SH-SY5Y human neuronal cells with mutations of the CDKN2B-AS1 gene are vulnerable under cultured conditions.

Glaucoma is a common cause of blindness worldwide. Genetic effects are believed to contribute to the onset and progress of glaucoma, but the underlying pathological mechanisms are not fully understood. Here, we set out to introduce mutations into the CDKN2B-AS1 gene, which is known as being the closely associated with glaucoma, in a human neuronal cell line in vitro. We introduced gene mutations with CRISPR/Cas9 into exons and introns into the CDKN2B-AS1 gene. Both mutations strongly promoted neuronal cell death in normal culture conditions. RNA sequencing and pathway analysis revealed that the transcriptional factor Fos is a target molecule regulating CDKN2B-AS1 overexpression. We demonstrated that gene mutation of CDKN2B-AS1 is directly associated with neuronal cell vulnerability in vitro. Additionally, Fos, which is a downstream signaling molecule of CDKN2B-AS1, may be a potential source of new therapeutic targets for neuronal degeneration in diseases such as glaucoma.

In-process sintering of Au nanoparticles deposited in laser-assisted electrophoretic deposition.

In this study, we developed an in-process sintering method for laser-assisted electrophoretic deposition (LAEPD) using an additional laser to sinter Au particles and improve the Young's modulus of the microstructures fabricated using LAEPD. Thus, in addition to the laser (λ = 488 nm) that traps nanoparticles, another laser (λ = 785 nm) was installed to effectively absorb and sinter the deposited nanoparticles. Deposition was performed via LAEPD and laser sintering alternatively during fabrication. A Young's modulus of 28.2 GPa was achieved for the Au pillar fabricated with a sintering laser irradiation time of 1000 ms/cycle.

The GPR84 molecule is a mediator of a subpopulation of retinal microglia that promote TNF/IL-1α expression via the rho-ROCK pathway after optic nerve injury.

Resident microglia are important to maintain homeostasis in the central nervous system, which includes the retina. The retinal microglia become activated in numerous pathological conditions, but the molecular signatures of these changes are poorly understood. Here, using an approach based on FACS and RNA-seq, we show that microglial gene expression patterns gradually change during RGC degeneration induced by optic nerve injury. Most importantly, we found that the microglial cells strongly expressed Tnf and Il1α, both of which are known to induce neurotoxic reactive astrocytes, and were characterized by Gpr84high -expressing cells in a particular subpopulation. Moreover, ripasudil, a Rho kinase inhibitor, significantly blunted Gpr84 expression and cytokine induction in vitro and in vivo. Finally, GPR84-deficient mice prevented RGC loss in optic nerve-injured retina. These results reveal that Rho kinase-mediated GPR84 alteration strongly contribute to microglial activation and promote neurotoxicity, suggesting that Rho-ROCK and GPR84 signaling may be potential therapeutic targets to prevent the neurotoxic microglial phenotype induced by optic nerve damage, such as occurs in traumatic optic neuropathy and glaucoma.

Reduced Plasma BDNF Levels in Normal Tension Glaucoma Compared to Open Angle Glaucoma.

PRCIS: The study suggests that a low level of systemic BDNF may contribute to the pathogenesis of glaucoma in an IOP-independent manner. AIMS: To evaluate differences in systemic brain-derived neurotrophic factor (BDNF) levels between primary open angle glaucoma (POAG) patients and normal tension glaucoma (NTG) patients. METHODS: This study collected blood samples from 260 NTG patients, 220 age-matched POAG patients, and 120 age-matched cataract patients (as controls). BDNF levels were measured with an antibody-conjugated bead assay system (Luminex). RESULTS: We found that plasma BDNF levels in the NTG group were significantly lower than in the POAG and cataract control groups. There was no significant difference between the POAG and cataract groups. CONCLUSION: This result suggests that a low level of systemic BDNF may contribute to the pathogenesis of glaucoma in an IOP-independent manner.

Neurosteroids as stress modulators and neurotherapeutics: lessons from the retina.

Neurosteroids are rapidly emerging as important new therapies in neuropsychiatry, with one such agent, brexanolone, already approved for treatment of postpartum depression, and others on the horizon. These steroids have unique properties, including neuroprotective effects that could benefit a wide range of brain illnesses including depression, anxiety, epilepsy, and neurodegeneration. Over the past 25 years, our group has developed ex vivo rodent models to examine factors contributing to several forms of neurodegeneration in the retina. In the course of this work, we have developed a model of acute closed angle glaucoma that involves incubation of ex vivo retinas under hyperbaric conditions and results in neuronal and axonal changes that mimic glaucoma. We have used this model to determine neuroprotective mechanisms that could have therapeutic implications. In particular, we have focused on the role of both endogenous and exogenous neurosteroids in modulating the effects of acute high pressure. Endogenous allopregnanolone, a major stress-activated neurosteroid in the brain and retina, helps to prevent severe pressure-induced retinal excitotoxicity but is unable to protect against degenerative changes in ganglion cells and their axons under hyperbaric conditions. However, exogenous allopregnanolone, at a pharmacological concentration, completely preserves retinal structure and does so by combined effects on gamma-aminobutyric acid type A receptors and stimulation of the cellular process of macroautophagy. Surprisingly, the enantiomer of allopregnanolone, which is inactive at gamma-aminobutyric acid type A receptors, is equally retinoprotective and acts primarily via autophagy. Both enantiomers are also equally effective in preserving retinal structure and function in an in vivo glaucoma model. These studies in the retina have important implications for the ongoing development of allopregnanolone and other neurosteroids as therapeutics for neuropsychiatric illnesses.

The impact of an additional implant under the saddle of removable partial dentures in Kennedy Class II edentulism on oral health-related quality of life and oral function: a case series report.

BACKGROUND: Implant-supported removable partial dentures (ISRPDs) provide effective prosthodontic treatment for partially edentulous patients. ISRPDs offer greater patient satisfaction and better oral function compared with removable partial dentures (RPDs) by enhancing denture stability and support. However, few clinical studies have focused on RPD design in patients with mandibular Kennedy Class II edentulism. The aim of this case reports was to investigate the oral function, oral health-related quality of life, and satisfaction of four patients with unilateral distal-extension mandibular RPDs with the same design which were replaced with ISRPDs. In addition, we investigated how each patient's evaluation varied with the change from RPD to ISRPD. CASE PRESENTATION: Four patients had unilateral distal-extension mandibular edentulism and were missing the first and second molars and the first and second premolars. They received one implant (4.0 mm in diameter, 8.0 mm in length; IAT EXA PLUS Bone level; Nippon Piston Ring Co. Ltd, Saitama, Japan) at the position equivalent to the first molar in the edentulous residual ridge perpendicular to the occlusal plane. Implant position was determined by surgical guide plate. RPDs were fabricated after the residual mucosal membrane had healed. The basic design of the RPD was as follows: a cobalt-chromium alloy cast metal framework denture with a lingual bar as the major connector, a double Akers clasp on the molars and an auxiliary retainer on the premolar as indirect retainers, and a wrought wire clasp and a cast cingulum rest (combination clasp) as direct retainers. Masticatory performance, occlusal force, oral health-related quality of life, and satisfaction were estimated at baseline, and at time points after insertion of the RPD and after insertion of the adapted ISRPD. Each evaluation item showed a tendency for improvement on insertion of the new RPD. Masticatory performance and satisfaction tended to be better after insertion of the ISRPD than after insertion of the RPD. CONCLUSION: Our findings suggest that ISRPDs provided better patient satisfaction and masticatory performance than RPDs in patients with mandibular Kennedy Class II edentulism. Trial registration UMIN Clinical Trials Registry and Japan Registry of Clinical Trials, UMIN000025283 and jRCTs012180003. Registered 19 February 2016 and 17 December 2018, https://www.umin.ac.jp/ and https://jrct.niph.go.jp/.

Magnetic resonance imaging of a pediatric case of arthritis associated with acute lymphoblastic leukemia: A case report.

In the present case report, a 3-year-old girl presented with a 1-week history of spontaneously resolving right knee pain. After 1 month, the patient had trouble ambulating due to painful swelling of their ankle. Rheumatic disease, specifically juvenile idiopathic arthritis, was considered. Blood examination could not be conducted because their blood sample was coagulated. T1-weighted magnetic resonance imaging (MRI) revealed abnormally low signals in the femur, tibia, fibula and foot bone marrow. Contrast-enhanced T1-weighted MRI revealed synovial contrast enhancement and synovial fluid retention in the right ankle joint. Blood analysis revealed a white blood cell count of 40,000/µl (blasts, 66%). In addition, a monoclonal increase in the number of lymphoblasts was observed. The patient was subsequently diagnosed with B-cell precursor acute lymphoblastic leukemia. Reports on leukemic arthritis resembling synovitis on MRI remain limited. The findings of this report indicated that pediatricians should consider leukemia in children presenting with joint symptoms.

The Enantiomer of Allopregnanolone Prevents Pressure-Mediated Retinal Degeneration Via Autophagy.

In an ex vivo rat ocular hypertension (OHT) model, the neurosteroid allopregnanolone (AlloP) exerts neuroprotective effects via enhancement of both GABAA receptors and autophagy. We now examine whether its enantiomer (ent-AlloP), which is largely inactive at GABA receptors, offers similar neuroprotection in ex vivo and in vivo rat OHT models. Ex vivo rat retinal preparations were incubated in a hyperbaric condition (10 and 75 mmHg) for 24 h. An in vivo ocular hypertension (OHT) model was induced by intracameral injection of polystyrene microbeads. We examined pharmacological effects of AlloP, ent-AlloP, picrotoxin (a GABAA receptor antagonist), and 3-MA (an autophagy inhibitor) histologically and biochemically. We found that both AlloP and ent-AlloP have marked neuroprotective effects in the retina, but effects of the unnatural enantiomer are independent of GABAA receptors. Electron microscopic analyses show that pressure elevation significantly increased autophagosomes (APs) in the nerve fiber layer and addition of AlloP also increased APs and degenerative autophagic vacuoles (AVds). ent-AlloP markedly increased APs and AVds compared to AlloP. Examination of LC3B-II and SQSTM1 protein levels using immunoblotting revealed that AlloP increased LC3B-II, and ent-AlloP further enhanced LC3B-II and suppressed SQSTM1, indicating that autophagy is a major mechanism underlying neuroprotection by ent-AlloP. In an rat in vivo OHT model, single intravitreal ent-AlloP injection prevented apoptotic cell death of retinal ganglion cells similar to AlloP. However, even in this model, ent-AlloP was more effective in activating autophagy than AlloP. We conclude that ent-AlloP may be a prototype of potential therapeutic for treatment of glaucoma as an autophagy enhancer without affecting GABA receptors.

Peripapillary choroidal thickness assessed by spectral-domain optical coherence tomography in normal Japanese.

PURPOSE: To investigate peripapillary choroidal thickness (PPCT) in normal Japanese subjects by using spectral-domain optical coherence tomography (SD-OCT) with enhanced depth imaging (EDI) technique and evaluate its association with ocular and systemic factors. STUDY DESIGN: Cross-sectional study. METHODS: This study included 85 eyes of 85 normal Japanese subjects. Normal subjects were defined as those without retinal and optic nerve disorders of any kind. The PPCT was measured at the location of 3.4 mm diameter peripapillary circle centered on the optic nerve head. It was measured as the distance between the retinal pigment epithelium and scleral-choroidal interface at the following six sectors; temporal, supra-temporal, supra-nasal, nasal, infero-nasal, and infero-temporal. Global PPCT was calculated based on these sectorial data. In addition, association between the PPCT and ocular and systemic factors were evaluated. RESULTS: Among the included subjects, 39 (45.9%) were men and mean age was 51.4 ± 17.6 years. The mean global PPCT was 135.8 ± 40.6 µm. The infero-nasal and infero-temporal sectors were significantly thinner than other sectors (all, P < 0.05). In multiple regression analysis, thinner global PPCT was significantly associated with older age (P < 0.0001) and female sex (P = 0.0330) after considering effects of other confounders. CONCLUSIONS: This study provided global PPCT and its profile in normal Japanese subjects by using EDI SD-OCT. These results may be used as a reference in the assessment of normal status of the PPCT. The age and sex of the subjects should be considered in interpreting the PPCT data.

The neurosteroid allopregnanolone protects retinal neurons by effects on autophagy and GABRs/GABAA receptors in rat glaucoma models.

In an ex vivo rat glaucoma model using dissected retinas, the neurosteroid allopregnanolone (AlloP) protects retinal ganglion cells (RGCs) via GABR/GABAA receptors. To determine the involvement of macroautophagy/autophagy in neuroprotection by AlloP, we examined the effects of autophagy activators, rapamycin and torin 2, and autophagy inhibitors, bafilomycin A1 and SAR405, on retinal retinal morphology and expression of MAP1 LC3B/LC3B (microtubule-associated protein 1 light chain 3 beta) and SQSTM1 (sequestosome 1). Administration of rapamycin or torin 2 exerted partial histological neuroprotection, while combined administration of AlloP with bafilomycin A1 or SAR405 induced severe degeneration in a hyperbaric condition. Electron microscopic analyses showed that the addition of AlloP significantly increased autophagosomes and degenerative autophagic vacuoles in the retinal nerve fiber layer. Immunoblotting showed that the addition of AlloP or autophagic activators increased the lipidated form of LC3B (LC3B-II) and suppressed SQSTM1. Moreover, bafilomycin A1 increased LC3B-II and SQSTM1 protein levels in the presence of AlloP without changes in corresponding mRNAs compared to AlloP-treated retinas in a hyperbaric condition. These data indicate that AlloP likely induces a protective form of autophagy in this model. In an in vivo rat model of glaucoma, we also observed neuroprotective effects of AlloP. Injection of polystyrene microbeads into the anterior chamber increased intraocular pressure about 3-fold and induced RGC apoptosis. A single intravitreal injection of AlloP or autophagy activators prevented apoptosis and protected RGCs with autophagy activation. We conclude that AlloP may serve as a potential therapeutic agent for the treatment of glaucoma via diverse mechanisms.Abbreviations: 2HBCD: 2-Hydroxypropyl)-ß-cyclodextrin; 3-MA: 3-methyladenine; AlloP: allopregnanolone; AP: autophagosome; AVd: degradative autophagic vacuoles; GCL: ganglion cell layer; INL: inner nuclear layer; IOP: intraocular pressure; IPL: inner plexiform layer; LC3B-I: cytosolic form of LC3B; LCB-II: lipidated form of LC3B; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mPTP: mitochondrial permeability transition pore; NDS: neuronal damage score; NFL: nerve fiber layer; OH: ocular hypertension; ON: optic nerve; ONL: outer nuclear layer; OPL: outer plexiform layer; p-STR: scotopic threshold response; RGC: retinal ganglion cells; RT-PCR: real-time reverse transcription polymerase chain reaction; SQSTM1: sequestosome 1; TUNEL: TdT-mediated dUTP Nick End Labeling.

Effects of Different Orthoses Used for Gait Training on Gait Function among Patients with Subacute Stroke.

OBJECTIVES: To facilitate selection of the appropriate orthosis, this study assessed functional ambulation outcomes of subacute stroke patients using either an ankle-foot orthosis (AFO) or a knee-ankle-foot orthosis (KAFO). METHODS: The subjects were newly diagnosed hemiplegic stroke patients admitted to Hatsudai Rehabilitation Hospital between January and June 2016. Differences between the AFO group and the KAFO group were examined using unpaired t-tests. Multiple regression analysis with stepwise regression was used to identify predictive factors for the functional ambulation category (FAC) score at discharge. RESULTS: A total of 164 patients (99 men and 65 women; mean age, 69.2 ± 15.3 years; mean days from onset to admission, 31.9 ± 12.3 days) were included in the study. The AFO, KAFO, and non-orthosis groups contained 38, 79, and 47 patients, respectively. In the AFO group, the median Stroke Impairment Assessment Set (SIAS) motor scores were 2.5-3, and the median sensory scores were 2. In the KAFO group, the median SIAS motor scores were 0-1, and the median sensory scores were 1. At discharge, 32 (84.2%) patients in the AFO group and 20 (25.3%) patients in the KAFO group had an FAC score ≥3. Multiple regression analysis found that age and the Functional Independence Measure cognitive score could be used to predict the FAC score at discharge in the AFO group. The Berg Balance Scale score was an additional predictive factor in the KAFO group. CONCLUSIONS: This study showed that the AFO group had good outcomes for independent ambulation. Furthermore, balance control is an important factor contributing to walking ability in patients with severe hemiparesis.

Cholesterol oxidase from Rhodococcus erythropolis with high specificity toward ß-cholestanol and pytosterols.

Two genes (choRI and choRII) encoding cholesterol oxidases belonging to the vanillyl-alcohol oxidase (VAO) family were cloned on the basis of putative cholesterol oxidase gene sequences in the genome sequence data of Rhodococcus erythropolis PR4. The genes corresponding to the mature enzymes were cloned in a pET vector and expressed in Escherichia coli. The two cholesterol oxidases produced from the recombinant E. coli were purified to examine their properties. The amino acid sequence of ChoRI showed significant similarity (57%) to that of ChoRII. ChoRII was more stable than ChoRI in terms of pH and thermal stability. The substrate specificities of these enzymes differed distinctively from one another. Interestingly, the activities of ChoRII toward ß-cholestanol, ß-sitosterol, and stigmasterol were 2.4-, 2.1-, and 1.7-fold higher, respectively, than those of cholesterol. No cholesterol oxidases with high activity toward these sterols have been reported so far. The cholesterol oxidation products from these two enzymes also differed. ChoRI and ChoRII oxidized cholesterol to form cholest-4-en-3-one and 6ß-hydroperoxycholest-4-en-3-one, respectively.

Clinical Assessment of Scleral Canal Area in Glaucoma Using Spectral-Domain Optical Coherence Tomography.

PURPOSE: To investigate anterior scleral canal (ASC) area in the eyes with glaucoma using spectral-domain optical coherence tomography (SDOCT). DESIGN: Cross-sectional study. METHODS: This study included 206 eyes of 103 patients with glaucoma, classified as 66 eyes of 33 patients with unilateral glaucoma and 140 eyes of 70 patients with bilateral glaucoma. Radial scan enhanced depth imaging SDOCT centered on the optic disc was performed, and parameters that present ASC area such as ASC opening and the largest ASC area were obtained in each eye. The largest ASC area was the largest cross-sectional area of the ASC region identified between the ASC opening and anterior lamina cribrosa insertion. These parameters were compared between eyes with and without glaucoma in unilateral glaucoma, and eyes with worse and better visual field defect (VFD) in bilateral glaucoma. RESULTS: In the patients with unilateral glaucoma, ASC opening and largest ASC area were significantly larger in the eyes with glaucoma than in those without glaucoma (both P < .001). In bilateral glaucoma, these parameters were significantly larger in the eyes with worse VFD than in those with better VFD (P = .0080 and P = .0018, respectively). Intereye differences of the ASC parameters in the glaucoma patients were significantly greater than that in the normal subjects. CONCLUSIONS: Significantly larger ASC area was first observed in the living human eyes with glaucoma compared to the normal eyes. Further longitudinal studies are required to determine if the ASC area is useful in the prevention and treatment of glaucoma.

Differences in Retinal Nerve Fiber Layer Thickness as Assessed on the Disc Center and Bruch's Membrane Opening Center in Myopic Eyes.

PURPOSE: To investigate the difference in circumpapillary retinal nerve fiber layer thickness (cpRNFLT) assessed on the conventional, clinically identified optic disc center and Bruch's membrane opening (BMO) center in myopic eyes. DESIGN: Cross-sectional study. PARTICIPANTS: One hundred nine eyes of 109 healthy myopic subjects with axial length of 24 mm or more. METHODS: The cpRNFLT was acquired on the disc center and BMO center aligned with the fovea. The global and sectorial cpRNFLT were computed in each eye and were compared between the 2 assessments. Furthermore, factors associated with the difference in cpRNFLT between the 2 assessments were analyzed. MAIN OUTCOME MEASURES: Differences in cpRNFLT assessed on the disc center and BMO center in myopic eyes. RESULTS: Among the included participants, the mean SE was -4.94±1.69 D, and the mean axial length was 25.55±0.89 mm. The global cpRNFLT was not significantly different between the 2 assessments; however, the temporal sector was significantly thicker, and the nasal sector was significantly thinner in the assessment on the disc center than on the BMO center (P < 0.0001 for both). Forty eyes (36.7%) exhibited more than 10 µm of difference between the 2 assessments in the temporal sector. The positions of the superior and inferior peaks of the cpRNFLT profile deviated temporally significantly in the disc-center assessment (P < 0.0001 for both). Multiple regression analysis showed that the width of γ-zone parapapillary atrophy (PPA) was associated significantly with greater difference in sectorial cpRNFLT between the 2 assessments. CONCLUSIONS: There was a significant amount of difference in the sectorial cpRNFLT acquired on the disc center and that acquired on the BMO center in the myopic eyes, which was considered to be derived from unique optic disc margin anatomy in these eyes. The eyes with wider γ-zone PPA exhibited greater cpRNFLT difference. The cpRNFLT data based on the BMO center were acquired at an anatomically accurate location, which indicated that the conventional disc-center assessment induced a substantial amount of error. The present results emphasize the importance of assessing cpRNFLT on the BMO center in myopic eyes for an improved structure-function relationship.

Additive neuroprotective effects of 24(S)-hydroxycholesterol and allopregnanolone in an ex vivo rat glaucoma model.

In a rat ex vivo acute glaucoma model, high pressure (75 mmHg) causes swelling of ganglion cell axons and elevates levels of the endogenous steroids 24(S)-hydroxycholesterol (24SH) and allopregnanolone (AlloP). Furthermore, 24SH (0.1 µM) alone elevates AlloP levels via NMDA receptors. With this model, we now investigate possible interactions between 24SH and AlloP. We found that inhibition of AlloP synthesis with dutasteride under high pressure results in severe excitotoxicity in addition to axonal swelling. The excitotoxicity is prevented by exogenous AlloP but not 24SH, indicating that endogenous AlloP is crucial for protection. However, inhibition of 24SH synthesis with voriconazole induces severe excitotoxicity under normal pressure. Paradoxically, the excitotoxicity by voriconazole is better prevented by AlloP than 24SH. These findings suggest that inhibition of 24SH synthesis becomes excitotoxic in the absence of AlloP. We also observed that co-administration of sub-micromolar 24SH (0.1 µM) and AlloP (0.1 µM), concentrations that are only partially effective when administered alone, prevents axonal swelling under high pressure. This apparent enhanced protection indicates strong interaction between the two neurosteroids to preserve neuronal integrity, with 24SH contributing to AlloP synthesis via NMDA receptors and with AlloP playing an essential role in neuroprotection via GABAA receptors.

Optic Disc Margin Anatomic Features in Myopic Eyes with Glaucoma with Spectral-Domain OCT.

PURPOSE: To investigate optic disc margin anatomic features in myopic eyes with open-angle glaucoma (OAG) using spectral-domain (SD) OCT. DESIGN: Cross-sectional study. PARTICIPANTS: Two hundred four eyes of 102 participants with OAG and 106 eyes of 53 participants without glaucoma with axial length of 24 mm or more. METHODS: Radial SD OCT B-scans centered on the optic discs were acquired in each eye, and the SD OCT data were colocalized with the optic disc stereophotographs. Optic disc margin anatomic features were evaluated as (1) SD OCT structure coinciding with the disc margin identified in the stereophotograph, (2) border tissue configuration, and (3) presence of Bruch's membrane overhang, and their frequency was computed in each clock-hour position. Further, paired eyes of myopic participants with OAG were divided into eyes with better or worse visual field defect (VFD), according to the mean deviation of the Humphrey visual field test, and associated factors were compared. MAIN OUTCOME MEASURES: Spectral-domain OCT structures coinciding with the visible optic disc margin in stereophotographs. RESULTS: In myopic eyes with OAG, mean axial length was 25.96±1.07 mm and mean deviation was -8.87±7.78 dB. In approximately 90% of the participants, anterior scleral opening (ASO) coincided with the temporal disc margin and Bruch's membrane opening (BMO) with the nasal disc margin. Border tissue configuration was externally oblique in the temporal region and internally oblique in the nasal region of the optic disc. Bruch's membrane overhang was observed in a relatively small percentage of eyes. The same pattern of disc margin anatomic features was observed in the myopic eyes without glaucoma. The myopic optic disc was shaped by the temporal shifting of the BMO from the ASO, and the extent of shifting was expressed as the width of γ zone parapapillary atrophy (PPA). The greater γ zone PPA width was associated significantly with the worse VFD between paired eyes. CONCLUSIONS: The myopic eyes with OAG exhibited characteristic optic disc margin anatomic features that was considered to be derived from myopic deformation of the eye. The greater γ zone PPA width may increase susceptibility to the glaucomatous stress.

Focal Lamina Cribrosa Defect in Myopic Eyes With Nonprogressive Glaucomatous Visual Field Defect.

PURPOSE: To investigate focal lamina cribrosa (LC) defect that spatially correspond to the nonprogressive glaucomatous visual field defect (VFD) in myopic subjects. DESIGN: Case-control study. SUBJECTS: We included 159 myopic eyes with glaucomatous VFD under treatment and followed up for 7 years. METHODS: Serial enhanced-depth imaging spectral-domain optical coherence tomography B-scans of the optic discs were acquired at the end of the follow-up and reviewed for the LC defect. Nonprogressive VFD was defined as having ≤1 progressing point of Humphrey visual field, with a slope calculated using pointwise linear regression worse than -1.0 dB/year at P < .01. Eyes were classified as having either progressive or nonprogressive VFD, and associating factors were evaluated. RESULTS: Sixty-four subjects (40.3%) exhibited nonprogressive VFD with mean deviation change -0.06 ± 0.22 dB/year. Multivariate logistic regression analysis revealed that presence of LC defect was significantly associated with nonprogressive VFD (odds ratio, 3.96; P = .002). The location of LC defect corresponded spatially to the location of VFD. Nonprogressive eyes with LC defect exhibited lower baseline intraocular pressure (IOP) (16.6 mm Hg vs 21.0 mm Hg, P = .0030) and smaller percentage of IOP change (12.9% vs 30.5%, P < .0001) than those without LC defect, but greater myopic optic disc deformation (10.1 degrees vs 1.2 degrees in torsion angle, P < .0001). When the eyes with LC defect had higher baseline IOP, they exhibited progressive VFD. CONCLUSIONS: In myopic eyes, there are specific patters of LC defect that are suggested to be associated with nonprogressive glaucomatous VFD.

Intravenous IgG Reduces Pathogenic Autoantibodies, Serum IL-6 Levels, and Disease Severity in Experimental Bullous Pemphigoid Models.

Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by autoantibodies to COL17. Currently, systemic corticosteroids are used as first-line treatments for BP; alternatively, intravenous administration of high-dose IgG (IVIG) has been shown to be effective for patients with steroid-resistant BP in clinical practice. However, the effect of IVIG on BP has not fully been investigated. To examine the effects and mechanisms of action of IVIG against BP, we performed IVIG experiments using two experimental BP mouse models. One is a passive-transfer BP model that reproduces subepidermal separation in neonatal mice by the passive transfer of IgGs against COL17, such as polyclonal or monoclonal mouse IgG or IgG from BP patients. The other is an active BP model that continuously develops a disease phenotype in adult mice. IVIG decreased pathogenic IgG and the disease scores in both models. Injected IVIG distributed throughout the dermis and the intercellular space of the lower epidermis. Notably, IVIG inhibited the increase of IL-6 in both models, possibly by suppressing the production of IL-6 by keratinocytes. These results suggest that the inhibitory effects of IVIG on BP are associated with the reduction of pathogenic IgG and the modulation of cytokine production.

Neurosteroids and oxysterols as potential therapeutic agents for glaucoma and Alzheimer's disease.

Glaucoma is one of the most frequent causes of visual impairment worldwide and involves selective damage to retinal ganglion cells (RGCs) resulting in degeneration of neural pathways connecting retina to visual cortex. It is of interest that similarities in pathological changes have been described in Alzheimer's disease (AD), the most common cause of progressive memory loss and dementia in older people. Accumulation of amyloid-beta (Abeta) and hyperphosphorylated tau is thought to contribute to apoptotic neuronal death in Alzheimer's disease, and similar changes have been linked to apoptotic RGC death in glaucoma. Both glaucoma and Alzheimer's disease also suffer from a lack of effective treatments prompting a search for novel therapeutic interventions. Neurosteroids (NSs) (including oxysterols) are endogenous molecules synthesized in the nervous system from cholesterol that can modulate glutamate and GABA receptors, the primary mediators of fast excitatory and inhibitory neurotransmission in the brain, respectively. Because changes in the glutamate and GABA neurotransmitter systems contribute to the pathogenesis of AD and glaucoma, NSs are possible therapeutic targets for these disorders. In this review, we present recent evidence supporting pathological links between Alzheimer's disease and glaucoma, and focus on the possible role of NSs in these diseases and how NSs might be developed for therapeutic purposes.