PurPose: Macrophages play a key role in axonal regeneration because they secrete IL-6 that is nec... more PurPose: Macrophages play a key role in axonal regeneration because they secrete IL-6 that is necessary for axonal guidance and remyelination. Pro-inflammatory cytokines stimulate macrophage migration into the lesion sites which is necessary for the removal of cell debris and Schwann cell invasion as guidance for axonal outgrowth followed by remyelination. α1-antitrypsin (AAT) is an acute phase protein and it is shown to express anti-inflammatory characteristics in neutrophil and monocyte/macrophage driven models in vitro and in vivo. We asked a question whether AAT can affect regeneration of injured peripheral nerve fibers by initial macrophage mobilization. We have established several models to study peripheral nerve injuries in small animals. In the rat sciatic nerve crush model we developed a standardized method for investigation of nerve regeneration parameters. We could demonstrate that axonal sprouting, as well as myelin sheaths and functional outcome can be improved by adjunct AAT therapy.
Morphological analyses are key outcome assessments for nerve regeneration studies but are histori... more Morphological analyses are key outcome assessments for nerve regeneration studies but are historically limited to tissue sections. Novel optical tissue clearing techniques enabling three-dimensional imaging of entire organs at a subcellular resolution have revolutionized morphological studies of the brain. To extend their applicability to experimental nerve repair studies we adapted these techniques to nerves and their motor and sensory targets in rats. The solvent-based protocols rendered harvested peripheral nerves and their target organs transparent within 24 hours while preserving tissue architecture and fluorescence. The optical clearing was compatible with conventional laboratory techniques, including retrograde labeling studies, and computational image segmentation, providing fast and precise cell quantitation. Further, optically cleared organs enabled three-dimensional morphometry at an unprecedented scale including dermatome-wide innervation studies, tracing of intramuscular nerve branches or mapping of neurovascular networks. Given their wide-ranging applicability, rapid processing times, and low costs, tissue clearing techniques are likely to be a key technology for next-generation nerve repair studies. All procedures were approved by the Hospital for Sick Children’s Laboratory Animal Services Committee (49871/9) on November 9, 2019.
Purpose: The cornea is the window through which we see the world and is one of the most densely i... more Purpose: The cornea is the window through which we see the world and is one of the most densely innervated structures in the body. Besides providing protective sensory input, corneal nerves have been postulated to stimulate limbal stem cells (LSCs), hence governing corneal epithelial maintenance and recovery. Loss of corneal innervation, through injury, diabetes, tumors, infections, and even improper contact lens use, leads to neurotrophic keratopathy (NK), a degenerative corneal disease that is characterized by corneal epithelial breakdown, scarring, and permanent vision loss1. The only non-invasive treatment option for NK is the human recombinant nerve growth factor (rhNGF), but the short half-life of exogenous neurotrophins-based therapies make this therapeutic approach less effective2. Development of the small molecule ligands for neurotrophins receptors that have better pharmacokinetics and plasma stability showed promising results in the treatment of several neurodegenerative ...
This is a digitally enhanced text. Readers can also see the coverage of this topic area in the se... more This is a digitally enhanced text. Readers can also see the coverage of this topic area in the second edition of Neuroglia. The second edition of Neuroglia was first published digitally in Oxford Scholarship Online and the bibliographic details provided, if cited, will direct people to that version of the text. Readers can also see the coverage of this topic area in the ...
American Journal of Physiology-heart and Circulatory Physiology, Nov 1, 1991
The purpose of this study was to determine how cardiomyopathy affects the beat-to-beat regulation... more The purpose of this study was to determine how cardiomyopathy affects the beat-to-beat regulation of contractile force in cardiac muscle. Isometric force produced by left atria from 80- to 85-day-old normal and cardiomyopathic (CM) hamsters was measured in vitro at 29 degrees C in 2.5 and 6.0 mM Ca2+. During steady-state stimulation at 1 Hz, single test stimuli were interpolated at varying test intervals (0.3-600 s). The force-interval curves were fitted with an equation using five parameters to define the curve and were compared under different conditions; the recovery of force after long rest intervals was fitted with a single exponential curve. Results showed that the force-interval curves were similar in normal and CM atria except that force was depressed at all intervals in 2.5 mM external Ca2+ concentration ([Ca2+]e) and that the parameter U(0), reflecting force produced at short test intervals, tended to be lower in CM muscles. At high [Ca2+]e (6.0 mM) the force-interval curves were similar, but recovery of steady-state force after long test intervals was much slower in CM atria (tau = 77.3 +/- 8.5 s, n = 11) than in normal atria (tau = 30.5 +/- 3.9 s, n = 11). Recovery was also slower at 2.5 mM [Ca2+]e. These findings suggest that, on a beat-to-beat basis, there is less Ca2+ available in intracellular compartments in the CM heart.
Semi-quantitative analysis revealed that the synthesis of the protein product of the p75 gene is ... more Semi-quantitative analysis revealed that the synthesis of the protein product of the p75 gene is rapidly enhanced to reach a peak within the 1 month after denervation. After that it gradually decreased and was barely detectable 6 months following denervation. Double ...
Journal of plastic, reconstructive & aesthetic surgery : JPRAS, 2020
Diagnosing the site and severity of peripheral nerve injuries can be challenging for clinicians. ... more Diagnosing the site and severity of peripheral nerve injuries can be challenging for clinicians. The current gold standards of evaluation with clinical examination and electrophysiology have respective limitations, particularly with determining the prognosis for spontaneous recovery. Current imaging techniques with ultrasound, computed tomography, and magnetic resonance imaging (MRI) may be used as adjuncts in the evaluation of peripheral nerve injuries but are limited in sensitivity and accuracy. Diffusion tensor imaging (DTI) is a recent advancement in MRI sequences that shows promise in evaluating peripheral nerve injuries. Unlike the qualitative traditional MRI, DTI captures the pattern of water diffusion along the nerves and provides quantitative information regarding the integrity of axons. Additionally, DTI images can be reconstructed into 3D images with tractography. This technique is well-established in the central nervous system but is only starting to be applied in the pe...
PurPose: Macrophages play a key role in axonal regeneration because they secrete IL-6 that is nec... more PurPose: Macrophages play a key role in axonal regeneration because they secrete IL-6 that is necessary for axonal guidance and remyelination. Pro-inflammatory cytokines stimulate macrophage migration into the lesion sites which is necessary for the removal of cell debris and Schwann cell invasion as guidance for axonal outgrowth followed by remyelination. α1-antitrypsin (AAT) is an acute phase protein and it is shown to express anti-inflammatory characteristics in neutrophil and monocyte/macrophage driven models in vitro and in vivo. We asked a question whether AAT can affect regeneration of injured peripheral nerve fibers by initial macrophage mobilization. We have established several models to study peripheral nerve injuries in small animals. In the rat sciatic nerve crush model we developed a standardized method for investigation of nerve regeneration parameters. We could demonstrate that axonal sprouting, as well as myelin sheaths and functional outcome can be improved by adjunct AAT therapy.
Morphological analyses are key outcome assessments for nerve regeneration studies but are histori... more Morphological analyses are key outcome assessments for nerve regeneration studies but are historically limited to tissue sections. Novel optical tissue clearing techniques enabling three-dimensional imaging of entire organs at a subcellular resolution have revolutionized morphological studies of the brain. To extend their applicability to experimental nerve repair studies we adapted these techniques to nerves and their motor and sensory targets in rats. The solvent-based protocols rendered harvested peripheral nerves and their target organs transparent within 24 hours while preserving tissue architecture and fluorescence. The optical clearing was compatible with conventional laboratory techniques, including retrograde labeling studies, and computational image segmentation, providing fast and precise cell quantitation. Further, optically cleared organs enabled three-dimensional morphometry at an unprecedented scale including dermatome-wide innervation studies, tracing of intramuscular nerve branches or mapping of neurovascular networks. Given their wide-ranging applicability, rapid processing times, and low costs, tissue clearing techniques are likely to be a key technology for next-generation nerve repair studies. All procedures were approved by the Hospital for Sick Children’s Laboratory Animal Services Committee (49871/9) on November 9, 2019.
Purpose: The cornea is the window through which we see the world and is one of the most densely i... more Purpose: The cornea is the window through which we see the world and is one of the most densely innervated structures in the body. Besides providing protective sensory input, corneal nerves have been postulated to stimulate limbal stem cells (LSCs), hence governing corneal epithelial maintenance and recovery. Loss of corneal innervation, through injury, diabetes, tumors, infections, and even improper contact lens use, leads to neurotrophic keratopathy (NK), a degenerative corneal disease that is characterized by corneal epithelial breakdown, scarring, and permanent vision loss1. The only non-invasive treatment option for NK is the human recombinant nerve growth factor (rhNGF), but the short half-life of exogenous neurotrophins-based therapies make this therapeutic approach less effective2. Development of the small molecule ligands for neurotrophins receptors that have better pharmacokinetics and plasma stability showed promising results in the treatment of several neurodegenerative ...
This is a digitally enhanced text. Readers can also see the coverage of this topic area in the se... more This is a digitally enhanced text. Readers can also see the coverage of this topic area in the second edition of Neuroglia. The second edition of Neuroglia was first published digitally in Oxford Scholarship Online and the bibliographic details provided, if cited, will direct people to that version of the text. Readers can also see the coverage of this topic area in the ...
American Journal of Physiology-heart and Circulatory Physiology, Nov 1, 1991
The purpose of this study was to determine how cardiomyopathy affects the beat-to-beat regulation... more The purpose of this study was to determine how cardiomyopathy affects the beat-to-beat regulation of contractile force in cardiac muscle. Isometric force produced by left atria from 80- to 85-day-old normal and cardiomyopathic (CM) hamsters was measured in vitro at 29 degrees C in 2.5 and 6.0 mM Ca2+. During steady-state stimulation at 1 Hz, single test stimuli were interpolated at varying test intervals (0.3-600 s). The force-interval curves were fitted with an equation using five parameters to define the curve and were compared under different conditions; the recovery of force after long rest intervals was fitted with a single exponential curve. Results showed that the force-interval curves were similar in normal and CM atria except that force was depressed at all intervals in 2.5 mM external Ca2+ concentration ([Ca2+]e) and that the parameter U(0), reflecting force produced at short test intervals, tended to be lower in CM muscles. At high [Ca2+]e (6.0 mM) the force-interval curves were similar, but recovery of steady-state force after long test intervals was much slower in CM atria (tau = 77.3 +/- 8.5 s, n = 11) than in normal atria (tau = 30.5 +/- 3.9 s, n = 11). Recovery was also slower at 2.5 mM [Ca2+]e. These findings suggest that, on a beat-to-beat basis, there is less Ca2+ available in intracellular compartments in the CM heart.
Semi-quantitative analysis revealed that the synthesis of the protein product of the p75 gene is ... more Semi-quantitative analysis revealed that the synthesis of the protein product of the p75 gene is rapidly enhanced to reach a peak within the 1 month after denervation. After that it gradually decreased and was barely detectable 6 months following denervation. Double ...
Journal of plastic, reconstructive & aesthetic surgery : JPRAS, 2020
Diagnosing the site and severity of peripheral nerve injuries can be challenging for clinicians. ... more Diagnosing the site and severity of peripheral nerve injuries can be challenging for clinicians. The current gold standards of evaluation with clinical examination and electrophysiology have respective limitations, particularly with determining the prognosis for spontaneous recovery. Current imaging techniques with ultrasound, computed tomography, and magnetic resonance imaging (MRI) may be used as adjuncts in the evaluation of peripheral nerve injuries but are limited in sensitivity and accuracy. Diffusion tensor imaging (DTI) is a recent advancement in MRI sequences that shows promise in evaluating peripheral nerve injuries. Unlike the qualitative traditional MRI, DTI captures the pattern of water diffusion along the nerves and provides quantitative information regarding the integrity of axons. Additionally, DTI images can be reconstructed into 3D images with tractography. This technique is well-established in the central nervous system but is only starting to be applied in the pe...
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