Optic neuropathies refer to a collection of diseases in which retinal ganglion cells (RGCs), the specialized neuron of the retina whose axons make up the optic nerve, are selectively damaged. ...Blindness secondary to optic neuropathies is irreversible as RGCs do not have the capacity for self-renewal and have a limited capacity for self-repair. Numerous strategies are being developed to either prevent further RGC degeneration or replace the cells that have degenerated. In this review, we aim to discuss known limitations to regeneration in central nervous system (CNS), followed by a discussion of previous, current, and future strategies for optic nerve neuroprotection as well as approaches for neuro-regeneration, with an emphasis on developments in the past two years.
Neuro-regeneration in the CNS is limited by both intrinsic and extrinsic factors. Environmental barriers to axon regeneration can be divided into two major categories: failure to clear myelin and formation of glial scar. Although inflammatory scars block axon growth past the site of injury, inflammation also provides important signals that activate reparative and regenerative pathways in RGCs. Neuroprotection with neurotrophins as monotherapy is not effective at preventing RGC degeneration likely secondary to rapid clearance of growth factors. Novel approaches involve exploiting different technologies to provide sustained delivery of neurotrophins. Other approaches include application of anti-apoptosis molecules and anti-axon retraction molecules. Although stem cells are becoming a viable option for generating RGCs for cell-replacement-based strategies, there are still many critical barriers to overcome before they can be used in clinical practice. Adjuvant treatments, such as application of electrical fields, scaffolds, and magnetic field stimulation, may be useful in helping transplanted RGCs extend axons in the proper orientation and assist with new synapse formation.
Different optic neuropathies will benefit from neuro-protective versus neuro-regenerative approaches. Developing clinically effective treatments for optic nerve disease will require a collaborative approach that not only employs neurotrophic factors but also incorporates signals that promote axonogenesis, direct axon growth towards intended targets, and promote appropriate synaptogenesis.
It is widely accepted that the growth and regeneration of tissues and organs is tightly controlled. Although experimental studies are beginning to reveal molecular mechanisms underlying such control, ...there is still very little known about the control strategies themselves. Here, we consider how secreted negative feedback factors ("chalones") may be used to control the output of multistage cell lineages, as exemplified by the actions of GDF11 and activin in a self-renewing neural tissue, the mammalian olfactory epithelium (OE). We begin by specifying performance objectives-what, precisely, is being controlled, and to what degree-and go on to calculate how well different types of feedback configurations, feedback sensitivities, and tissue architectures achieve control. Ultimately, we show that many features of the OE-the number of feedback loops, the cellular processes targeted by feedback, even the location of progenitor cells within the tissue-fit with expectations for the best possible control. In so doing, we also show that certain distinctions that are commonly drawn among cells and molecules-such as whether a cell is a stem cell or transit-amplifying cell, or whether a molecule is a growth inhibitor or stimulator-may be the consequences of control, and not a reflection of intrinsic differences in cellular or molecular character.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The purpose of this study was to characterize the ability of applied electrical fields (EFs) to direct retinal ganglion cell (RGC) axon growth as well as to assess whether Rho GTPases play a role in ...translating electrical cues to directional cues.
Full-thickness, early postnatal mouse retina was cultured in electrotaxis chambers and exposed to EFs of varying strengths (50-200 mV/mm). The direction of RGC axon growth was quantified from time-lapsed videos. The rate of axon growth and responsiveness to changes in EF polarity were also assessed. The effect of toxin B, a broad-spectrum inhibitor of Rho GTPase signaling, and Z62954982, a selective inhibitor of Rac1, on EF-directed growth was determined.
In the absence of an EF, RGC axons demonstrated indiscriminate directional growth from the explant edge. Retinal cultures exposed to an EF of 100 and 200 mV/mm showed markedly asymmetric growth, with 74.2% and 81.2% of axons oriented toward the cathode, respectively (P < 0.001). RGC axons responded to acute changes in EF polarity by redirecting their growth toward the "new" cathode. This galvanotropic effect was partially neutralized by toxin B and Rac1 inhibitor Z62954982.
RGC axons exhibit cathode-directed growth in the presence of an EF. This effect is mediated in part by the Rho GTPase signaling cascade.
Given the rising number of patients with blindness from macular, optic nerve, and visual pathway disease, there is considerable interest in the potential of electrical stimulation devices to restore ...vision. Electrical devices for restoration of visual function can be grouped into three categories: (1) visual prostheses whose goal is to bypass damaged areas and directly activate downstream intact portions of the visual pathway; (2) electric field stimulation whose goal is to activate endogenous transcriptional and molecular signaling pathways to promote neuroprotection and neuro-regeneration; and (3) neuromodulation whose stimulation would resuscitate neural circuits vital to coordinating responses to visual input. In this review, we discuss these three approaches, describe advances made in the different fields, and comment on limitations and potential future directions.
Significantinterest exists in the potential of electric field (EF) application to be developed into a technology to direct neuronal regeneration. In vitro, EFs were shown to direct the growth of ...retinal ganglion cell (RGC) axons, the neurons that make up the optic nerve. As larger EF gradients were shown to direct more efficient growth,investigations into the most effective stimulation strategies that can generate the greatest voltage gradient are needed before EF application can be developed into a technology to direct optic nerve regeneration in vivo. We performed ex-vivo experiments to compare the ability of different electrode materials, platinum vs. tungsten, to generate an EF gradient along the rat optic nerve. Platinum electrodes at both source and ground positions were found to generate the greatest voltage gradient along the optic nerve. Experimental results were used to inform an equivalent computational model of the optic nerve, which was subsequently employed to predict more effective electrode pair combinations. Our results confirmed that the platinum-platinum electrode pair generates the maximum voltage gradient which are highly dependent on electrode size and electrode-electrolyte interfaces. This computational platform can serve as a foundation for the development of electrical stimulation therapies for nerve regeneration.
Giant cell arteritis (GCA) is a vasculitis that affects large and medium sized arteries. The aetiology of GCA is unknown and numerous risk factors have been proposed. In this article, we evaluate the ...incidence of biopsy-positive GCA in Northern California and assess for seasonal variation.
We performed a retrospective review based on billing codes of temporal artery biopsies performed at the University of California, Davis from 2003 to 2014.
We identified 174 biopsies (119 female, 55 male). Of these, 21 positive biopsies were female while 8 were male. Although three times as many women had a positive biopsy compared to men, twice as many biopsies were performed on women. Women were not found to have a significantly higher risk of developing GCA over men. Patients with a positive biopsy averaged 76.4±8.9 years of age. The odds of having a positive biopsy increased significantly with age. Positive biopsies were significantly more likely to occur in the months of May through July than the rest of the year (p<0.028).
Our retrospective study is the first report of the seasonal incidence of biopsy-proven GCA in California. Our data suggest that increased age and summer months are risk factors for developing biopsy-proven GCA in our region.
Studies of the olfactory epithelium model system have demonstrated that production of neurons is regulated by negative feedback. Previously, we showed that a locally produced signal, the TGFβ ...superfamily ligand GDF11, regulates the genesis of olfactory receptor neurons by inhibiting proliferation of the immediate neuronal precursors (INPs) that give rise to them. GDF11 is antagonized by follistatin (FST), which is also produced locally. Here, we show that Fst(-/-) mice exhibit dramatically decreased neurogenesis, a phenotype that can only be partially explained by increased GDF11 activity. Instead, a second FST-binding factor, activin βB (ACTβB), inhibits neurogenesis by a distinct mechanism: whereas GDF11 inhibits expansion of INPs, ACTβB inhibits expansion of stem and early progenitor cells. We present data supporting the concept that these latter cells, previously considered two distinct types, constitute a dynamic stem/progenitor population in which individual cells alternate expression of Sox2 and/or Ascl1. In addition, we demonstrate that interplay between ACTβB and GDF11 determines whether stem/progenitor cells adopt a glial versus neuronal fate. Altogether, the data indicate that the transition between stem cells and committed progenitors is neither sharp nor irreversible and that GDF11, ACTβB and FST are crucial components of a circuit that controls both total cell number and the ratio of neuronal versus glial cells in this system. Thus, our findings demonstrate a close connection between the signals involved in the control of tissue size and those that regulate the proportions of different cell types.
Here, we present a semi-automated method for quantifying retinal ganglion cell (RGC) axon density at different distances from the optic nerve crush site using longitudinal, confocal microscopy images ...taken from whole-mounted optic nerves. This method employs the algorithm AxonQuantifier which operates on the freely available program, ImageJ.
To validate this method, seven adult male Long Evans rats underwent optic nerve crush injury followed by in vivo treatment with electric fields of varying strengths for 30 days to produce optic nerves with a wide range of axon densities distal to the optic nerve crush site. Prior to euthanasia, RGC axons were labelled with intravitreal injections of cholera toxin B conjugated to Alexa Fluor 647. After dissection, optic nerves underwent tissue clearing, were whole-mounted, and imaged longitudinally using confocal microscopy.
Five masked raters quantified RGC axon density at 250, 500, 750, 1000, 1250, 1500, 1750, and 2000 µm distances past the optic nerve crush site for the seven optic nerves manually and using AxonQuantifier. Agreement between these methods was assessed using Bland-Altman plots and linear regression. Inter-rater agreement was assessed using the intra-class coefficient.
Semi-automated quantification of RGC axon density demonstrated improved inter-rater agreement and reduced bias values as compared to manual quantification, while also increasing time efficiency 4-fold. Relative to manual quantification, AxonQuantifier tended to underestimate axon density.
AxonQuantifier is a reliable and efficient method for quantifying axon density from whole mount optic nerves.
•AQ rapidly quantifies axon density from longitudinal optical sections of whole-mounted optic nerves.•AQ has improved inter-rater agreement and reduced bias values when compared to manual quantification.•AQ is applicable to a wide range of axon densities, sparsely or densely labeled nerves.
Purpose: To assess the accuracy of radiographic interpretation between the clinician and radiologist when compared to histopathology of orbital lesions.
Methods: A retrospective chart review of ...patients at the University of California Davis Eye Center who underwent orbitotomy from 1/1/2000 to 5/22/2019 was performed. Charts with a preoperative imaging report, preoperative clinical assessment including the clinician's interpretation of imaging, and histopathologic diagnosis were included. The specific diagnoses were grouped into related classes of pathology for the analysis. The clinical and radiologic assessments were compared against the final histopathologic diagnosis for concordance. A concordance analysis was performed.
Results: 242 patients (mean age 49 years, 53.5% female) were reviewed. Of these records 185 documented the clinician's clinical impression, the radiology report, as well as the histopathology report. The clinician's preoperative assessment had substantial agreement kappa = 0.72 (0.65,0.79) with the final histopathologic result and was correct in 75.7% (140/185) of cases whereas the radiology report was correct in 52.4% (97/185) with a moderate level of agreement kappa = 0.47 (0.39, 0.55). In 49.2% (91/185) of cases the final histopathology correlated with both the clinical impression and radiology report kappa = 0.58 (0.55, 0.61).
Conclusions: The accurate interpretation of orbital imaging is a challenge and histopathologic examination remains the gold standard for diagnosis. While orbital imaging is a valuable diagnostic tool the interpretation of these studies is most accurate when conducted in the context of the patient's medical history, clinical exam, and with the physician most familiar with various orbital lesions.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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