Heterogenous thinning of peripapillary tissues occurs early during high myopia development in juvenile tree shrews.

Myopia is an independent risk factor for glaucoma, but the link between both conditions remains unknown. Both conditions induce connective tissue remodeling at the optic nerve head (ONH), including the peripapillary tissues. The purpose of this study was to investigate the thickness changes of the peripapillary tissues during experimental high myopia development in juvenile tree shrews. Six juvenile tree shrews experienced binocular normal vision, while nine received monocular -10D lens treatment starting at 24 days of visual experience (DVE) to induce high myopia in one eye and the other eye served as control. Daily refractive and biometric measurements and weekly optical coherence tomography scans of the ONH were obtained for five weeks. Peripapillary sclera (Scl), choroid-retinal pigment epithelium complex (Ch-RPE), retinal nerve fiber layer (RNFL), and remaining retinal layers (RRL) were auto-segmented using a deep learning algorithm after nonlinear distortion correction. Peripapillary thickness values were quantified from 3D reconstructed segmentations. All lens-treated eyes developed high myopia (-9.8 ± 1.5 D), significantly different (P < 0.001) from normal (0.69 ± 0.45 D) and control eyes (0.76 ± 1.44 D). Myopic eyes showed significant thinning of all peripapillary tissues compared to both, normal and control eyes (P < 0.001). At the experimental end point, the relative thinning from baseline was heterogeneous across tissues and significantly more pronounced in the Scl (-8.95 ± 3.1%) and Ch-RPE (-16.8 ± 5.8%) when compared to the RNFL (-5.5 ± 1.6%) and RRL (-6.7 ± 1.8%). Furthermore, while axial length increased significantly throughout the five weeks of lens wear, significant peripapillary tissue thinning occurred only during the first week of the experiment (until a refraction of -2.5 ± 1.9 D was reached) and ceased thereafter. A sectorial analysis revealed no clear pattern. In conclusion, our data show that in juvenile tree shrews, experimental high myopia induces significant and heterogeneous thinning of the peripapillary tissues, where the retina seems to be protected from profound thickness changes as seen in Ch-RPE and Scl. Peripapillary tissue thinning occurs early during high myopia development despite continued progression of axial elongation. The observed heterogeneous thinning may contribute to the increased risk for pathological optic nerve head remodeling and glaucoma later in life.

Case report: human granulocytic anaplasmosis causes acute myopericarditis with atrial fibrillation.

Background: Tick-borne illness are becoming increasingly common, in a spreading geographic area. Lyme disease is a well-known cause of cardiovascular disease, but anaplasmosis has previously had relatively little reported association with conduction and myocardial disease. Case Summary: A 65-year-old man with fever and malaise was admitted to the intensive care unit in shock. Electrocardiogram showed new atrial fibrillation and conduction abnormalities. Transthoracic echocardiogram demonstrated normal left ventricular ejection fraction but significant right ventricle dysfunction. Cardiac magnetic resonance imaging findings were consistent with myopericarditis. Workup revealed human granulocytic anaplasmosis without Lyme. He recovered with doxycycline. Conclusion: To our knowledge, this is one of the first reported cases of anaplasmosis causing electrical conduction and myocardial disease with haemodynamic instability in an isolated infection. Treatment with appropriate antibiotics and supportive care allowed the patient to recover to his functional baseline within a month from being discharged from the hospital. Recognition of anaplasmosis in the absence of Lyme disease as a potential cause of electrical and myocardial disease is important in the context of increasing anaplasmosis incidence across the United States.

Scleral crosslinking using genipin can compromise retinal structure and function in tree shrews.

Scleral crosslinking using genipin has been identified as a promising treatment approach for myopia control. The efficacy of genipin to alter biomechanical properties of the sclera has been shown in several animal models of myopia but its safety profile remains unclear. In this safety study, we aim to investigate the effect of scleral crosslinking using retrobulbar injections of genipin on retinal structure and function at genipin doses that were shown to be effective in slowing myopia progression in juvenile tree shrews. To this end, three or five retrobulbar injections of genipin at 0 mM (sham), 10 mM, or 20 mM were performed in one eye every other day. Form deprivation myopia was induced in the injected eye. We evaluated retinal function using full-field electroretinography and retinal structure using in vivo optical coherence tomography imaging and ex vivo histology. The optical coherence tomography results revealed significant thinning of the peripapillary retinal nerve fiber layer in all genipin treated groups including the lowest dose group, which showed no significant treatment effect in slowing myopia progression. In contrast, inducing form deprivation myopia alone and in combination with sham injections caused no obvious thinning of the retinal nerve fiber layer. Electroretinography results showed a significant desensitizing shift of the b-wave semi-saturation constant in the sham group and the second highest genipin dose group, and a significant reduction in b-wave maxima in the two highest genipin dose groups. The ex vivo histology revealed noticeable degeneration of photoreceptors and retinal pigment epithelium in one of two investigated eyes of the highest genipin dose group. While scleral crosslinking using genipin may still be a feasible treatment option for myopia control, our results suggest that repeated retrobulbar injections of genipin at 10 mM or higher are not safe in tree shrews. An adequate and sustained delivery strategy of genipin at lower concentrations will be needed to achieve a safe and effective scleral crosslinking treatment for myopia control in tree shrews. Caution should be taken if the proposed treatment approach is translated to humans.

Effect of different preconditioning protocols on the viscoelastic inflation response of the posterior sclera.

Preconditioning by repeated cyclic loads is routinely used in ex vivo mechanical testing of soft biological tissues. The goal of preconditioning is to achieve a steady and repeatable mechanical response and to measure material properties that are representative of the in vivo condition. Preconditioning protocols vary across studies, and their effect on the viscoelastic response of tested soft tissue is typically not reported or analyzed. We propose a methodology to systematically analyze the preconditioning process with application to inflation testing. We investigated the effect of preconditioning on the viscoelastic inflation response of tree shrew posterior sclera using two preconditioning protocols: (i) continuous cyclic loading-unloading without rest and (ii) cyclic loading-unloading with 15-min rest between cycles. Posterior scleral surface strain was measured using three-dimensional Digital Image Correlation (3D-DIC). We used five variables of characterizing features of the stress-strain loop curve to compare the two preconditioning protocols. Our results showed protocol-dependent differences in the tissue response during preconditioning and at the preconditioned state. Incorporating a resting time between preconditioning cycles significantly decreased the number of cycles (10.5 ± 2.9 cycles vs. 3.1 ± 0.5 cycles, p < 0.001) but increased the total time (15.8 ± 4.4 min vs. 51.2 ± 8.3 min, p < 0.001) needed to reach preconditioned state. At the preconditioned state, 2 of 5 characteristic variables differed significantly between protocols: hysteresis loop area (difference=0.023 kJ/m3, p = 0.0020) and elastic modulus at high IOPs (difference=24.0 MPa, p = 0.0238). Our results suggest that the analysis of the preconditioning process is an essential part of inflation experiments and a prerequisite to properly characterize the tissue viscoelastic response. Furthermore, material properties obtained at the preconditioned state can be impacted by the resting time used during preconditioning and may not be directly compared across studies if the resting time varies by 15 min between studies. STATEMENT OF SIGNIFICANCE: Although applying a preconditioning protocol by repeated cyclic loads is common practice in ex vivo mechanical characterization of soft tissues, the tissue response is typically not reported or analyzed, and the protocol's potential effect on the response remains unclear. This is partially caused by lack of a standardized methodology to precondition soft tissues. We present the first systematic analysis of two representative preconditioning protocols used during inflation testing in ocular biomechanics. Our results show protocol-dependent differences in the viscoelastic response during the preconditioning process and at the preconditioned state. Consequently, the analysis of the preconditioning response represents an essential part of mechanical testing and a prerequisite to properly characterize the tissue viscoelastic response. The effect of preconditioning on the preconditioned state response must be considered when comparing results across studies with different preconditioning protocols.

Effect of Scleral Crosslinking Using Multiple Doses of Genipin on Experimental Progressive Myopia in Tree Shrews.

Purpose: To evaluate the effect of scleral crosslinking (SXL) on slowing experimental progressive myopia in tree shrew eyes using sub-Tenon's injections of genipin (GEN) at different concentrations and number of injections. Methods: Three or five sub-Tenon's injections of GEN at 0 mM (sham), 10 mM, or 20 mM were performed in one eye every other day starting at 18 days of visual experience. Form deprivation (FD) myopia was induced in the injected eye between 24 and 35 days of visual experience; the fellow eye served as control. Tree shrews were randomly assigned to five experimental groups: FD (n = 8); FD + 5 × sham injections (n = 6); FD + 3 × GEN injections at 10 mM (n = 6) and 20 mM (n = 6); and FD + 5 × GEN injections at 20 mM (n = 6). Refractive state and ocular dimensions were measured daily. Results: Compared with the FD group, the sham-injected group showed a transient effect on slowing vitreous chamber elongation. With increasing GEN dose, SXL had an increasing treatment effect on slowing vitreous chamber elongation and myopia progression. In addition, SXL led to a dose-dependent shortening of the aqueous chamber depth and corneal thickening. Lens thickening was observed in the group with the highest concentration. Conclusions: We have shown that SXL using GEN can slow axial elongation and myopia progression in tree shrews. The extent of this treatment effect was dose dependent. Several unexpected effects were observed (corneal thickening, decrease of the anterior chamber depth, and lens thickening), which require further optimization of the GEN delivery approach before clinical consideration. Translational Relevance: The results of this preclinical study suggest that scleral crosslinking using genipin can slow myopia progression.

Activation of the Protective Arm of the Renin Angiotensin System in Demyelinating Disease.

The renin angiotensin system (RAS), which is classically known for blood pressure regulation, has functions beyond this. There are two axes of RAS that work to counterbalance each other and are active throughout the body, including the CNS. The pathological axis, consisting of angiotensin II (A1-8), angiotensin converting enzyme (ACE) and the angiotensin II type 1 receptor (AT1R), is upregulated in many CNS diseases, including multiple sclerosis (MS). MS is an autoimmune and neurodegenerative disease of the CNS characterized by inflammation, demyelination and axonal degeneration. Published research has described increased expression of AT1R and ACE in tissues from MS patients and in animal models of MS such as experimental autoimmune encephalomyelitis (EAE). In contrast to the pathological axis, little is known about the protective axes of RAS in MS and EAE. In other neurological conditions the protective axis, which includes A1-7, ACE2, angiotensin II type 2 receptor and Mas receptor, has been shown to have anti-inflammatory, regenerative and neuroprotective effects. Here we show, for the first time, changes in the protective arm of RAS in both EAE and MS CNS tissue. We observed a significant increase in expression of the protective arm during stages of disease stabilization in EAE, and in MS tissue showing evidence of remyelination. These data provide evidence that the protective arm of RAS, through both ligand and receptor expression, is associated with reductions in the pathological processes that occur in the earlier stages of MS and EAE, possibly slowing the neurodegenerative process and enhancing neural repair. Graphical Abstract.

Experimental myopia increases and scleral crosslinking using genipin inhibits cyclic softening in the tree shrew sclera.

PURPOSE: Myopia progression is thought to involve biomechanical weakening of the sclera, which leads to irreversible deformations and axial elongation of the eye. Scleral crosslinking has been proposed as a potential treatment option for myopia control by strengthening the mechanically weakened sclera. The biomechanical mechanism by which the sclera weakens during myopia and strengthens after crosslinking is not fully understood. Here, we assess the effect of lens-induced myopia and exogenous crosslinking using genipin on the inelastic mechanical properties of the tree shrew sclera measured by cyclic tensile tests. METHODS: Cyclic tensile tests were performed on 2-mm wide scleral strips at physiological loading conditions (50 cycles, 0-3.3 g, 30 s cycle-1 ). Two scleral strips were obtained from each eye of juvenile tree shrews exposed to two different visual conditions: normal and 4 days of monocular -5 D lens wear to accelerate scleral remodelling and induce myopia. Scleral strips were mechanically tested at three alternative conditions: immediately after enucleation; after incubation in phosphate buffered saline (PBS) for 24 h at 37°C; and after incubation for 24 h in PBS supplemented with genipin at a low cytotoxicity concentration (0.25 mm). Cyclic softening was defined as the incremental strain increase from one cycle to the next. RESULTS: -5D lens treatment significantly increased the cyclic softening response of the sclera when compared to contralateral control eyes (0.10% ± 0.029%, mean ± standard error, P = 0.037). Exogenous crosslinking of the lens treated sclera significantly decreased the cyclic softening response (-0.12% ± 0.014%, P = 2.2 × 10-5 ). Contrary to all other groups, the genipin-cross-linked tissue did not exhibit cyclic softening significantly different from zero within the 50-cycle test. CONCLUSIONS: Results indicated that cyclic tensile loading leads to an inelastic, cyclic softening of the juvenile tree shrew sclera. The softening rate increased during lens-induced myopia and was diminished after genipin crosslinking. This finding suggests that axial elongation in myopia may involve a biomechanical weakening mechanism that increased the cyclic softening response of the sclera, which was inhibited by scleral crosslinking using genipin.

Dynamic near-infrared imaging reveals transient phototropic change in retinal rod photoreceptors.

Stiles-Crawford effect (SCE) is exclusively observed in cone photoreceptors, but why the SCE is absent in rod photoreceptors is still a mystery. In this study, we employed dynamic near infrared light imaging to monitor photoreceptor kinetics in freshly isolated frog and mouse retinas stimulated by oblique visible light flashes. It was observed that retinal rods could rapidly (onset: ∼10 ms for frog and 5 ms for mouse; time-to-peak: ∼200 ms for frog and 30 ms for mouse) shift toward the direction of the visible light, which might quickly compensate for the loss of luminous efficiency due to oblique illumination. In contrast, such directional movement was negligible in retinal cones. Moreover, transient rod phototropism could contribute to characteristic intrinsic optical signal (IOS). We anticipate that further study of the transient rod phototropism may not only provide insight into better understanding of the nature of vision but also promise an IOS biomarker for functional mapping of rod physiology at high resolution.