Realizing the full potential of magnetic nanoparticles (MNPs) in nanomedicine requires the optimization of their physical and chemical properties. Elucidation of the effects of these properties on ...clinical diagnostic or therapeutic properties, however, requires the synthesis or purification of homogenous samples, which has proved to be difficult. While initial simulations indicated that size-selective separation could be achieved by flowing magnetic nanoparticles through a magnetic field, subsequent in vitro experiments were unable to reproduce the predicted results. Magnetic field-flow fractionation, however, was found to be an effective method for the separation of polydisperse suspensions of iron oxide nanoparticles with diameters greater than 20 nm. While similar methods have been used to separate magnetic nanoparticles before, no previous work has been done with magnetic nanoparticles between 20 and 200 nm. Both transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis were used to confirm the size of the MNPs. Further development of this work could lead to MNPs with the narrow size distributions necessary for their in vitro and in vivo optimization.
Sandhoff disease (SD) is a fatal neurodegenerative disease caused by a mutation in the enzyme β-N-acetylhexosaminidase. Children with infantile onset SD develop seizures, loss of motor tone and ...swallowing problems, eventually reaching a vegetative state with death typically by 4years of age. Other symptoms include vertebral gibbus and cardiac abnormalities strikingly similar to those of the mucopolysaccharidoses. Isolated fibroblasts from SD patients have impaired catabolism of glycosaminoglycans (GAGs). To evaluate mucopolysaccharidosis-like features of the feline SD model, we utilized radiography, MRI, echocardiography, histopathology and GAG quantification of both central nervous system and peripheral tissues/fluids. The feline SD model exhibits cardiac valvular and structural abnormalities, skeletal changes and spinal cord compression that are consistent with accumulation of GAGs, but are much less prominent than the severe neurologic disease that defines the humane endpoint (4.5±0.5months). Sixteen weeks after intracranial AAV gene therapy, GAG storage was cleared in the SD cat cerebral cortex and liver, but not in the heart, lung, skeletal muscle, kidney, spleen, pancreas, small intestine, skin, or urine. GAG storage worsens with time and therefore may become a significant source of pathology in humans whose lives are substantially lengthened by gene therapy or other novel treatments for the primary, neurologic disease.
•SD cats exhibit cardiac and bony changes, GAG storage and excretion similar to MPS.•Bony changes are present in growth plate and in bone trabeculae.•Cardiac abnormalities include GAG storage in valves.•Intracranial AAV gene therapy corrects GAG storage in the brain and liver.
Background
Ivabradine selectively inhibits the pacemaker current of the sinoatrial node, slowing heart rate. Few studies have examined the effects of ivabradine on the mechanical properties of the ...heart after reperfused myocardial infarction (MI). Advances in ultrasound speckle‐tracking allow strain analyses to be performed in small‐animal models, enabling the assessment of regional mechanical function.
Methods and Results
After 1 hour of coronary occlusion followed by reperfusion, mice received 10 mg/kg per day of ivabradine dissolved in drinking water (n=10), or were treated as infarcted controls (n=9). Three‐dimensional high‐frequency echocardiography was performed at baseline and at days 2, 7, 14, and 28 post‐MI. Speckle‐tracking software was used to calculate intramural longitudinal myocardial strain (Ell) and strain rate. Standard deviation time to peak radial strain (SD Tpeak Err) and temporal uniformity of strain were calculated from short‐axis cines acquired in the left ventricular remote zone. Ivabradine reduced heart rate by 8% to 16% over the course of 28 days compared to controls (P<0.001). On day 28 post–MI, the ivabradine group was found to have significantly smaller end‐systolic volumes, greater ejection fraction, reduced wall thinning, and greater peak Ell and Ell rate in the remote zone, as well as globally. Temporal uniformity of strain and SD Tpeak Err were significantly smaller in the ivabradine‐treated group by day 28 (P<0.05).
Conclusions
High‐frequency ultrasound speckle‐tracking demonstrated decreased left ventricular remodeling and dyssynchrony, as well as improved mechanical performance in remote myocardium after heart rate reduction with ivabradine.
Cardiac magnetic resonance imaging has not been used previously to document the attenuation of left ventricular (LV) remodeling after systemic gene delivery. We hypothesized that targeted expression ...of extracellular superoxide dismutase (EcSOD) via the cardiac troponin-T promoter would protect the mouse heart against both myocardial infarction (MI) and subsequent LV remodeling.
Using reporter genes, we first compared the specificity, time course, magnitude, and distribution of gene expression from adeno-associated virus (AAV) 1, 2, 6, 8, and 9 after intravenous injection. The troponin-T promoter restricted gene expression largely to the heart for all AAV serotypes tested. AAV1, 6, 8, and 9 provided early-onset gene expression that approached steady-state levels within 2 weeks. Gene expression was highest with AAV9, which required only 3.15×10(11) viral genomes per mouse to achieve an 84% transduction rate. AAV9-mediated, cardiac-selective gene expression elevated EcSOD enzyme activity in heart by 5.6-fold (P=0.015), which helped protect the heart against both acute MI and subsequent LV remodeling. In acute MI, infarct size in EcSOD-treated mice was reduced by 40% compared with controls (P=0.035). In addition, we found that cardiac-selective expression of EcSOD increased myocardial capillary fractional area and decreased neutrophil infiltration after MI. In a separate study of LV remodeling, after a 60-minute coronary occlusion, cardiac magnetic resonance imaging revealed that LV volumes at days 7 and 28 post-MI were significantly lower in the EcSOD group compared with controls.
Cardiac-selective expression of EcSOD from the cardiac troponin-T promoter after systemic administration of AAV9 provides significant protection against both acute MI and LV remodeling.
•Highest resolution cat MRI anatomy is provided with 119 structures in three planes.•The constituents of the visual, auditory and motor pathways are clearly visualized.•Previously unresolvable ...cerebellar and vestibular nuclei are clearly identified.•The detail is sufficient to illustrate cerebral vasculature.•These findings are applicable to human diseases modeled in the cat.
Feline models of neurologic diseases, such as lysosomal storage diseases, leukodystrophies, Parkinson's disease, stroke and NeuroAIDS, accurately recreate many aspects of human disease allowing for comparative study of neuropathology and the testing of novel therapeutics. Here we describe in vivo visualization of fine structures within the feline brain that were previously only visible post mortem.
3Tesla MR images were acquired using T1-weighted (T1w) 3D magnetization-prepared rapid gradient echo (MPRAGE) sequence (0.4mm isotropic resolution) and T2-weighted (T2w) turbo spin echo (TSE) images (0.3mm×0.3mm×1mm resolution). Anatomic structures were identified based on feline and canine histology.
T2w high resolution MR images with detailed structural identification are provided in transverse, sagittal and dorsal planes. T1w MR images are provided electronically in three dimensions for unrestricted spatial evaluation.
Many areas of the feline brain previously unresolvable on MRI are clearly visible in three orientations, including the dentate, interpositus and fastigial cerebellar nuclei, cranial nerves, lateral geniculate nucleus, optic radiation, cochlea, caudal colliculus, temporal lobe, precuneus, spinocerebellar tract, vestibular nuclei, reticular formation, pyramids and rostral and middle cerebral arteries. Additionally, the feline brain is represented in three dimensions for the first time.
These data establish normal appearance of detailed anatomical structures of the feline brain, which provide reference when evaluating neurologic disease or testing efficacy of novel therapeutics in animal models.
Feline models of neurologic diseases, such as lysosomal storage diseases, leukodystrophies, Parkinson's disease, stroke and NeuroAIDS, accurately recreate many aspects of human disease allowing for ...comparative study of neuropathology and the testing of novel therapeutics. Here we describe in vivo visualization of fine structures within the feline brain that were previously only visible post mortem.
3Tesla MR images were acquired using T1-weighted (T1w) 3D magnetization-prepared rapid gradient echo (MPRAGE) sequence (0.4mm isotropic resolution) and T2-weighted (T2w) turbo spin echo (TSE) images (0.3mm×0.3mm×1mm resolution). Anatomic structures were identified based on feline and canine histology.
T2w high resolution MR images with detailed structural identification are provided in transverse, sagittal and dorsal planes. T1w MR images are provided electronically in three dimensions for unrestricted spatial evaluation.
Many areas of the feline brain previously unresolvable on MRI are clearly visible in three orientations, including the dentate, interpositus and fastigial cerebellar nuclei, cranial nerves, lateral geniculate nucleus, optic radiation, cochlea, caudal colliculus, temporal lobe, precuneus, spinocerebellar tract, vestibular nuclei, reticular formation, pyramids and rostral and middle cerebral arteries. Additionally, the feline brain is represented in three dimensions for the first time.
These data establish normal appearance of detailed anatomical structures of the feline brain, which provide reference when evaluating neurologic disease or testing efficacy of novel therapeutics in animal models.
•Creation of a novel, MRI-safe, pressure-based pain tolerance device.•Strong correlation between pain tolerance as assessed by MRI-safe device and as assessed by commercially available algometer ...(Experiment 1).•With additional pressure, increased activation in insula, anterior cingulate cortex (Experiment 2).•Activations found in Experiment 2 were comparable with activations found with other types of pain (e.g., thermal, mechanical).
One of the barriers to studying the behavioral and emotional effects of pain using functional Magnetic Resonance Imaging (fMRI) is the absence of a commercially available, MRI-compatible, pressure-based algometer to elicit pain. The present study sought to address this barrier through creation and validation of a novel MRI-safe apparatus capable of delivering incremental, measurable amounts of pressure inside a scanning bore.
We introduced an MR-safe device used to administer pressure-based pain. To test against a commercially available, MRI-incompatible algometer (AlgoMed), 199 participants reported their pain tolerance for both devices. A second experiment tested the validity of pressure-based pain in an MRI environment by comparing brain activation with established neural networks for pain. 10 participants performed an identical procedure to test for pain tolerance while being scanned in a 7T MRI scanner.
Results support the validity and reliability of our novel device. In Study 1, pain tolerance with this device was strongly correlated with pain tolerance as measured by a commercially available algometer (r=0.78). In Study 2, this device yielded BOLD activation within the insula (BA 13) and anterior cingulate gyrus (BA 24); as pressure increased, activation in these areas parametrically increased.
These findings correspond to other studies using thermal, electrical, or mechanical pain applications. Behavioral and functional data demonstrate that this new device is a valid method of administering pressure-related pain in MRI environments.
Our novel MRI-safe device is a valid instrument to measure and administer pressure-based pain.
Prior functional Magnetic Resonance Imaging (fMRI) studies have indicated increased neural activation when zinc nanoparticles are added to odorants in canines. Here we demonstrate that zinc ...nanoparticles up-regulate directional brain connectivity in parts of the canine olfactory network. This provides an explanation for previously reported enhancement in the odor detection capability of the dogs in the presence of zinc nanoparticles. In this study, we obtained fMRI data from awake and unrestrained dogs while they were being exposed to odorants with and without zinc nanoparticles, zinc nanoparticles suspended in water vapor, as well as just water vapor alone. We obtained directional connectivity between the brain regions of the olfactory network that were significantly stronger for the condition of odorant + zinc nanoparticles compared to just odorants, water vapor + zinc nanoparticles and water vapor alone. We observed significant strengthening of the paths of the canine olfactory network in the presence of zinc nanoparticles. This result indicates that zinc nanoparticles could potentially be used to increase canine detection capabilities in the environments of very low concentrations of the odorants, which would have otherwise been undetected.
The overproduction of reactive oxygen species has been linked to a wide array of health disorders. The ability to noninvasively monitor oxidative stress in vivo could provide substantial insight into ...the progression of these conditions and, in turn, could facilitate the development of better diagnosis and treatment options. A mononuclear Mn(II) complex with the redox-active ligand N,N'-bis(2,5-dihydroxybenzyl)-N,N'-bis(2-pyridinylmethyl)-1,2-ethanediamine (H
qtp2) was made and characterized. A previously prepared Mn(II) complex with a ligand containing a single quinol subunit was found to display a modest T
-derived relaxivity response to H
O
. The introduction of a second redox-active quinol both substantially improves the relaxivity response of the complex to H
O
and reduces the cytotoxicity of the sensor but renders the complex more susceptible to transmetalation. The addition of H
O
partially oxidizes the quinol subunits to para-quinones, concomitantly increasing the r
from 5.46 mM
s
to 7.17 mM
s
. The oxidation of the ligand enables more water molecules to coordinate to the metal ion, providing an explanation for the enhanced relaxivity. That the diquinol complex is only partially oxidized by H
O
is attributed to its activity as an antioxidant; the complex can both catalytically degrade superoxide and serve as a hydrogen atom donor.
To determine whether exercise on alternative terrain affects the development of the digital cushion and bony structures of the bovine foot.
20 weaned bull calves.
Two-month-old calves were randomly ...allocated to an exercise or control group. For 4 months, the control group was maintained in grass paddocks, and the exercise group was maintained in a 0.8-km lane with a mixed terrain of dirt, stones (0.32- to 0.95-cm pea gravel and 5-cm crusher run), and grass. Water and food for the exercise group were located at opposite ends of the lane; calves were fed twice daily, which ensured they walked 3.2 km/d. Pedometers were applied to all calves to measure distance traveled. All calves were slaughtered at 6 months of age. The right forefeet and hind feet were harvested for MRI and CT evaluation.
Control calves walked a mean of 1.1 km daily, whereas the exercised calves walked a mean of 3.2 km daily. Mean digital cushion volume and surface area were 25,335 mm(3) and 15,647 mm(2), respectively, for the exercised calves and 17,026 mm(3) and 12,745 mm(2), respectively, for the control calves. When weight was controlled, mean digital cushion volume and surface area for the exercise group were increased by 37.10% and 18.25%, respectively, from those for the control group.
Results indicated that exercise on alternative terrain increased the volume and surface area of the digital cushion of the feet of dairy calves, which should make them less susceptible to lameness.
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