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Extraintestinal pathogenic Escherichia coli expressing cytotoxic necrotizing factor (CNF) 1 and 2 virulence factors is a rarely reported cause of acute, fatal necrohemorrhagic pneumonia in canines. A review of cases of necrohemorrhagic pneumonia in beagles at our facility between 2013 and 2021 revealed 21 dogs that died or were euthanized after acute onset lethargy, dyspnea, and hemorrhage. Some affected animals had recently been transported to the facility. In all dogs, lung lobes were discolored dark red and consolidated. Histologic lesions in 17 of these included alveolar necrosis, hemorrhage, edema, fibrin, acute inflammation, and intralesional colonies of bacilli. Lung was cultured for 10 dogs with E. coli isolated and CNF1 identified by virulence factor PCR in 7 of those. Based on these findings, extraintestinal E. coli should be considered an important cause of acute fatal necrohemorrhagic pneumonia in purpose-bred beagle research dogs and may be associated with a recent history of transport.

Intense surface eruptions are observed along the curved surface of a confined cylindrical film of hydrogel subject to laser-induced converging-diverging shock loading. Detailed numerical simulations are used to identify the dominant mechanisms causing mechanical instability. The mechanisms that produce surface instability are found to be fundamentally different from both acoustic parametric instability and shock-driven Richtmyer-Meshkov instability. The time scale of observed and simulated eruption formation is much larger than that of a single shock reflection, in stark contrast to previously studied shock-driven instabilities. Moreover, surface undulations are only found along external, as opposed to internal, soft solid boundaries. Specifically, classic bubble surface instability mechanisms do not occur in our experiments and here we comment only on the new surface undulations found along the outer boundary of solid hydrogel cylinders. Our findings indicate a new class of impulsively excited surface instability that is driven by cycles of internal shock reflections.

Extraintestinal pathogenic

Göttingen minipigs are increasingly used as an alternative large animal model in nonclinical toxicology studies, and proliferative lesions in this species are rare. Here, we report four cases of cardiac rhabdomyoma in Göttingen minipigs, an incidental and benign mass in the heart. Three cases lacked gross observations and had a microscopic nodule in either the left ventricle or interventricular septum. The last case had a large, firm, raised nodule on a left ventricular papillary muscle noted at necropsy, with additional microscopic intramural masses in the left ventricular wall. In all cases, microscopic evaluation revealed well-circumscribed, expansile nodules composed of bundles of large, highly vacuolated, ovoid to polygonal cells with variable cytoplasmic processes radiating from a centrally located nucleus. Cells displayed patchy accumulation of intracytoplasmic, PAS-positive material and haphazardly arranged cytoplasmic cross-striations. There was no evidence of cardiac insufficiency or other data to suggest the masses were clinically meaningful. Cardiac rhabdomyomas have been reported in meat-hybrid swine, with a breed predisposition in red wattle. This lesion is well established in guinea pigs, but documentation in other laboratory species used in toxicologic studies is limited to two beagle dogs. To our knowledge, this is the first report of spontaneous cardiac rhabdomyoma in Göttingen minipigs.

The design and execution of toxicology studies supporting vaccine development have some unique considerations relative to those supporting traditional small molecules and biologics. A working group of the Society of Toxicologic Pathology Scientific and Regulatory Policy Committee conducted a review of the scientific, technical, and regulatory considerations for veterinary pathologists and toxicologists related to the design and evaluation of regulatory toxicology studies supporting vaccine clinical trials. Much of the information in this document focuses on the development of prophylactic vaccines for infectious agents. Many of these considerations also apply to therapeutic vaccine development (such as vaccines directed against cancer epitopes); important differences will be identified in various sections as appropriate. The topics addressed in this Points to Consider article include regulatory guidelines for nonclinical vaccine studies, study design (including species selection), technical considerations in dosing and injection site collection, study end point evaluation, and data interpretation. The intent of this publication is to share learnings related to nonclinical studies to support vaccine development to help others as they move into this therapeutic area. [Box: see text]

The number of patients undergoing diagnostic radiology and radiation therapy procedures has increased drastically owing to improvements in cancer diagnosis and treatment, and consequently, patient survival. However, the risk of secondary malignancies owing to radiation exposure remains a matter of concern. We previously published three hybrid computational fetal phantoms, which contained 27 fetal organs, as a starting point for developing the whole hybrid computational pregnant phantom set, which is the final objective of this study. An International Commission on Radiological Protection (ICRP) reference female voxel model was converted to a non-uniform rational B-spline (NURBS) surface model to construct a hybrid computational female phantom as a pregnant mother for each fetal model. Both fetal and maternal organs were matched with the ICRP- 89 reference data. To create a complete standard pregnant computational phantom set at 20, 30, and 35 weeks of pregnancy, the model mother’s reproductive organs were removed, and fetal phantoms with appropriate placental and uterine models were added to the female pelvis using a 3D-modeling software. With the aid of radiological image sets that had originally been used to construct the fetal models, each fetal position and rotation inside the uterus were carefully adjusted to represent the real fetal locations inside the uterus. The major abdominal soft tissue organs below the diaphragm, namely the small intestine, large intestine, liver, gall bladder, stomach, pancreas, uterus, and urinary bladder, were removed from non-pregnant females. The resulting fetal phantom was positioned in the appropriate location, matching the original radiological image sets. An obstetrician-gynecologist reviewed the complete internal anatomy of all fetus phantoms and the pregnant women for accuracy, and suggested changes were implemented as needed. The remaining female anatomical tissues were reshaped and modified to accommodate the location of the fetus inside the uterus. This new series of hybrid computational pregnant phantom models provides realistic anatomical details that can be useful in evaluating fetal radiation doses in pregnant patients undergoing diagnostic imaging or radiotherapy procedures where realistic fetal computational human phantoms are required.

Minipigs are commonly utilized in dermal toxicology studies, necessitating documentation of background findings, including neoplastic lesions. We describe a case of a Yucatan minipig with a squamous cell carcinoma at the mucocutaneous junction of the lip. The neoplasm appeared grossly as a slightly raised area of skin with ulceration. Histologically, there were nests and trabeculae of neoplastic squamous epithelial cells undergoing keratinization. Multifocally, rafts of these cells were within lymphatic vessels. Squamous cell carcinoma has not previously been reported in Yucatan or other laboratory minipigs, however, has been reported uncommonly in nonlaboratory pot-bellied pigs. Although squamous cell carcinoma has been associated with ultraviolet exposure or papillomavirus in various species, this was unable to be confirmed in this case.

Wireline formation testing has evolved from discrete pressure measurements, introduced in the 1950s to measuring pressure gradients and fluid contacts since the 1970s. Technology introduced in the late 1980s and onwards added interval pressure transient testing, focused sampling, and downhole fluid analysis. Thirty years later, this paper shows data examples of a recently developed formation testing platform in a wide range of environments, and applications, that change how we plan, acquire, and use formation testing. The dual-flow-line architecture of the formation testing platform is designed to systematically address shortcomings of legacy technology, enabling focused sampling in the tightest conventional formations, as well as transient testing in high mobility environments. Specialized pre-job planning software evaluates conveyance options to minimize friction and borehole contact, estimates the available flow rate, compares cleanup performance of the different inlets, and simulates transient testing responses. During the operation, the platform uses hardware embedded automation algorithms that execute routine tasks in a consistent and highly efficient manner, leaving more time for the user to focus on data quality and value of the measurements. Case studies from Mexico, Norway, and the US demonstrate specific improvements in capability and performance. Field data from Mexico shows focused sampling of gas condensate from a heterogeneous submillidarcy carbonate formation in an HP/HT well drilled with oil-based mud. Controlled downhole decompression of crude oil in the flowline at a sampling station in Norway enabled real-time measurement of its bubblepoint pressure to within 6 psi of that measured in the laboratory. Another case study integrates accurate relative asphaltene gradients into an existing reservoir fluid study to prove reservoir connectivity across a large lateral distance in a producing field. Application of the dual packer subsystem demonstrates inflation within four minutes and pure oil samples within 90 minutes on station in a 1.5-md/cp fractured basement formation. The fine pump control at a low rate enabled sampling just below reservoir pressure in Alaska and a case from the Gulf of Mexico demonstrates the real-time impact of fluid properties on the understanding of reservoir architecture and completion design. The presented examples highlight the impact of downhole automation, define the new operating envelope for formation testing in the most challenging environments, and highlight how the technology development leads to decision making on a broad reservoir scale by providing contextual answers rather than an accumulation of facts and figures.

Thermosets play a key role in the modern plastics and rubber industries, comprising ~18% of polymeric materials with a worldwide annual production of 65 million tons. The high density of crosslinks that give these materials their useful properties comes at the expense of facile degradability and re/upcyclability. Here, using the high-performance industrial thermoset plastic poly-dicyclopentadiene (pDCPD) as a model system, we show that when a small number of cleavable bonds are selectively installed within the strands of thermoset plastics using a low-cost comonomer approach, the resulting materials display the same exceptional properties as the native material yet they can undergo triggered degradation to yield soluble, re/upcyclable products of controlled size and functionality. In contrast, installation of cleavable crosslinks, even at comparably high loadings, does not produce degradable materials. These findings shed new light on the topology of polymer networks, revealing cleavable bond location as a universal design principle for controlled thermoset degradation and re/upcycling.

Radiation exposure and associated radiation risks are major concerns for fetal development for pregnant patients who undergo radiation therapy or diagnostic imaging procedures. In order to accurately estimate the radiation dose to the fetus and assess the uncertainty of fetal position and rotation, three hybrid computational fetus phantoms were constructed using magnetic resonance imaging (MRI) for each fetus model as a starting point to construct a complete anatomically accurate fetus, gravid uterus, and placenta. A total of 27 fetal organs were outlined from radiological images via the Velocity Treatment Planning System. The DICOM-Structure set was imported to Rhinoceros software for further reconstruction of 3D fetus phantom model sets. All fetal organ masses were compared with ICRP-89 reference data. Our fetal model series corresponds to 20, 31, and 35 weeks of pregnancy, thus covering the second and third trimester. Fetal positions and locations were carefully adapted to represent the real fetus locations inside the uterus for each trimester of pregnancy. The new series of hybrid computational fetus models together with pregnant female models can be used in evaluating fetal radiation doses in diagnostic imaging and radiotherapy procedures.

This article provides a perspective on the development of polymer nanodielectrics for electrical insulation applications. It includes a short history of the development of the field, barriers to implementation, a chemical toolbox available for optimizing properties, some examples of potential commercial development, and the latest advances. It offers opinions on critical research needed to fully develop the models needed to predict the behavior and to develop design tools. Key findings include the need for quantification of nanofiller dispersion, investment in long term aging data research, better scale-up methods, a data resource that brings the broad data together in a format that enables faster scientific discovery, and a commercial entity willing to take the risk in implementing these promising materials.

The toxicologic pathologist plays a vital role in the scientific community, using their unique blend of diagnostic and investigative skills to advance biomedical research, public health, drug discovery, or regulatory practices. But what exactly do toxicologic pathologists contribute? Where do these specialized professionals work? How can toxicologic pathologists maximize their efficiency and potential? To enlighten students and trainees, as well as early- or mid-career toxicologic pathologists, or even those approaching retirement, the Career Development and Outreach Committee of the Society of Toxicologic Pathology (STP) sponsored a career development workshop entitled “Practical Strategies for Navigating Toxicologic Pathology in One’s Early Career…and Beyond!” in conjunction with the STP 37th annual symposium. The workshop featured toxicologic pathologists from contract research organizations and the pharmaceutical industry, who provided their perspectives on career preparation, evolving veterinary pathologist roles within various sectors of toxicologic pathology, the fundamentals of safety assessment, logistics of projects involving good laboratory practices, tools for effective interpretation and communication of anatomic and clinical pathology results, and a recap of scientific resources available to support the toxicologic pathologist in his or her journey. This article provides brief summaries of the talks presented during this career development workshop.

To understand the influence of nanofillers on the dielectric spectra of nanocomposites, this paper examines the low frequency dielectric responses for silicone/ZrO 2 nanocomposites with different filler loadings. The ZrO 2 nanoparticles were grafted with 1k and 10k molecular weight polydimethylsiloxane (PDMS) in order to achieve good dispersion in the PDMS matrix. The relative permittivity at infinite frequency and dc conductance were calculated through Kramers-Kronig relations and successfully differentiated from the measured spectra. The influence of temperature and filler loading on these two parameters and the shape of dielectric spectra is discussed.

This contribution examines a number of possibilities for achieving a measure of self-healing in dielectric structures locally damaged by being subjected to electrical stresses. The principle explored is the use of agencies which can be activated by the presence of photon irradiation arising from internal discharges due to field concentrations or gaseous inclusions. It is suggested that nanoparticles can provide a vehicle for introducing active moieties into a polymer nanodielectric through surface ligands already demonstrated to bring about electric strength enhancements. Preliminary results for one of these possibilities are provided in which photon-activated cross-linking is stimulated in an epoxy-SiO 2 nanocomposite subjected to partial discharge.

A toxicity/toxicokinetic swine-adapted infant formula feeding study was conducted in Domestic Yorkshire Crossbred Swine from lactation day 3 for 28 consecutive days during the preweaning period at carrageenan concentrations of 0, 300, 1000 and 2250 ppm under GLP guidelines. This study extends the observations in newborn baboons (McGill et al., 1977) to piglets and evaluates additional parameters: organ weights, clinical chemistry, special gastrointestinal tract stains (toluidine blue, Periodic Acid-Schiff), plasma levels of carrageenan; and evaluation of potential immune system effects. Using validated methods, immunophenotyping of blood cell types (lymphocytes, monocytes, B cells, helper T cells, cytotoxic T cells, mature T cells), sandwich immunoassays for blood cytokine evaluations (IL-6, IL-8, IL1β, TNF-α), and immunohistochemical staining of the gut for IL-8 and TNF-α were conducted. No treatment-related adverse effects at any carrageenan concentration were found on any parameter. Glucosuria in a few animals was not considered treatment-related. The high dose in this study, equivalent to ~430 mg/kg/day, provides an adequate margin of exposure for human infants, as affirmed by JECFA and supports the safe use of carrageenan for infants ages 0-12 weeks and older and infants with special medical needs.

A core–shell nano-scale mixing technique was applied to fabricate BaTiO3/glass nanocomposites in order to preserve the nano-grain dielectric properties of BaTiO3 after sintering and enhance the bulk composite energy storage capability. Coating layers of low melting glasses of lead borosilicate glass (65PbO–20B2O3–15SiO2, mol%) and bismuth borosilicate glass (65Bi2O3–20B2O3–15SiO2, mol%) were deposited onto BaTiO3 nanoparticles in chemical solution by a sol-precipitation method under ultrasonic agitation. Transmission electron microscopy (TEM) results confirmed the formation of core–shell nanostructures with controllable shell thicknesses between 2 and 18 nm. X-ray diffraction (XRD) patterns showed that no crystalline peaks were detected from the glass coating layer. Fourier transform infrared (FT-IR) spectra indicated a glass network structure of lead borosilicate glass and bismuth borosilicate glass, respectively. High densifications were achieved for both composites by sintering at low temperatures (≤900 °C). Noticeable grain growth was observed for the lead borosilicate glass-coated BaTiO3 (Pb-BT) composite while almost no grain growth was observed for the bismuth borosilicate glass-coated BaTiO3 (Bi-BT) nanocomposite. This disparity was attributed to the different interactions between the BaTiO3 core and two glasses during the sintering process, as revealed by the XRD study. Dielectric properties and energy storage capability of the Bi-BT nanocomposite were investigated in detail. The Bi-BT nanocomposite showed high polarization, high dielectric breakdown strength (≥1000 kV cm−1), postponed polarization saturation, and low remnant polarization with the discharge energy density of ∼10 J cm−3 at 1000 kV cm−1. Thus, the Bi-BT core–shell nanocomposite appears to be a promising material system for energy storage capacitor applications.

The central goal of dielectric nanocomposite design is to create a large interfacial area between the matrix polymer and nanofillers and to use it to tailor the properties of the composite. The interface can create sites for trapping electrons leading to increased dielectric breakdown strength (DBS). Nanoparticles with a bimodal population of covalently anchored molecules were created using ligand engineering. Electrically active short molecules (oligothiophene or ferrocene) and matrix compatible long poly(glycidyl methacrylate) (PGMA) chains comprise the bimodal brush. The dielectric breakdown strength was evaluated from recessed samples and dielectric spectroscopy was used to study the dielectric constant and loss as a function of frequency. The dielectric breakdown strength and permittivity increased considerably with only 2 wt% filler loading while the dielectric loss remained comparable to the reference epoxy. peerReviewed

Beginning in 1997 Michigan State University Mara Hyena Project investigators observed waxing and waning progression of oral and genital masses during long-term behavioral observations of a population of wild spotted hyenas (Crocuta crocuta) from the Masai Mara Game Reserve, Kenya. From 1999-2000, we darted adult spotted hyenas to obtain routine physiologic and hematologic data and collected small, raised, lobulated, pigmented masses from the oral or genital areas of eight animals. Microscopically, masses consisted of variably thickened epidermis with thick elongate rete pegs, prominent stratum spinosum, and few koilocytes, consistent with papillomavirus-induced lesions. Immunohistochemistry on formalin-fixed, paraffin-embedded papilloma tissue revealed positive intranuclear labeling for papillomavirus antigen in the superficial stratum granulosum and in sloughing keratin layers of multiple samples. Polymerase chain reaction on DNA extracts from tumor tissue amplified a papillomavirus-specific 418 base pair amplicon in the E1 ORF. Basic Local Alignment Search Tool analysis of the sequenced amplicon suggests a novel hyaenid papillomavirus. Confirmatory complete genomic sequencing was performed later by the Rega Institute in Belgium. To our knowledge, this is the first report of a papillomavirus in a Hyaenidae species. Spotted hyena social behavior might facilitate oral-genital transmission of papillomavirus in this population. Refereed/Peer-reviewed

Crosslinked polyethylene (XLPE)/silica nanocomposites are promising candidates for future cable insulation. While a significant number of studies have demonstrated improved dielectric properties in nanocomposites compared to XLPE, the performance of polyolefin nanocomposites in humid environments has not received much attention. This paper presents and explains the dielectric behavior of XLPE/silica nanocomposites in humid environments such as the decrease in AC breakdown strength, increases in loss and space charge formation, and the significant reduction in water tree aging. XLPE/silica nanocomposites are found to have an increased moisture uptake compared to the XLPE base polymer due to inclusion of silica particles. It is hypothesized that the formation of a concentric shell surrounding the particle with a high concentration of water (water shell), and the change in the inter-particle/cluster distances are two major factors governing the dielectric behavior in wet XLPE/silica nanocomposites. The dispersion and distribution of the nanofillers were quantified using a new tool and a method to reconstruct the 3D structure was used to determine the size of the water shell required for percolation. It was found that a water layer thickness of tens of nanometers could initiate percolation in the XLPE/silica nanocomposites studied. Notwithstanding that, water tree growth was substantially reduced in the XLPE/silica nanocomposites, and some speculative explanations are provided on the basis of the characteristics observed.

A finite element model was used to study the dielectric constant and breakdown strength of polymer composite filled with high aspect ratio fillers. The impact of composite microstructure and filler aspect ratio on the dielectric properties was investigated. The results were used to explain the experimental data for BaTiO 3 fiber filled poly(dimethyl siloxane) published previously. The effect of filler shape, aspect ratio distribution, curvature, grain boundary and alignment on the composite permittivity was studied. A model was proposed to correlate the composite microstructure, the electric field distribution in the polymer matrix, and the dielectric breakdown strength of composites.

A crystallizable glass which can precipitate barium titanate was added to BaTiO3 ceramics to study its effect on sintering behavior and dielectric properties of the composites. High densification (>95 % theoretical density) was achieved by addition of glass phase and the dielectric constant of composites was enhanced through the crystallization of glass phase. A composite with 90 wt% BaTiO3 and 10 wt% glass showed a dielectric constant of ~2,300 at room temperature at 1 kHz and a dielectric breakdown strength about 140 kV/cm.

Adding nano-sized fillers to epoxy has proven to be an effective method for improving dielectric breakdown strength (DBS). Evidence suggests that dispersion state, as well as chemistry at the filler-matrix interface can play a crucial role in property enhancement. Herein we investigate the contribution of both filler dispersion and surface chemistry on the AC dielectric breakdown strength of silica-epoxy nanocomposites. Ligand engineering was used to synthesize bimodal ligands onto 15nm silica nanoparticles consisting of long epoxy compatible, poly(glycidyl methacrylate) (PGMA) chains, and short, π-conjugated, electroactive surface ligands. Surface initiated RAFT polymerization was used to synthesize multiple graft densities of PGMA chains, ultimately controlling the dispersion of the filler. Thiophene, anthracene, and terthiophene were employed as π-conjugated surface ligands that act as electron traps to mitigate avalanche breakdown. Investigation of the synthesized multifunctional nanoparticles was effective in defining the maximum particle spacing or free space length (Lf) that still leads to property enhancement, as well as giving insight into the effects of varying the electronic nature of the molecules at the interface on breakdown strength. Optimization of the investigated variables was shown to increase the AC dielectric breakdown strength of epoxy composites as much as 34% with only 2wt% silica loading.

In this article, we report the synthesis of a new bimodal surface ligand morphology on silica nanoparticles. Combining grafting-to and grafting-from approaches, in this study, we demonstrated the efficacy of anthracene surface modification for improving the dielectric breakdown strength (DBS) under alternating-current and direct-current conditions and that of a matrix-compatible polymer brush for controlling the nanofiller (NF) dispersion. Ligand-modified spherical colloidal SiO2 nanoparticles (∼14 nm in diameter) were mixed into polypropylene, and the resulting dispersion was improved over the unmodified particles, as shown with transmission electron microscopy. The results suggest that the electronic structure of the anthracene-modified particle surface was critical to the improvement in DBS. In addition, the DBS of the composite was shown to depend on the dispersion state of the filler and the mode of stress; this indicated that the individually dispersed nanoparticles were not necessarily the optimal morphology for all stress conditions. Additionally, the precise nature of the matrix-compatible brush was less important than the NF dispersion it produced. The bimodal grafted architectural design has provided a promising solution for the control of the dispersion and surface properties, especially for high-molecular-weight polymer matrices. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 44347.

One of the major scientific challenges and societal concerns is to make informed decisions to ensure sustainable groundwater availability when facing deep uncertainties. A major computational requirement associated with this is on-demand computing for risk analysis to support timely decision. This paper presents a scientific modeling service called ‘ModflowOnAzure’ which enables large-scale ensemble runs of groundwater flow models to be easily executed in parallel in the Windows Azure cloud. Several technical issues were addressed, including the conjunctive use of desktop tools in MATLAB to avoid license issues in the cloud, integration of Dropbox with Azure for improved usability and ‘Drop-and-Compute,’ and automated file exchanges between desktop and the cloud. Two scientific use cases are presented in this paper using this service with significant computational speedup. One case is from Arizona, where six plausible alternative conceptual models and a streamflow stochastic model are used to eva...

A sustained-release DepoFoam injection formulation of bupivacaine (EXPAREL, 15 mg/mL) is currently being investigated for postsurgical analgesia via peripheral nerve block (PNB). Single-dose toxicology studies of EXPAREL (9, 18, and 30 mg/kg), bupivacaine solution (Bsol, 9 mg/kg), and saline injected around the brachial plexus nerve bundle were performed in rabbits and dogs. The endpoints included clinical pathology, pharmacokinetics, and histopathology evaluation on Day 3 and Day 15 (2/sex/group/period). EXPAREL resulted in a nearly 4-fold lower Cmax versus Bsol at the same dose. EXPAREL was well tolerated at doses up to 30 mg/kg. The only EXPAREL-related effect seen was minimal to mild granulomatous inflammation of adipose tissue around nerve roots (8 of 24 rabbits and 7 of 24 dogs) in the brachial plexus sites. The results indicate that EXPAREL was well tolerated in these models and did not produce nerve damage after PNB in rabbits and dogs.

EXPAREL (bupivacaine extended-release liposome injection), DepoFoam bupivacaine, is in development for prolonged postsurgical analgesia. Repeat-dose toxicity studies were conducted in rabbits and dogs to compare the potential local and systemic toxicities of EXPAREL and bupivacaine HCl (Bsol), and the reversibility of any effects. Dogs tolerated much larger doses than rabbits. EXPAREL-related minimal-to-moderate granulomatous inflammation was noted at the injection sites. In recovery animals, the granulomatous inflammation was observed less frequently and was characterized by an increased number of multinucleated giant cells. These effects were considered a normal response to liposomes and nonadverse. Rabbits are more sensitive than dogs. In rabbits, convulsions were noted with EXPAREL and more frequently with Bsol; a NOAEL was not identified. In dogs, EXPAREL was well tolerated (NOAEL > 30 mg/kg/dose). The cumulative exposure of EXPAREL in these studies is well in excess of the proposed maximum single-dose exposure that is intended in humans.

AVI-4658 is a phosphorodiamidate morpholino oligomer (PMO) designed to induce skipping of dystrophin exon 51 and restore its expression in patients with Duchenne muscular dystrophy (DMD). Preclinically, restoration of dystrophin in the dystrophic mdx mouse model requires skipping of exon 23, achieved with the mouse-specific PMO, AVI-4225. Herein, we report the potential toxicological consequences of exon skipping and dystrophin restoration in mdx mice using AVI-4225. We also evaluated the toxicological effects of AVI-4658 in both mdx and wild-type mice. In both studies, animals were dosed once weekly for 12 weeks up to the maximum feasible dose of 960 mg/kg per injection. Both AVI-4658 and AVI-4225 were well-tolerated at all doses. Findings in AVI-4225-treated animals were generally limited to mild renal tubular basophilia/vacuolation, without any significant changes in renal function and with evidence of reversing. No toxicity associated with the mechanism of action of AVI-4225 in a dystrophic animal was observed.

Results and assessment are provided from a nearly 10 year study of the application of a variety of diagnostic methods applied to the condition monitoring of generator stator insulation. The methods studied included various forms of Partial Discharge (PD) techniques and Electromagnetic Interference (EMI) in the frequency domain. The condition of a number of operating machines was tracked by the various techniques and, in most cases, the findings compared with the actual condition determined by subsequent inspection after the rotors had been removed. This has permitted the effectiveness of the various methods to be gauged and allowed an appraisal of the attendant best practices and pitfalls.