The lamina cribrosa is a primary site of damage in glaucoma. While mechanical distortion is hypothesized to cause reduction of axoplasmic flow, little is known about how the pores, which contains the ...retinal ganglion cell axons, traverse the lamina cribrosa. We investigated lamina cribrosa pore paths in vivo to quantify differences in tortuosity of pore paths between healthy and glaucomatous eyes. We imaged 16 healthy, 23 glaucoma suspect and 48 glaucomatous eyes from 70 subjects using a swept source optical coherence tomography system. The lamina cribrosa pores were automatically segmented using a previously described segmentation algorithm. Individual pore paths were automatically tracked through the depth of the lamina cribrosa using custom software. Pore path convergence to the optic nerve center and tortuosity was quantified for each eye. We found that lamina cribrosa pore pathways traverse the lamina cribrosa closer to the optic nerve center along the depth of the lamina cribrosa regardless of disease severity or diagnostic category. In addition, pores of glaucoma eyes take a more tortuous path through the lamina cribrosa compared to those of healthy eyes, suggesting a potential mechanism for reduction of axoplasmic flow in glaucoma.
The successful treatment of cancer in a disseminated stage using chemotherapy is limited by the occurrence of drug resistance, often mediated by anti-apoptotic mechanisms. Thus the challenge is to ...pinpoint the underlying key factors and to develop therapies for their direct targeting. Protein kinase C (PKC) enzymes are promising candidates, as some PKCs were shown to be involved in regulation of apoptosis. Our studies and others have shown that PKCη is an anti-apoptotic kinase, able to confer protection on tumour cells against stress and chemotherapy. We have demonstrated that PKCη shuttles between the cytoplasm and the nucleus and that upon DNA damage is tethered at the nuclear membrane. The C1b domain mediates translocation of PKCη to the nuclear envelope and, similar to the full-length protein, could also confer protection against cell death. Furthermore, its localization in cell and nuclear membranes in breast cancer biopsies of neoadjuvant-treated breast cancer patients was an indicator for poor survival and a predictor for the effectiveness of treatment. PKCη is also a novel biomarker for poor prognosis in non-small-cell lung cancer (NSCLC). Thus PKCη presents a potential target for therapy where inhibition of its activity and/or translocation to membranes could interfere with the resistance to chemotherapy.
Myopia and glaucoma are both increasing in prevalence and are linked by an unknown mechanism as many epidemiologic studies have identified moderate to high myopia as an independent risk factor for ...glaucoma. Myopia and glaucoma are both chronic conditions that lead to connective tissue remodeling within the sclera and optic nerve head. The mechanobiology underlying connective tissue remodeling differs substantially between both diseases, with different homeostatic control mechanisms. In this article, we discuss similarities and differences between connective tissue remodeling in myopia and glaucoma; selected multiscale mechanisms that are thought to underlie connective tissue remodeling in both conditions; how asymmetric remodeling of the optic nerve head may predispose a myopic eye for pathological remodeling and glaucoma; and how neural tissue deformations may accumulate throughout both pathologies and increase the risk for mechanical insult of retinal ganglion cell axons.
To investigate the biomechanical response of the optic nerve head (ONH) connective tissues to IOP elevation in three pairs of monkey eyes in which one eye had early experimental glaucoma (EG).
A ...serial imaging technique was used to reconstruct the ONH and peripapillary sclera of three pairs of unilateral EG eyes fixed at 10 mm Hg. Eye-specific finite element models of the posterior pole were constructed with inhomogeneous material properties defined for the lamina cribrosa (LC) based on local connective tissue volume fraction (CTVF) and predominant LC beam orientation. These models were used to simulate an IOP increase from 10 to 45 mm Hg. A laminar material constant was varied to produce a range of LC displacements and scleral canal expansions, and the associated LC stress and strain were characterized.
The models suggest that the LC of normal and EG eyes can deform posteriorly or anteriorly when the LC material stiffness is low or high, respectively. Scleral canal expansion was generally, but not always, reduced in EG eyes. Strains in the EG eye were similar to or lower than those in the contralateral eye for the same average LC displacement and increased when the LC was more plaint. Laminar stresses were consistently lower in the EG eye, regardless of LC stiffness.
Connective tissue remodeling in EG alters the biomechanical response of the LC to IOP elevation in an eye-specific manner. The models indicated that the LC tissues in EG eyes were more plaint than those in the contralateral normal eyes in two of three monkeys.
To determine the reproducibility of automated segmentation of the three-dimensional (3D) lamina cribrosa (LC) microarchitecture scanned in-vivo using optical coherence tomography (OCT).
Thirty-nine ...eyes (8 healthy, 19 glaucoma suspects and 12 glaucoma) from 49 subjects were scanned twice using swept-source (SS-) OCT in a 3.5×3.5×3.64 mm (400×400×896 pixels) volume centered on the optic nerve head, with the focus readjusted after each scan. The LC was automatically segmented and analyzed for microarchitectural parameters, including pore diameter, pore diameter standard deviation (SD), pore aspect ratio, pore area, beam thickness, beam thickness SD, and beam thickness to pore diameter ratio. Reproducibility of the parameters was assessed by computing the imprecision of the parameters between the scans.
The automated segmentation demonstrated excellent reproducibility. All LC microarchitecture parameters had an imprecision of less or equal to 4.2%. There was little variability in imprecision with respect to diagnostic category, although the method tends to show higher imprecision amongst healthy subjects.
The proposed automated segmentation of the LC demonstrated high reproducibility for 3D LC parameters. This segmentation analysis tool will be useful for in-vivo studies of the LC.
Optimizing access to recanalization therapies in acute ischemic stroke patients is crucial. Our aim was to measure the short and long term effectiveness, at the acute phase and 1 year after stroke, ...of four sets of actions implemented in the Rhône County.
The four multilevel actions were 1) increase in stroke units bed capacity and development of endovascular therapy; 2) improvement in knowledge and skills of healthcare providers involved in acute stroke management using a bottom-up approach; 3) development and implementation of new organizations (transportation routes, pre-notification, coordination by the emergency call center physician dispatcher); and 4) launch of regional public awareness campaigns in addition to national campaigns. A before-and-after study was conducted with two identical population-based cohort studies in 2006-7 and 2015-16 in all adult ischemic stroke patients admitted to any emergency department or stroke unit of the Rhône County. The primary outcome criterion was in-hospital management times, and the main secondary outcome criteria were access to reperfusion therapy (either intravenous thrombolysis or endovascular treatment) and pre-hospital management times in the short term, and 12-month prognosis measured by the modified Rankin Scale (mRS) in the long term.
Between 2015-16 and 2006-7 periods ischemic stroke patients increased from 696 to 717, access to reperfusion therapy increased from 9 to 23% (p < 0.0001), calls to emergency call-center from 40 to 68% (p < 0.0001), first admission in stroke unit from 8 to 30% (p < 0.0001), and MRI within 24 h from 18 to 42% (p < 0.0001). Onset-to-reperfusion time significantly decreased from 3h16mn 2 h54-4 h05 to 2h35mn 2 h05-3 h19 (p < 0.0001), mainly related to a decrease in delay from admission to imaging. A significant decrease of disability was observed, as patients with mild disability (mRS 0-2) at 12 months increased from 48 to 61% (p < 0.0001). Pre-hospital times, however, did not change significantly.
We observed significant improvement in access to reperfusion therapy, mainly through a strong decrease of in-hospital management times, and in 12-month disability after the implementation of four sets of actions between 2006 and 2016 in the Rhône County. Reducing pre-hospital times remains a challenge.
Glaucoma, the second most common cause of blindness worldwide, is an ocular disease characterized by progressive loss of retinal ganglion cell (RGC) axons. Biomechanical factors are thought to play a ...central role in RGC loss, but the specific mechanism underlying this disease remains unknown. Our goal was to characterize the biomechanical environment in the optic nerve head (ONH)—the region where RGC damage occurs—in human eyes. Post mortem human eyes were imaged, fixed at either 5 or 50 mmHg pressure and processed histologically to acquire serial sections through the ONH. Three-dimensional models of the ONH region were reconstructed from these sections and embedded in a generic scleral shell to create a model of an entire eye. We used finite element simulations to quantify the effects of an acute change in intraocular pressure from 5 to 50 mmHg on the ONH biomechanical environment. Computed strains varied substantially within the ONH, with the pre-laminar neural tissue and the lamina cribrosa showing the greatest strains. The mode of strain having the largest magnitude was third principal strain (compression), reaching 12–15% in both the lamina cribrosa and the pre-laminar neural tissue. Shear strains were also substantial. The distribution of strains in all ONH tissues was remarkably similar between eyes. Inter-individual variations in ONH geometry (anatomy) have only modest effects on ONH biomechanics, and may not explain inter-individual susceptibility to elevated intraocular pressure. Consistent with previous results using generic ONH models, the displacements of the vitreo-retinal interface and the anterior surface of the lamina cribrosa can differ substantially, suggesting that currently available optical imaging methods do not provide information of the acute deformations within ONH tissues. Predicted strains within ONH tissues are potentially biologically significant and support the hypothesis that biomechanical factors contribute to the initial insult that leads to RGC loss in glaucoma.
Glaucoma is among the leading causes of blindness worldwide. The ocular disease is characterized by irreversible damage of the retinal ganglion cell axons at the level of the lamina cribrosa (LC). ...The LC is a porous, connective tissue structure whose function is believed to provide mechanical support to the axons as they exit the eye on their path from the retina to the brain. Early experimental glaucoma studies have shown that the LC remodels into a thicker, more posterior structure which incorporates more connective tissue after intraocular pressure (IOP) elevation. The process by which this occurs is unknown. Here we present a microstructure motivated growth and remodeling (G&R) formulation to explore a potential mechanism of these structural changes. We hypothesize that the mechanical strain experienced by the collagen fibrils in the LC stimulates the G&R response at the micro-scale. The proposed G&R algorithm controls collagen fibril synthesis/degradation and adapts the residual strains between collagen fibrils and the surrounding tissue to achieve biomechanical homeostasis. The G&R algorithm was applied to a generic finite element model of the human eye subjected to normal and elevated IOP. The G&R simulation underscores the biomechanical need for a LC at normal IOP. The numerical results suggest that IOP elevation leads to LC thickening due to an increase in collagen fibril mass, which is in good agreement with experimental observations in early glaucoma monkey eyes. This is the first study to demonstrate that a biomechanically-driven G&R mechanism can lead to the LC thickening observed in early experimental glaucoma.
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