Case report: MRI findings with CNS blastomycosis in three domestic cats.

Blastomycosis is a systemic mycotic infection caused by dimorphic fungi. The disease is rare in cats, and reports on imaging findings with central nervous system (CNS) involvement are limited. Magnetic resonance imaging (MRI) was performed antemortem in three feline patients. Imaging findings that may allow prioritization of intracranial blastomycosis over other differential diagnoses included focal or multifocal intra-axial mass lesions with dural contact, lesion hypointensity on T2-weighted images and diffusion-weighted imaging/apparent diffusion coefficient map (DWI/ADC), strong and homogeneous contrast enhancement of the lesion(s), concurrent meningeal enhancement, marked perilesional edema and mass-effect, and ocular abnormalities. One cat was managed successfully and had a recurrence of CNS blastomycosis more than 4.5 years after the initial diagnosis. Repeat MRI at that point revealed both new and persistent (chronic) abnormalities.

The clinical utility of neostigmine administration in the diagnosis of acquired myasthenia gravis.

OBJECTIVE: To assess the clinical utility of neostigmine methylsulfate administration in the diagnosis of suspected acquired myasthenia gravis (MG) in dogs and cats. DESIGN: Retrospective study (2017-2019). SETTING: Five university teaching hospitals and 2 private referral hospitals. ANIMALS: Twenty-two dogs and 3 cats. Criteria for inclusion were clinical signs consistent with acquired MG, performance of a neostigmine challenge and acetylcholine receptor antibody titers. INTERVENTIONS: None. MEASUREMENTS & MAIN RESULTS: The route of neostigmine administration was recorded. Response to neostigmine challenge was determined via sequential evaluation of muscle strength and ambulation following administration of neostigmine methylsulfate. Response to neostigmine challenge was compared to acetylcholine receptor antibody titers, which were used as the biochemical gold standard in this study. Sixteen out of 22 dogs were diagnosed with acquired MG. Thirteen of 16 had a strong positive response to neostigmine challenge whereas 3 of 16 had no response. Two out of 3 dogs with polymyositis also had a strong positive response to neostigmine challenge. Weak positive results were seen with intracranial neoplasia (n = 1) and a dog with dilated cardiomyopathy and coxofemoral joint disease (n = 1). One cat was diagnosed with acquired MG and had a positive response to neostigmine challenge. Two cats had no response to neostigmine challenge and were diagnosed with alternate conditions. Two cats were premedicated with glycopyrrolate, one of which had a mild adverse response to neostigmine challenge (sialorrhea and mild transient tremors). Three out of 22 dogs had minimal adverse effects (sialorrhea and 1 dog with muscle tremors). CONCLUSIONS: The neostigmine challenge appears to be safe and viable alternative to the previously utilized edrophonium challenge, particularly when weak positive responses are considered negative for acquired MG. Polymyositis cases may have a false positive response to neostigmine challenge.

A mixed breed dog with neuronal ceroid lipofuscinosis is homozygous for a CLN5 nonsense mutation previously identified in Border Collies and Australian Cattle Dogs.

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterized by progressive declines in neurological functions following normal development. The NCLs are distinguished from similar disorders by the accumulation of autofluorescent lysosomal storage bodies in neurons and many other cell types, and are classified as lysosomal storage diseases. At least 13 genes contain pathogenic sequence variants that underlie different forms of NCL. Naturally occurring canine NCLs can serve as models to develop better understanding of the disease pathologies and for preclinical evaluation of therapeutic interventions for these disorders. To date 14 sequence variants in 8 canine orthologs of human NCL genes have been found to cause progressive neurological disorders similar to human NCLs in 12 different dog breeds. A mixed breed dog with parents of uncertain breed background developed progressive neurological signs consistent with NCL starting at approximately 11 to 12 months of age, and when evaluated with magnetic resonance imaging at 21 months of age exhibited diffuse brain atrophy. Due to the severity of neurological decline the dog was euthanized at 23 months of age. Cerebellar and cerebral cortical neurons contained massive accumulations of autofluorescent storage bodies the contents of which had the appearance of tightly packed membranes. A whole genome sequence, generated with DNA from the affected dog contained a homozygous C-to-T transition at position 30,574,637 on chromosome 22 which is reflected in the mature CLN5 transcript (CLN5: c.619C > T) and converts a glutamine codon to a termination codon (p.Gln207Ter). The identical nonsense mutation has been previously associated with NCL in Border Collies, Australian Cattle Dogs, and a German Shepherd-Australian Cattle Dog mix. The current whole genome sequence and a previously generated whole genome sequence for an Australian Cattle Dog with NCL share a rare homozygous haplotype that extends for 87 kb surrounding 22: 30, 574, 637 and includes 21 polymorphic sites. When genotyped at 7 of these polymorphic sites, DNA samples from the German Shepherd-Australian Cattle Dog mix and from 5 Border Collies with NCL that were homozygous for the CLN5: c.619 T allele also shared this homozygous haplotype, suggesting that the NCL in all of these dogs stems from the same founding mutation event that may have predated the establishment of the modern dog breeds. If so, the CLN5 nonsence allele is probably segregating in other, as yet unidentified, breeds. Thus, dogs exhibiting similar NCL-like signs should be screened for this CLN5 nonsense allele regardless of breed.

Incremental scattering of the A0 Lamb wave mode from a notch emanating from a through-hole.

Lamb wave scattering from a crack originating at a through-hole is of practical importance because of the abundance of fastener holes used in engineering structures. Notches are often used to simulate cracks so that Lamb wave methods can be more conveniently investigated in the laboratory. A linear, three-dimensional finite element model is employed in this paper to study incremental scattering of the fundamental anti-symmetric (A0) Lamb wave mode from notches emanating from through-holes. The term "incremental scattering" refers to the change in scattering caused by introduction of the notch and is motivated by structural health monitoring for which transducers are fixed and signal changes are interpreted to detect damage. Far-field angular scattering patterns are generated for multiple incident angles and frequencies, and such patterns are experimentally validated at one frequency by laser vibrometry measurements. Comparisons are made between a vertical notch alone (no hole) and notches located above and below the through-hole. Additionally, holes of different sizes are considered to investigate the effect of hole diameter on incremental scattering patterns. Results show that the presence, location and size of the through-hole affect both the shape and strength of notch incremental scattering patterns.

Congenital Myasthenic Syndrome in a Mixed Breed Dog.

A 6-month-old, male, intact mixed breed dog was presented for a 3-month history of progressive generalized weakness. Neurologic examination revealed non-ambulatory tetraparesis, weakness of the head and neck, and decreased withdrawal reflexes in all limbs consistent with a generalized neuromuscular disorder. Electromyography and motor nerve conduction velocity were normal. Repetitive nerve stimulation showed a decremental response of the compound muscle action potential with improvement upon intravenous administration of edrophonium chloride. The serum acetylcholine receptor (AChR) antibody titer was within reference range. Cerebrospinal fluid analysis was unremarkable. A presumptive diagnosis of post-synaptic congenital myasthenic syndrome (CMS) was made. Treatment with pyridostigmine bromide was initiated with titrated increases in dosage resulting in an incomplete improvement in clinical signs. The dog was euthanized 2 months after initiation of treatment due to poor quality of life. Immunostaining for localization of antibodies against end-plate proteins in muscle biopsies was negative. Immunofluorescence staining for AChRs in external intercostal muscle biopsies showed absence of AChRs and biochemical quantitation showed a markedly decreased concentration of AChRs with no detectable AChR-bound autoantibody which confirmed the diagnosis of a CMS. Evaluation for the CHRNE mutation previously identified as the causative mutation of CMS in Jack Russell Terriers was performed and was negative. This is the first reported confirmed case of CMS in a mixed breed dog and provides a review of typical clinical and diagnostic findings as well as treatment considerations.

Quantification of Shear Wave Scattering From Far-Surface Defects via Ultrasonic Wavefield Measurements.

Nondestructive evaluation methods rely on prior knowledge of the expected interaction of ultrasonic waves with defects to inform detection and characterization decisions. Wavefield imaging, which refers to the measurement of signals originating from a spatially fixed source on a 2-D rectilinear grid, can be applied to visualize the effect of a subsurface scatterer on surface-measured wave motion. Here, obliquely incident shear waves are directed at the far surface of a plate containing a through-hole using the well-known angle-beam ultrasonic inspection method. A laser vibrometer and laboratory scanner are used to record the resulting out-of-plane motion on the plate surface in the vicinity of the through-hole both before and after a far-surface corner notch is introduced and subsequently enlarged. Waves scattered from the notch are isolated from the incident and hole-scattered waves via baseline subtraction of wavefields. The scattered wavefields are then filtered in the frequency-wavenumber domain to separate Rayleigh, shear, and longitudinal contributions to the scattered wavefield. The filtered wavefields are interpolated in space to obtain 2-D radial wavefield slices originating at the base of the notch. Each radial slice is analyzed to quantify scattering as a function of observation direction, resulting in Rayleigh, shear, and longitudinal scattering profiles for each notch size. The results are compared for four different notch sizes and two transducer orientations.

Pharmacokinetics of zonisamide following rectal administration to healthy dogs.

OBJECTIVE To evaluate the pharmacokinetics of zonisamide following rectal administration of 20 or 30 mg/kg suspended in sterile water or polyethylene glycol (PEG) to healthy dogs and determine whether either dose resulted in plasma zonisamide concentrations within the recommended therapeutic target range (10 to 40 µg/mL). ANIMALS 8 healthy mixed-breed dogs. PROCEDURES Each dog received each of 2 doses (20 or 30 mg/kg) of zonisamide suspended in each of 2 delivery substrates (sterile water or PEG) in a randomized crossover study with a 7-day washout period between phases. A blood sample was collected from each dog immediately before and at predetermined times for 48 hours after zonisamide administration. Plasma zonisamide concentrations were determined by high-performance liquid chromatography, and data were analyzed with a noncompartmental model. RESULTS Mean maximum plasma concentration, time to maximum plasma concentration, mean residence time, and elimination half-life did not differ significantly among the 4 treatments. The mean maximum plasma concentration for all 4 treatments was less than the therapeutic target range. The mean ± SD area under the concentration-time curve for the 30 mg/kg-in-water treatment (391.94 ± 237.00 h•µg/mL) was significantly greater than that for the 20 mg/kg-in-water (146.19 ± 66.27 h•µg/mL) and 20 mg/kg-in-PEG (87.09 ± 96.87 h•µg/mL) treatments. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that rectal administration of zonisamide at doses of 20 and 30 mg/kg failed to achieve plasma zonisamide concentrations within the recommended therapeutic target range. Therefore, rectal administration of zonisamide cannot be recommended as a suitable alternative to oral administration.

Clinical Features of Spinal Cord Hemangioblastoma in a Dog.

A 2-year-old male, intact Yorkshire terrier presented with a 1-month history of progressive paraparesis. Neurological examination revealed paraplegia with absent deep pain perception, decreased right pelvic limb withdrawal reflex, and lumbar pain consistent with an L4-S2 neurolocalization. Magnetic resonance imaging (MRI) showed a single, well-demarcated, intramedullary mass centered over the L3-4 disk space. A hemilaminectomy was performed, and the mass was removed en bloc. Histopathological evaluation was consistent with a hemangioblastoma. Follow-up MRI 9 months after surgery showed no evidence of tumor recurrence, and the dog was ambulatory paraparetic at that time. This case is consistent with a previous histopathological report of spinal cord hemangioblastoma in a dog and provides additional clinical information regarding diagnosis, treatment, and outcome associated with this tumor type.

A methodology for estimating guided wave scattering patterns from sparse transducer array measurements.

Ultrasonic guided waves are one of the primary methods being investigated for structural health monitoring of plate-like components. A common practice is to collect measurements from a sparse transducer array using the pitch-catch method, which enables interrogation of defects from multiple directions. Thus, knowledge of how guided waves scatter from defects is very useful for detection, localization, and characterization of damage. One way to describe scattering patterns is with a matrix indexed by incident angle and scattered angle, and sparse array measurements essentially sample this matrix. A methodology is proposed in this paper to estimate the complete scattering matrix from these limited array measurements. First, recorded array signals are compensated for geometric spreading loss, wave packet spreading loss, and transducer differences. Initial scattering values are then extracted from the scattered wave packets after baseline subtraction and are augmented using transducer reciprocity and any a priori knowledge of defect geometric symmetry. Finally, radial basis function interpolation is performed on these values to obtain the complete scattering matrix. Scattering matrices are generated from experimental data by cutting notches of different lengths originating from a through-hole in an aluminum plate specimen that is instrumented with a sparse transducer array. The methodology is validated by laser vibrometry measurements performed on a nominally identical specimen for one notch length.

Block-sparse reconstruction and imaging for Lamb wave structural health monitoring.

A frequently investigated paradigm for monitoring the integrity of plate-like structures is a spatially-distributed array of piezoelectric transducers, with each array element capable of both transmitting and receiving ultrasonic guided waves. This configuration is relatively inexpensive and allows interrogation of defects from multiple directions over a relatively large area. Typically, full sets of pairwise transducer signals are acquired by exciting one transducer at a time in a round-robin fashion. Many algorithms that operate on such data use differential signals that are created by subtracting prerecorded baseline signals, leaving only signal differences introduced by scatterers. Analysis methods such as delay-and-sum imaging operate on these signals to detect and locate point-like defects, but such algorithms have limited performance and suffer when potential scatterers have high directionality or unknown phase-shifting behavior. Signal envelopes are commonly used to mitigate the effects of unknown phase shifts, but this further reduces performance. The blocksparse technique presented here uses a different principle to locate damage: each pixel is assumed to have a corresponding multidimensional linear scattering model, allowing any possible amplitude and phase shift for each transducer pair should a scatterer be present. By assuming that the differential signals are linear combinations of a sparse subset of these models, it is possible to split such signals into location-based components. Results are presented here for three experiments using aluminum and composite plates, each with a different type of scatterer. The scatterers in these images have smaller spot sizes than delay-and-sum imaging, and the images themselves have fewer artifacts. Although a propagation model is required, block-sparse imaging performs well even with a small number of transducers or without access to dispersion curves.

Model-based imaging of damage with Lamb waves via sparse reconstruction.

Ultrasonic guided waves are gaining acceptance for structural health monitoring and nondestructive evaluation of plate-like structures. One configuration of interest is a spatially distributed array of fixed piezoelectric devices. Typical operation consists of recording signals from all transmit-receive pairs and subtracting pre-recorded baselines to detect changes, possibly due to damage or other effects. While techniques such as delay-and-sum imaging as applied to differential signals are both simple and capable of detecting flaws, their performance is limited, particularly when there are multiple damage sites. Here a very different approach to imaging is considered that exploits the expected sparsity of structural damage; i.e., the structure is mostly damage-free. Differential signals are decomposed into a sparse linear combination of location-based components, which are pre-computed from a simple propagation model. The sparse reconstruction techniques of basis pursuit denoising and orthogonal matching pursuit are applied to achieve this decomposition, and a hybrid reconstruction method is also proposed and evaluated. Noisy simulated data and experimental data recorded on an aluminum plate with artificial damage are considered. Results demonstrate the efficacy of all three methods by producing very sparse indications of damage at the correct locations even in the presence of model mismatch and significant noise.

Food label accuracy of common snack foods.

UNLABELLED: Nutrition labels have raised awareness of the energetic value of foods, and represent for many a pivotal guideline to regulate food intake. However, recent data have created doubts on label accuracy. OBJECTIVE: We tested label accuracy for energy and macronutrient content of prepackaged energy-dense snack food products. We measured "true" caloric content of 24 popular snack food products in the U.S. and determined macronutrient content in 10 selected items. DESIGN AND METHODS: Bomb calorimetry and food factors were used to estimate energy content. Macronutrient content was determined according to Official Methods of Analysis. Calorimetric measurements were performed in our metabolic laboratory between April 20th and May 18th and macronutrient content was measured between September 28th and October 7th of 2010. RESULTS AND CONCLUSION: Serving size, by weight, exceeded label statements by 1.2% [median] (25th percentile -1.4, 75th percentile 4.3, P = 0.10). When differences in serving size were accounted for, metabolizable calories were 6.8 kcal (0.5, 23.5, P = 0.0003) or 4.3% (0.2, 13.7, P = 0.001) higher than the label statement. In a small convenience sample of the tested snack foods, carbohydrate content exceeded label statements by 7.7% (0.8, 16.7, P = 0.01); however fat and protein content were not significantly different from label statements (-12.8% [-38.6, 9.6], P = 0.23; 6.1% [-6.1, 17.5], P = 0.32). Carbohydrate content explained 40% and serving size an additional 55% of the excess calories. Among a convenience sample of energy-dense snack foods, caloric content is higher than stated on the nutrition labels, but overall well within FDA limits. This discrepancy may be explained by inaccurate carbohydrate content and serving size.

In situ estimation of applied biaxial loads with Lamb waves.

Spatially distributed arrays of piezoelectric disks are being applied to monitor structural integrity using Lamb waves. Applied loads directly affect waves propagating between array elements because of dimensional changes and the acoustoelastic effect. Resulting changes in phase velocity depend upon the propagation direction as well as the Lamb wave mode and frequency. This paper shows from numerical solutions of the acoustoelastic wave equation for an isotropic plate that it is possible to decouple the effects of a homogeneous biaxial stress into its two principal components. As a consequence of both this decoupling and material isotropy, the acoustoelastic response of a specific mode and frequency is described by only two constants, which can be determined from a uniaxial loading experiment. Using this formulation, a method is developed and verified via simulations to estimate an arbitrary biaxial load from phase velocity changes measured along multiple directions of propagation. Results from uniaxial loading experiments on two different plates further demonstrate the efficacy of the method. It is also shown that opening fatigue cracks may significantly degrade results by interfering with Lamb wave direct arrivals, but that this degradation can be mitigated by using a reduced set of data from unaffected paths of propagation.

Chirp excitation of ultrasonic guided waves.

Most ultrasonic guided wave methods require tone burst excitations to achieve some degree of mode purity while maintaining temporal resolution. In addition, it is often desirable to acquire data using multiple frequencies, particularly during method development when the best frequency for a specific application is not known. However, this process is inconvenient and time-consuming, particularly if extensive signal averaging at each excitation frequency is required to achieve a satisfactory signal-to-noise ratio. Both acquisition time and data storage requirements may be prohibitive if responses from many narrowband tone burst excitations are measured. Here chirp excitations are utilized to address the need to both test at multiple frequencies and achieve a high signal-to-noise ratio to minimize acquisition time. A broadband chirp is used to acquire data at a wide range of frequencies, and deconvolution is applied to extract multiple narrowband responses. After optimizing the frequency and duration of the desired tone burst excitation, a long-time narrowband chirp is used as the actual excitation, and the desired tone burst response is similarly extracted during post-processing. Results are shown that demonstrate the efficacy of both broadband and narrowband chirp excitations.

Acoustoelastic Lamb wave propagation in biaxially stressed plates.

Acoustoelasticity, or the change in elastic wave speeds with stress, is a well-studied phenomenon for bulk waves. The effect of stress on Lamb waves is not as well understood, although it is clear that anisotropic stresses will produce anisotropy in the Lamb wave dispersion curves. Here the theory of acoustoelastic Lamb wave propagation is developed for isotropic media subjected to a biaxial, homogeneous stress field. It is shown that, as expected, dispersion curves change anisotropically for most stresses, modes, and frequencies. Interestingly, for some mode-frequency combinations, changes in phase velocity are isotropic even for a biaxial stress field. Theoretical predictions are compared to experimental results for several Lamb wave modes and frequencies for uniaxial loads applied to an aluminum plate, and the agreement is reasonably good.

Dystrophin-compromised sarcoglycan-δ-knockout diaphragm requires full wild-type embryonic stem cell reconstitution for correction.

Limb-girdle muscular dystrophy-2F (LGMD-2F) is an incurable degenerative muscle disorder caused by a mutation in the sarcoglycan-δ (SGδ)-encoding gene (SGCD in humans). The lack of SGδ results in the complete disruption of the sarcoglycan complex (SGC) in the skeletal and cardiac muscle within the larger dystrophin-glycoprotein complex (DGC). The long-term consequences of SG ablation on other members of the DGC are currently unknown. We produced mosaic mice through the injection of wild-type (WT) embryonic stem cells (ESCs) into SGδ-knockout (KO) blastocysts. ESC-derived SGδ was supplied to the sarcolemma of 18-month-old chimeric muscle, which resulted in the restoration of the SGC. Despite SGC rescue, and contrary to previous observations obtained with WT/mdx chimeras (a mouse rescue paradigm for Duchenne muscular dystrophy), low levels of ESC incorporation were insufficient to produce histological corrections in SGδ-KO skeletal muscle or heart. The inefficient process of ESC rescue was more evident in the SGδ-KO diaphragm, which had reduced levels of dystrophin and no compensatory utrophin, and needed almost full WT ESC reconstitution for histological improvement. The results suggest that the SGδ-KO mouse model of LGMD is not amenable to ESC treatment.

A second case of Marburg's variant of multiple sclerosis with vasculitis and extensive demyelination.

Marburg's variant of multiple sclerosis is a rapidly progressive and malignant form of multiple sclerosis (MS) that usually leads to severe disability or death within weeks to months without remission. Few cases have been described in the literature since the original description by Marburg. The classic pathological findings usually include highly destructive zones of extensive demyelination, necrosis with dense cellular infiltrate, and giant reactive astrocytes. We report a case of a 31-year-old woman with Marburg's variant of MS who, over a period of eight months, became totally disabled, blind, and quadriplegic, with vocal cord paralysis, requiring a tracheostomy. The patient underwent diagnostic stereotactic brain biopsy. Clinical findings, magnetic resonance imaging (MRI), serologic and cerebrospinal fluid (CSF) findings, and neuropathology are discussed. MRI showed extensive white matter involvement in the brain and spinal cord that continuously progressed over time. A diagnostic stereotactic brain biopsy revealed extensive active demyelination with unexpected finding of active vasculitis and fibrinoid necrosis with a vascular inflammatory cell infiltrate, including polymorphonuclear neutrophils and rare eosinophils. Serologic work-up for vasculitis and neuromyelitis optica was unremarkable and the CSF showed only one oligoclonal band (OCB) not present in serum. This is the second case of Marburg's variant of MS that demonstrated both demyelination and vasculitis. In our case these features were demonstrated simultaneously, even though the demyelination was the predominant pathological finding. Since vasculitis is not a feature of classic MS, these findings pose the question as to whether Marburg's variant of MS is a true variant or different entity altogether.

Differential requirement for utrophin in the induced pluripotent stem cell correction of muscle versus fat in muscular dystrophy mice.

Duchenne muscular dystrophy (DMD) is an incurable degenerative muscle disorder. We injected WT mouse induced pluripotent stem cells (iPSCs) into mdx and mdx∶utrophin mutant blastocysts, which are predisposed to develop DMD with an increasing degree of severity (mdx <<< mdx∶utrophin). In mdx chimeras, iPSC-dystrophin was supplied to the muscle sarcolemma to effect corrections at morphological and functional levels. Dystrobrevin was observed in dystrophin-positive and, at a lesser extent, utrophin-positive areas. In the mdx∶utrophin mutant chimeras, although iPSC-dystrophin was also supplied to the muscle sarcolemma, mice still displayed poor skeletal muscle histopathology, and negligible levels of dystrobrevin in dystrophin- and utrophin-negative areas. Not only dystrophin-expressing tissues are affected by iPSCs. Mdx and mdx∶utrophin mice have reduced fat/body weight ratio, but iPSC injection normalized this parameter in both mdx and mdx∶utrophin chimeras, despite the fact that utrophin was compromised in the mdx∶utrophin chimeric fat. The results suggest that the presence of utrophin is required for the iPSC-corrections in skeletal muscle. Furthermore, the results highlight a potential (utrophin-independent) non-cell autonomous role for iPSC-dystrophin in the corrections of non-muscle tissue like fat, which is intimately related to the muscle.