Additional evidence supports GRM6 p.Thr178Met as a cause of congenital stationary night blindness in three horse breeds.

Congenital stationary night blindness (CSNB) is an ocular disorder characterized by nyctalopia. An autosomal recessive missense mutation in glutamate metabotropic receptor 6 (GRM6 c.533C>T, p.(Thr178Met)), called CSNB2, was previously identified in one Tennessee Walking Horse and predicted to reduce binding affinity of the neurotransmitter glutamate, impacting the retinal rod ON-bipolar cell signaling pathway. Thus, the first aim was to identify the allele frequency (AF) of CSNB2 in breeds with reported cases of CSNB and breeds closely related to the Tennessee Walking Horse. The second aim was to perform ocular examinations in multiple breeds to confirm the link between genotype and CSNB phenotype. In evaluating 3518 horses from 14 breeds, the CSNB2 allele was identified in nine previously unreported breeds. The estimated AF was highest in pacing Standardbreds (0.17) and lowest in American Quarter Horses (0.0010). Complete ophthalmic examinations and electroretinograms (ERG) were performed on 19 horses from three breeds, including one CSNB2 homozygote from each breed. All three CSNB2/CSNB2 horses had an electronegative ERG waveform under scotopic light conditions consistent with CSNB. The remaining 16 horses (seven CSNB2/N and nine N/N) had normal scotopic ERG results. All horses had normal photopic ERGs. This study provides additional evidence that GRM6 c.533C>T homozygosity is likely causal to CSNB in Tennessee Walking Horses, Standardbreds, and Missouri Fox Trotting Horses. Genetic testing is recommended for breeds with the CSNB2 allele to limit the production of affected horses. This study represents the largest across-breed identification of CSNB in the horse and suggests that this disorder is likely underdiagnosed.

Natural history of Tay-Sachs disease in sheep.

Tay-Sachs disease (TSD) is a fatal neurodegenerative disease caused by a deficiency of the enzyme ß-N-acetylhexosaminidase A (HexA). TSD naturally occurs in Jacob sheep is the only experimental model of TSD. TSD in sheep recapitulates neurologic features similar to juvenile onset and late onset TSD patients. Due to the paucity of human literature on pathology of TSD, a better natural history in the sheep TSD brain, which is on the same order of magnitude as a child's, is necessary for evaluating therapy and characterizing the pathological events that occur. To provide clinicians and researchers with a clearer understanding of longitudinal pathology in patients, we compare spectrum of clinical signs and brain pathology in mildly symptomatic (3-months), moderately symptomatic (6-months), or severely affected TSD sheep (humane endpoint at ~9-months of age). Increased GM2 ganglioside in the CSF of TSD sheep and a TSD specific biomarker on MRS (taurine) correlate with disease severity. Microglial activation and reactive astrocytes were observed globally on histopathology in TSD sheep with a widespread reduction in oligodendrocyte density. Myelination is reduced primarily in the forebrain illustrated by loss of white matter on MRI. GM2 and GM3 ganglioside were increased and distributed differently in various tissues. The study of TSD in the sheep model provides a natural history to shed light on the pathophysiology of TSD, which is of utmost importance due to novel therapeutics being assessed in human patients.

Long-term results (>1 year) in 19 dogs treated with MicroPulse transscleral diode cyclophotocoagulation for refractory glaucoma.

OBJECTIVE: To report the long-term (>1 year) outcome of MicroPulse transscleral diode cyclophotocoagulation (MP-TSCP) in dogs. ANIMALS STUDIED: Client owned dogs that underwent MP-TSCP at a veterinary referral center. PROCEDURE: Retrospective study of 19 dogs treated with MP-TSCP. Dogs were evaluated at a median follow-up time of 30.5 months postoperatively. Reported outcomes were intraocular pressure (IOP), retention or loss of vision, number of medications, and additional procedures performed. Variables associated with time to treatment failure were evaluated. RESULTS: Data from 19 dogs (24 eyes) was available. Median laser settings employed were 140 s and 2200 mW at 31.3% duty cycle. Long-term postoperative IOP was lower than preoperative IOP values (14 mmHg (IQR = 22 mmHg, range: 4-52 mmHg) versus 30 mmHg (IQR = 31 mmHg, range: 8-62 mmHg), respectively). Laser settings >2000 mW were associated with a significantly longer time to reported failure. MP-TSCP was the sole therapy performed in 16/24 eyes resulting in long-term IOP control in 13/24 eyes and retention of vision in 6 of the 14 sighted eyes. Repeat MP-TSCP was performed in 10/24 eyes. Eight of 24 eyes required additional procedures with long-term IOP control in 4/8 eyes. CONCLUSIONS: MicroPulse transscleral diode cyclophotocoagulation can be an effective treatment for refractory glaucoma in select cases. Higher laser settings increased time to reported failure, whereas age, glaucoma type, and preoperative IOP did not affect survival. MP-TSCP as sole therapy or coupled with additional glaucoma procedures controlled the IOP in 70% of cases.

Measurement of Three-Dimensional Structural Displacement Using a Hybrid Inertial Vision-Based System.

Accurate three-dimensional displacement measurements of bridges and other structures have received significant attention in recent years. The main challenges of such measurements include the cost and the need for a scalable array of instrumentation. This paper presents a novel Hybrid Inertial Vision-Based Displacement Measurement (HIVBDM) system that can measure three-dimensional structural displacements by using a monocular charge-coupled device (CCD) camera, a stationary calibration target, and an attached tilt sensor. The HIVBDM system does not require the camera to be stationary during the measurements, while the camera movements, i.e., rotations and translations, during the measurement process are compensated by using a stationary calibration target in the field of view (FOV) of the camera. An attached tilt sensor is further used to refine the camera movement compensation, and better infers the global three-dimensional structural displacements. This HIVBDM system is evaluated on both short-term and long-term synthetic static structural displacements, which are conducted in an indoor simulated experimental environment. In the experiments, at a 9.75 m operating distance between the monitoring camera and the structure that is being monitored, the proposed HIVBDM system achieves an average of 1.440 mm Root Mean Square Error (RMSE) on the in-plane structural translations and an average of 2.904 mm RMSE on the out-of-plane structural translations.

Tip cross-sectional geometry predicts the penetration depth of stone-tipped projectiles.

Understanding prehistoric projectile weaponry performance is fundamental to unraveling past humans' survival and the evolution of technology. One important debate involves how deeply stone-tipped projectiles penetrate a target. Theoretically, all things being equal, projectiles with smaller tip cross-sectional geometries should penetrate deeper into a target than projectiles with larger tip cross-sectional geometries. Yet, previous experiments have both supported and questioned this theoretical premise. Here, under controlled conditions, we experimentally examine fourteen types of stone-tipped projectile each possessing a different cross-sectional geometry. Our results show that both tip cross-sectional area (TCSA) and tip cross-sectional perimeter (TCSP) exhibit a strong, significant inverse relationship with target penetration depth, although TCSP's relationship is stronger. We discuss why our experimental results support what is mathematically predicted while previous experiments have not. Our results are consistent with the hypothesis that when stone tip cross-sectional geometries become smaller over time in particular contexts, this evolution may be due to the selection of these attributes for increased penetration.

Canine Models of Inherited Musculoskeletal and Neurodegenerative Diseases.

Mouse models of human disease remain the bread and butter of modern biology and therapeutic discovery. Nonetheless, more often than not mouse models do not reproduce the pathophysiology of the human conditions they are designed to mimic. Naturally occurring large animal models have predominantly been found in companion animals or livestock because of their emotional or economic value to modern society and, unlike mice, often recapitulate the human disease state. In particular, numerous models have been discovered in dogs and have a fundamental role in bridging proof of concept studies in mice to human clinical trials. The present article is a review that highlights current canine models of human diseases, including Alzheimer's disease, degenerative myelopathy, neuronal ceroid lipofuscinosis, globoid cell leukodystrophy, Duchenne muscular dystrophy, mucopolysaccharidosis, and fucosidosis. The goal of the review is to discuss canine and human neurodegenerative pathophysiologic similarities, introduce the animal models, and shed light on the ability of canine models to facilitate current and future treatment trials.