and unilaterally. Cortical bone in subchondral plates and long bone diaphyses of Opg−/− mice but not Opg+/+ or Opg+/− animals was osteoporotic by 3 months of age (P ≤ .05); the extent of porosity was less than the degree of DJD. Closure of the physes in long bones (P ≤ .05) and cartilage retention in the femoral primary spongiosa (P ≤ .05) affected chiefly Opg−/− mice. These data suggest that OPG plays an essential direct role in maintaining cartilage integrity in the articular surfaces and physes. [ABSTRACT FROM AUTHOR]

Veterinary pathologists working as toxicologic pathologists in academic settings fill many vital roles, such as diagnosticians, educators, and/or researchers. These individuals have spent years investigating pathology problems that mainly or exclusively focus on the reactions of cells, organs, or systems to toxic materials. Thus, academic toxicologic pathologists are uniquely suited both to help trainees understand toxicity as a cause of pathology responses and also to provide expert consultation on toxicologic pathology. Most toxicologic pathologists in academia are employed at colleges of medicine or veterinary medicine, even though specific toxicologic pathology faculty appointments are uncommon in Europe and North America. Academic toxicologic pathologists typically receive lower financial compensation than do toxicologic pathologists in industry, but academic positions generally provide alternative rewards, such as higher workplace autonomy and scheduling flexibility, professional enrichment through student interactions, and enhanced opportunities for collaborative research and advanced diagnostic investigations. Regular participation by academic toxicologic pathologists in professional training opportunities (eg, as pathology and toxicology instructors in medical and veterinary medical courses, graduate programs, and residencies) offers an important means of engendering interest and inspiring veterinarians to select toxicologic pathology and toxicology as their own areas of future expertise. [ABSTRACT FROM PUBLISHER]

The article presents a study on morphological manifestations of gene-specific molecular changes in laboratory mice. It identifies neoplasia as caused in part by lasting activation of tumor-promoting genes or declining function of genes tasked to prevent neoplastic induction. It explains that neoplastic cells cannot acquire their malignancy without sustained genotypic abnormalities related to aberrant activity of oncogenes.

This article presents numerous reference materials including books, journal articles, and websites which can assist researchers in phenotyping newly-engineered rodent lines. Among the materials offered include, first, the "Mouse Phenotypes: A Handbook of Mutation Analysis," by Virginia Papaioannou. Second, the "International Classification of Rodent Tumors: The Mouse," by Ulrich Mohr. And third, "Mouse Nomenclature" http://www.informatics.jax.org/mgihome/nomen/index.shtml.

The article investigates the divergence in actions among three oncostatin Ms (OSM), namely, mouse OSM (mOSM), human OSM (hOSM) and bovine OSM (bOSM), occurs in vivo in mouse models. Results reveal that animals overexpression either hOSM or bOSM had an identical phenotype resembling that associated with leukemia inhibitory factor (LIF) activation, which includes hematologic abnormalities, weight loss, enlargement and/or structural reorganization of lymphoid organs, and osteosclerosis. On the other hand, mice overexpressing mOSM did not develop hematologic changes, weight loss or osteoclerosis and demonstrated more modest and anatomically distinct restructuring of lymphoid organs.

OBJECTIVE: To investigate whether the bone-preserving effects of a RANKL antagonist or a tumor necrosis factor (TNF) antagonist could be further improved by the addition of a bone anabolic agent in inflammatory arthritis. METHODS: Lewis rats with either adjuvant-induced arthritis (AIA) or collagen-induced arthritis (CIA) were treated for 10 days with PEGylated soluble tumor necrosis factor receptor type I (PEG sTNFRI), interleukin-1 receptor antagonist (IL-1Ra), osteoprotegerin (OPG), parathyroid hormone (PTH), or combinations of these agents starting on day 4 after disease onset. Treatment effects were assessed clinically, radiologically, and histologically, and by morphometry for the extent of paw swelling, bone erosive changes, and synovial inflammation. RESULTS: Paw swelling and synovial inflammation were significantly inhibited by PEG sTNFRI in AIA and CIA, and by IL-1Ra in CIA. OPG and PTH had no significant effect on these parameters. Analysis of bone erosion revealed a significant bone-sparing effect of monotherapy with PEG sTNFRI or OPG in both models, whereas IL-1Ra was only effective in CIA. PTH treatment alone did not show a bone-protective effect in either model. With the combination of PEG sTNFRI and PTH, erosion scores (-74% in AIA and -61% in CIA versus controls) were significantly lower than those elicited by PEG sTNFRI alone (-41% and -29%, respectively, versus controls). Similar results were also obtained with the combination of OPG and PTH (-88% in AIA and -73% in CIA, compared with -70% and -55%, respectively, with OPG monotherapy). Coadministration of IL-1Ra and PTH had no synergistic bone-sparing effect. Morphometric analysis revealed that the addition of PTH to PEG sTNFRI or OPG resulted in higher bone volume and higher osteoblast numbers in both AIA and CIA. CONCLUSION: The bone-protective effects resulting from RANKL or TNF antagonism can be further improved by the addition of a bone anabolic agent. [ABSTRACT FROM AUTHOR]

Magnetic and magnetotransport measurements on polycrystalline thin film Co1-xFexS2, a system that exhibits tunable conduction electron spin polarization in bulk, are reported. The films exhibit a low field hysteretic magnetoresistance (MR) due to spin-dependent intergranular tunneling, thus providing a simple probe of the spin polarization. The MR increases rapidly with x, saturating as the magnetization reaches 1.0μB/Co, demonstrating that high, doping tunable, spin polarization can be readily achieved in thin films synthesized by simple methods. Quantitative estimates yield spin polarizations as high as 90%. [ABSTRACT FROM AUTHOR]

Chronic exposure to trace levels of waste anesthetic gases has been linked to higher incidences of neurologic and reproductive dysfunction, hepatic and renal toxicity, and neoplasia in health care professionals. We have shown that low levels of isoflurane emissions are likely in conventional laboratory animal treatment rooms during the use of standard anesthesia delivery systems equipped with activated charcoal canisters for passive gas scavenging. In the present study, we surveyed the effectiveness of canisters (attached to well-maintained precision isoflurane vaporizers) in current use throughout our AAALAC-accredited laboratory animal facility. Canisters (Omnicon f/air) had been weighed prior to use and then attached to dual-loop systems (face mask and induction box circuits) from 1 week to 6 months of service. Isoflurane emissions were measured using a pre-calibrated, portable infrared spectrophotometer by attaching each canister to the face-mask circuit, occluding the face mask and closing the stopcock to the induction circuit, and running the system at uniform isoflurane concentration (2%) and oxygen flow rate (1 L minute-1 ). Samples were taken in animal procedure rooms (size range, 45–80 m3 ) in which the air turnover rate ranged between 20 and 30 nonrecirculating changes per hour. Nine of the 60 canisters (15%) in current use were found to have exceeded the manufacturer's recommended use-life (defined as a weight increase of 50 g). Of these nine, seven canisters did not scavenge isoflurane at all (indicated by emissions greatly exceeding 100 ppm). Isoflurane was not detected in the operator's breathing zone under normal use conditions (i.e. gas directed to both circuits at once). Of the 51 canisters that had not exceeded their rated use-life, 12 (23.5%) exhausted isoflurane at >2 ppm. Our data show that (i) the potential for exposure to waste isoflurane emissions will depend on the configuration of the delivery system and that (ii) enhanced attention to canister surveillance may be warranted even in well-run facilities. [ABSTRACT FROM AUTHOR]

In the nonlocal spin valve (NLSV) geometry, four-terminal electrical Hanle effect measurements have the potential to provide a particularly simple determination of the lifetime (τs) and diffusion length (λN) of spins injected into nonmagnetic (N) materials. Recent papers, however, have demonstrated that traditional models typically used to fit such data provide an inaccurate measurement of τs in ferromagnet (FM)/N metal devices with low interface resistance, particularly when the separation of the source and detector contacts is small. In the transparent limit, this shortcoming is due to the back diffusion and subsequent relaxation of spins within the FM contacts, which is not properly accounted for in standard models of the Hanle effect. Here we have used the separation dependence of the spin accumulation signal in NLSVs with multiple FM/N combinations, and interfaces in the diffusive limit, to determine λN in traditional spin valve measurements. We then compare these results to Hanle measurements as analyzed using models that either include or exclude spin sinking. We demonstrate that differences between the spin valve and Hanle measurements of λN can be quantitatively modelled provided that both the FM contact-induced isotropic spin sinking and the full three-dimensional geometry of the devices, which is particularly important at small contact separations, are accounted for. We find, however, that considerable difficulties persist, in particular due to the sensitivity of fitting to the contact interface resistance and the FM contact magnetization rotation, in precisely determining λN with the Hanle technique alone, particularly at small contact separations. [ABSTRACT FROM AUTHOR]