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The oral mucosa is one of the first lines of the innate host defense system against microbial invasion. Interferon (IFN) lambda-1 (IFN-λ1), a type III IFN, exhibits type I IFN-like antiviral activity. In contrast to ubiquitously expressed type I IFN receptors, IFN-λ receptor 1 (IFN-λR1), which has higher affinity for type III IFNs than low-affinity interleukin (IL)-10 receptor 2, is mainly expressed on epithelial cells. Although IFN-λ1 has been shown to exert antiviral effects in the respiratory tract, gastrointestinal tract, and skin, the regulation of type III IFN receptor expression and its functions in the oral mucosa remain unclear. We herein showed the expression of IFN-λR1 in human gingival keratinocytes. The expression of IL-6, angiotensin-converting enzyme 2 (a critical molecule for severe acute respiratory syndrome coronavirus 2 infection), and IL-8 in human primary gingival keratinocytes (HGK) were significantly higher following treatments with either type I IFN (IFN-β) or type II IFN (IFN-γ) than with IFN-λ1. However, the IFN-λ1 treatment strongly induced toll-like receptor (TLR) 3 and retinoic acid-inducible gene I (RIG-I), which mainly recognize viral nucleic acids, via the STAT1-mediated pathway. Furthermore, a stimulation with a RIG-I or TLR3 agonist promoted the production of IL-6, IL-8, and IFN-λ in HGK, which was significantly enhanced by a pretreatment with IFN-λ1. These results suggest that IFN-λ1 may contribute to the activation of innate immune responses to oral viral infections by up-regulating the expression of RIG-I and TLR3 and priming their functions in keratinocytes. Supplementary Information The online version contains supplementary material available at 10.1007/s10753-022-01624-1.

PURPOSE: Trend analysis of visual field (VF) global indices may underestimate the rate of progression in severe glaucoma due to the influence of test points without detectable sensitivity. To test this hypothesis, we compared the rates of change of VF global indices with and without exclusion of undetectable points at various disease stages. METHODS: Six hundred and forty-eight eyes of 366 glaucoma patients with 8 or more reliable 30–2 standard automated perimetry over more than 2 years were enrolled. We calculated targeted mean total deviation (TMTD) by averaging total deviation except points which were consistently undetectable in 3 baseline tests. Eyes were classified as early (≥ −6 dB), moderate (− 6 dB to −12 dB), advanced (−12 dB to −20 dB), and severe (< −20 dB) based on baseline mean deviation (MD). The rates of change of MD and TMTD in each stage were statistically compared RESULTS: Mean age ± standard deviation at baseline was 56.9 ± 11.9 years. The MD slope (−0.34 dB/year) in severe glaucoma was significantly slower than TMTD slope (−0.42 dB/year, P=0.028) and was slower than MD slopes in the other stages. Difference between MD slopes and TMTD slopes was most prominent in eyes with MD values less than −25 dB (P=0.002). CONCLUSIONS: Undetectable locations in eyes with severe glaucoma may lead to an underestimate of the rates of VF progression. Trend analysis of TMTD rather than global indices offers a practical and simple approach for alleviating underestimation of VF progression in severe glaucoma.

We report a case in which intraocular endoscopy clarified the cause of Ahmed glaucoma valve (AGV) failure with a cloudy cornea. A 42-year-old patient with glaucoma underwent AGV implant surgery to treat secondary glaucoma due to chronic iridocyclitis in his left eye. After AGV, he developed bullous keratopathy (BK) in that eye. After Descemet stripping automated endothelial keratoplasty (DSAEK) was performed to treat BK, the intraocular pressure (IOP) increased and early failure of the DSAEK resulted again in a cloudy cornea. We could not precisely detect any cause of AGV failure with ordinary imaging instrumentation. An intraocular endoscope was used to determine that cause, and we found that the fibrous tissue occluded the tube of the AGV. The IOP decreased soon after the tissue was removed. We conclude that intraocular endoscopy was useful for diagnosing AGV failure with BK.

Childhood glaucoma is one of the major causes of blindness in children, however, its diagnosis is of great challenge. The study aimed to demonstrate and evaluate the performance of a deep-learning (DL) model for detecting childhood glaucoma based on periocular photographs. Primary gaze photographs of children diagnosed with glaucoma with appearance features (corneal opacity, corneal enlargement, and/or globe enlargement) were retrospectively collected from the database of a single referral center. DL framework with the RepVGG architecture was used to automatically recognize childhood glaucoma from photographs. The average receiver operating characteristic curve (AUC) of 5-fold cross-validation was 0.91. When the 5-fold result was assembled, the DL model achieved an AUC of 0.95 with a sensitivity of 0.85 and specificity of 0.94. The DL model showed comparable accuracy to the pediatric ophthalmologists and glaucoma specialists in diagnosing childhood glaucoma (0.90 vs 0.81, p = 0.22, chi-square test), outperforming the average of human examiners in the detection rate of childhood glaucoma in cases without corneal opacity (72% vs. 34%, p = 0.038, chi-square test), with a bilateral corneal enlargement (100% vs. 67%, p = 0.03), and without skin lesions (87% vs. 64%, p = 0.02). Hence, this DL model is a promising tool for diagnosing missed childhood glaucoma cases.

Tooth loss and decreased masticatory function reportedly affect cognitive function; tooth loss allegedly induces astrogliosis and aging of astrocytes in the hippocampus and hypothalamus, which is a response specific to the central nervous system owing to homeostasis in different brain regions. Capsaicin, a component of red peppers, has positive effects on brain disorders in mice. Decreased expression of transient receptor potential vanilloid 1, a receptor of capsaicin, is associated with the development of dementia. In this study, we investigated the effect of capsaicin administration in aged mice (C57BL/6N mice) with reduced masticatory function owing to the extraction of maxillary molars to investigate preventive/therapeutic methods for cognitive decline attributed to age-related masticatory function loss. The results demonstrated that mice with impaired masticatory function showed decreased motor and cognitive function at the behavioral level. At the genetic level, neuroinflammation, microglial activity, and astrogliosis, such as increased glial fibrillary acidic protein levels, were observed in the mouse brain. The mice with extracted molars fed on a diet containing capsaicin for 3 months demonstrated improved behavioral levels and astrogliosis, which suggest that capsaicin is useful in maintaining brain function in cases of poor oral function and prosthetic difficulties.

The relationship between caloric and nutrient intake and overall health has been extensively studied. However, little research has focused on the impact of the hardness of staple foods on health. In this study, we investigated the effects of a soft diet on brain function and behavior in mice from an early age. Mice fed a soft diet for six months exhibited increased body weight and total cholesterol levels, along with impaired cognitive and motor function, heightened nocturnal activity, and increased aggression. Interestingly, when these mice were switched back to a solid diet for three months, their weight gain ceased, total cholesterol levels stabilized, cognitive function improved, and aggression decreased, while their nocturnal activity remained high. These findings suggest that long-term consumption of a soft diet during early development can influence various behaviors associated with anxiety and mood regulation, including weight gain, cognitive decline, impaired motor coordination, increased nocturnal activity, and heightened aggression. Therefore, the hardness of food can impact brain function, mental well-being, and motor skills during the developmental stage. Early consumption of hard foods may be crucial for promoting and maintaining healthy brain function.

Introduction Neovascular glaucoma is characterized by neovascularization of the iris and the anterior angle chamber. Intravitreal anti-vascular endothelial growth factor agents may improve intraocular pressure (IOP) and neovascularization. Methods The VEGA trial assessed the efficacy and safety of intravitreal aflibercept (IVT-AFL) in patients with neovascular glaucoma in a 13-week, randomized, double-masked, sham-controlled, phase 3 study performed at multiple sites in Japan that enrolled patients with anterior segment neovascularization and IOP > 25 mmHg. Patients received background therapy plus IVT-AFL (2 mg) or sham injection at baseline. Patients were re-treated if presenting with IOP > 21 mmHg and incomplete regression of iris neovascularization, receiving additional sham or IVT-AFL injections at week 1 and IVT-AFL injections at weeks 5 and/or 9. Double-masking was maintained throughout. The primary endpoint was change in IOP from baseline to week 1. Results Fifty-four patients were randomly assigned (full analysis set); the per-protocol set comprised 52 patients. At week 1, the least squares mean change in IOP was −9.9 mmHg for IVT-AFL versus −5.0 mmHg for sham [full analysis set: difference −4.9 mmHg (95% confidence interval −10.2 to 0.3; P = 0.06); per-protocol set: −5.5 mmHg (95% CI −10.8 to −0.2; P = 0.04)]. At week 1, a greater proportion of patients administered IVT-AFL versus sham achieved IOP ≤ 21 mmHg and had improved neovascularization grades. Patients in the sham group who met re-treatment criteria and received IVT-AFL at week 1 [n = 22 (81.5%)] had an additional mean IOP decrease of 9.2 mmHg by week 2, and the proportion with improvement in neovascularization grades increased from 11.5% to 69.2%. Increases in the proportion of patients with improved neovascularization grades and the proportion who achieved IOP control (≤ 21 mmHg) were also observed by week 2 in this group. Overall, 77.8% and 74.1% of patients treated with IVT-AFL and sham/IVT-AFL, respectively, received a single IVT-AFL injection. The most common ocular treatment-emergent adverse event was punctate keratitis (9.3%: 7.4% and 11.1% in the IVT-AFL and sham/IVT-AFL groups, respectively). Conclusions IVT-AFL was associated with clinically meaningful improvements in IOP control, indicating that IVT-AFL may be a potential treatment option for patients with neovascular glaucoma. Trial Registration Clinicaltrials.gov identifier, NCT02396316. Electronic supplementary material The online version of this article (10.1007/s12325-020-01579-5) contains supplementary material, which is available to authorized users.

Background To report a case of severe acute bilateral outer retinitis after tonsillitis and rapid morphologic and functional recovery after steroid treatment. Methods Observational case report. Results A 26-year-old woman with acute bilateral blurred vision that developed after tonsillitis underwent spectral-domain optical coherence tomography (SD-OCT) that showed photoreceptor outer segment damage. Full-field electroretinography (ERG) and multifocal ERG were nonrecordable. The patient had a remarkable anatomic and functional recovery in response to steroid treatment; however, partial damage remained around the macula on SD-OCT, and an adaptive optics imaging system showed damaged cone photoreceptors. Conclusions Prednisolone is an effective treatment for a disease that is believed to be due to suspicious involvement of the autoimmune system. Even severe outer retinitis can recover completely with rapid diagnosis and treatment.

The presence of blood during ophthalmic surgery is problematic, as it can obstruct a surgeon’s view of the operative field. This is particularly true when performing trabeculectomy surgery to enhance ocular fluid outflow and reduce intraocular pressure as a treatment for glaucoma, one of the most common vision loss conditions worldwide. In this study, we investigated the performance of a transparent, self-assembling peptide gel (SPG-178) and its ability to maintain visibility during trabeculectomy surgery. Unlike the hyaluronic acid gel commonly used in ophthalmic surgery, SPG-178 did not permit the ingress of blood into the gel itself. Rather, it forced blood to flow peripherally to the gel. Moreover, if bleeding occurred under the SPG-178 gel, perfusion with saline was able to effectively flush the blood away along the interface between the SPG-178 and the ocular tissue (in this case scleral) to clear the surgical field of view. In experimental trabeculectomy surgeries with mitomycin C used as an adjuvant, there were no differences in the postoperative recovery of intraocular pressure or bleb morphology with or without the use of SPG-178. SPG-178, therefore, when used in a gel formulation, represents a new material for use in intraocular surgery to ensure a clear operative field with likely beneficial treatment outcomes.

The needle revision procedure to address failing filtering blebs is a blind technique that might easily damage the scleral flap, conjunctiva, and choroid. We propose a new surgical procedure, infrared monitor-guided bleb revision, to perform bleb revision minimally invasively and effectively, and demonstrate the procedure in a patient. We developed the guided procedure with the infrared monitor to observe the bleb interior with greater contrast. Under the monitor, we dissect the hard fibrotic tissue with a bleb knife and, if necessary, remove adhesions using a needle and vitreous forceps. Finally, 5-fluorouracil is injected into the subconjunctiva. We have performed bleb revisions safely with clear visualization of the scleral flap using an infrared light. In the current case, the patient had good intraocular pressure control for about 1 year. The new infrared monitor-guided bleb revision procedure facilitates successful bleb revisions without damage to the underlying structures.

Visualization of the iridocorneal angle, which contains the aqueous humor circulatory system and controls intraocular pressure, is important for diagnosing and managing glaucoma; however, the presence of keratoconus, keratoglobus, or severe myopia may enable direct angle visualization without gonioscopy contact lenses or applying a coupling gel. We present the first report of a case in which the iridocorneal angle was viewed directly in an eye with keratoconus using the RetCam without applying gel to the cornea. This method overcame the inability to view the angle directly in a normal eye because of the total internal reflection.

To compare early-stage intrableb structural changes after Ex-PRESS surgery using anterior-segment optical coherence tomography between primary open-angle glaucoma (POAG) and exfoliation glaucoma (XFG).Twenty-five POAG eyes and 15 XFG eyes that underwent Ex-PRESS surgery were evaluated. Intrableb images were classified into four categories based on previously reported scattering intensity: high-, medium-, and low-scattering walls and fluid-filled spaces. Bleb measurements were evaluated in both groups throughout 6 postoperative months. The 3-year surgical success was defined by the criteria intraocular pressure (IOP)18 mmHg and IOP15 mmHg with or without medications.The fluid-filled space volume at 3 and 6 months (P = 0.005 and P = 0.022, respectively) and the volume ratio of the low-scattering wall to the bleb wall (P = 0.028) at 6 months were significantly smaller in XFG than POAG postoperatively. The volume ratio of the high-scattering wall to the bleb wall was correlated positively (P = 0.007) with the IOP, and that of the low-scattering wall to the bleb wall was correlated negatively (P = 0.002) with the IOP in XFG. The 3-year surgical success rates for both criteria were significantly lower in XFG than POAG.Fluid-filled spaces were smaller in XFG than in POAG after Ex-PRESS surgery. The proportion of the high-scattering wall tended to increase and the low-scattering wall tended to decrease in XFG eyes with high IOP. Early-stage intrableb structural changes differed between POAG and XFG and may affect the prognosis.Our cutting-edge observation of intrableb fibrosis can be an important predictor of the surgical outcome.

Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor, is constitutively produced by endothelial cells and plays a vital role in maintaining vascular homeostasis. Chronic periodontitis is an inflammatory disease characterized by bleeding of periodontal tissues that support the tooth. In this study, we aimed to determine the role of PAI-1 produced by endothelial cells in response to infections caused by the primary periodontal pathogen Porphyromonas gingivalis. We demonstrated that P. gingivalis infection resulted in significantly reduced PAI-1 levels in human endothelial cells. This reduction in PAI-1 levels could be attributed to the proteolysis of PAI-1 by P. gingivalis proteinases, especially lysine-specific gingipain-K (Kgp). We demonstrated the roles of these degradative enzymes in the endothelial cells using a Kgp-specific inhibitor and P. gingivalis gingipain-null mutants, in which the lack of the proteinases resulted in the absence of PAI-1 degradation. The degradation of PAI-1 by P. gingivalis induced a delayed wound healing response in endothelial cell layers via the low-density lipoprotein receptor-related protein. Our results collectively suggested that the proteolysis of PAI-1 in endothelial cells by gingipains of P. gingivalis might lead to the deregulation of endothelial homeostasis, thereby contributing to the permeabilization and dysfunction of the vascular endothelial barrier.

The aim of this study was to report a technique for the removal of dislocated polymethyl methacrylate (PMMA) intraocular lenses (IOLs) in glaucomatous eyes.Dislocated PMMA IOLs were removed from the inferior sclerocorneal incision, and sutureless intrascleral fixation of each IOL was performed to preserve the intact superior conjunctiva and sclera for future trabeculectomy or to maintain a functional filtering bleb of trabeculectomy.In two cases, the condition of the bleb did not change, while the intraocular pressure improved or did not change after the procedures. IOL fixation was stable with no complications, such as tilt, decentration, or extrication of the IOL haptics.This procedure of preserving the superior conjunctiva and sclera can maintain the function of the bleb, superior cornea and sclera and may contribute to the success of future trabeculectomy.

Common age-related changes in the human eye contribute to the development of dry eye, including decreases in aqueous tear production. Although the infiltration of lymphocytes into the lacrimal glands occurs with age, age-related increases in tear production have also been observed in mice; however, the mechanisms underlying this increase remain unclear. We herein demonstrated that increases in tear production were not dependent on body weight gain or systemic conditions, such as insulin resistance, using aged mice and high-fat diet-fed mice. The results obtained also showed that senescence-associated T (SA-T) cells accumulated in the lacrimal glands of aged mice, particularly females. Expression levels of the nuclear transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) in whole lacrimal glands and epithelial cells isolated from lacrimal glands were significantly higher in aged mice than in young mice. The expression levels of adiponectin and one of its receptors, AdipoR2, also increased in the lacrimal glands of aged mice, but not in those of high-fat diet-fed mice. Collectively, the present results indicate that PPARγ and adiponectin-mediated signaling contribute to age-related increases in tear production in mice and have potential as therapeutic targets for the treatment of dry eye in humans.

Purpose Infrared monitor-guided bleb revision (IRGBR), an alternative needling system, visualizes anterior-segment tissues around the bleb not visible during needle revision after trabeculectomy. This study determined the safety and efficiency of 5-fluorouracil (5-FU) as an adjunctive anti-metabolite in IRGBR. Methods We retrospectively analyzed 43 consecutive eyes (40 patients; 14 eyes, primary open-angle; 29 eyes, secondary glaucoma) treated with IRGBR for failing filtering blebs. The patients were divided into two groups. The first one had IRGBR without adjunctive 5-FU subconjunctival injection, and the second one had IRGBR with 5-FU. We performed Kaplan-Meier survival analysis using log-rank tests after 2 years of follow-up and Cox proportional hazards regression model to analyze the dependence of the survival time on predictor variables. Two failure criteria were defined as the need for additional surgery for intraocular pressure (IOP) reduction and the IOP at two consecutive follow-up visits based on definition 1, IOP ≧22 mmHg and definition 2, IOP ≧17 mmHg. Results Thirty eyes (29 cases) underwent IRGBR with subconjunctival 5-FU injection (group A in the second term) and 13 eyes (11 cases) without 5-FU (group B in the first term). The success rates 24 months after IRGBR were 73.3 and 23.1%, respectively, in groups A and B based on the definition 1 failure and 56.7 and 7.7% based on the definition 2 failure. Complications included transient bleb leaks (group A, 3 eyes; group B, none) and choroidal detachment (group A, 1 eye; group B, none). No use of 5-FU and IOPs ≧10 mmHg 1 week after IRGBR were significant risk factors. Conclusions Adjunctive 5-FU in IRGBR achieved a better success rate for failing trabeculectomy blebs.

Senescence in periodontal tissues may be involved in the pathogenesis of periodontitis. In this study, we analyzed cellular senescence in gingival tissues of aged mice and in gingival fibroblast cultures and investigated the relationship of cellular senescence with the pathogenesis of periodontal disease. The proportions of senescence-associated β-galactosidase (SA-β-gal)-positive cells and the mRNA expression levels of p16 and p21 in gingival tissues and gingival fibroblasts from 20-month-old mice were significantly higher than those in gingival tissues and gingival fibroblasts from 10-week-old mice. The mRNA expression levels of IL-1β and TNF-α as well as the numbers of total macrophages and M1 macrophages were increased in gingival tissues of aged mice. Expression of these senescence-associated molecules was also increased in long-term passaged or hydrogen peroxide-stimulated human gingival fibroblasts; however, it was significantly suppressed by treatment with the senolytic drug ABT-263. These results suggest that cellular senescence can be induced in gingival fibroblasts in culture as was observed in gingival tissues of aged mice. An increase in senescent cells in the gingiva may be associated with the pathogenesis of periodontitis in part through activating an inflammatory response in periodontal tissues.

Objectives Tooth bleaching has become one of the most frequently requested esthetic procedures in dental practice. A side effect of bleaching is gingival irritation. This study examined the efficacy of propolis to treat gingival irritation caused by bleaching in vivo and in vitro. Methods Gingival irritation was mimicked by a mild burn injury to oral mucosa in young (10 week old) and aged (18 month old) mice. Propolis ointment was immediately applied to the burn area. After 24 h, gingiva was collected to determine the efficacy of propolis by hematoxylin and eosin staining and real-time polymerase chain reaction (PCR). Results Topical application of propolis ointment reduced the infiltration of inflammatory cells at irritated sites and promoted the repair of the mucosal epithelium in young and aged mice. It also suppressed the expression of IL-1 β and TNF-α and increased keratin 1 and 5 expression in the irritated gingiva. Propolis suppressed an increase in IL-1β and TNF- α upon stimulation with H2O2 in young and SA- β -gal-expressing senescent human gingival fibroblasts (HGFs) cultures. Conclusions Propolis may be effective for mucosal repair in gingival irritation as it suppresses the expression of proinflammatory cytokines and promotes keratin expression.

Introduction Neovascular glaucoma is characterized by neovascularization of the iris and anterior angle chamber. Intravitreal anti-vascular endothelial growth factor agents may decrease intraocular pressure (IOP) and improve neovascularization. The VENERA study assessed the efficacy and safety of intravitreal aflibercept (IVT-AFL) in patients with neovascular glaucoma. Methods This was a 5-week, single-arm, nonrandomized, open-label, phase 3 study performed at 7 study sites in Japan that enrolled Japanese patients with anterior segment neovascularization and IOP > 25 mmHg who had not undergone (within 30 days prior), nor were imminently scheduled to undergo (within 8 days following) intraocular surgeries, including panretinal photocoagulation (PRP). Patients received background therapy plus 2 mg IVT-AFL at baseline. Background therapy with systemic IOP-lowering drugs was prohibited for 3 days before day 1 and until IOP evaluation at week 1. The primary endpoint was the change in IOP from baseline to week 1 and the secondary endpoint was the proportion of patients with an improvement of ≥ 1 grade of neovascularization of the angle (NVA) from baseline to week 1. Results Sixteen patients received treatment (full analysis set); the per-protocol set comprised 15 patients. The mean IOP decreased from 34.1 mmHg at baseline to 25.8 mmHg at week 1 (mean change, −8.3 mmHg [95% confidence interval; CI −12.2 to −4.4; P = 0.0004]). At week 1, 81.3% of patients had an improvement in the grade of neovascularization of the iris (NVI) and 50.0% of patients had an improvement in NVA grade. The proportion of patients with controlled IOP (≤ 21 mmHg) was 43.8% (95% CI 19.8–70.1) at week 1, and increased to 56.3% at week 2 and 86.7% at week 5. The most common ocular treatment-emergent adverse event was eye pain, which occurred in 4 patients (25.0%). Conclusions IVT-AFL was associated with statistically significant and clinically meaningful IOP reductions, without concomitant use of systemic IOP-lowering drugs or PRP. The safety profile was consistent with the known safety profile of IVT-AFL. These findings supplement those from the previous VEGA study, and suggest that IVT-AFL may be a potential treatment option for patients with neovascular glaucoma. Trial Registration Clinicaltrials.gov identifier NCT03639675. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-020-01580-y.

Purpose This study aimed to quantitatively analyze the association between follow-up duration and the severity of limbal stem cell deficiency (LSCD) or visual acuity in patients with aniridia. Methods A total of 52 eyes of 27 patients with aniridia were enrolled at Osaka University Hospital. Medical records were retrospectively reviewed to obtain information on the severity of LSCD and corrected distance visual acuity (CDVA). LSCD severity was based on a modified severity grading scale. We used an ordered logistic regression model to examine the association between follow-up duration and LSCD severity, and a linear regression model with a generalized linear mixed model for the association between follow-up duration and visual acuity. Results The mean follow-up duration was 5.2 ± 6.3 years. The mean age at the last follow-up visit was 40.5 ± 18.9 years. The mean CDVA was 1.52 ± 1.09 logMAR. At the last follow-up, 1 examined eye (1.9%) was categorized as stage 0, 7 (13.5%) as Ia, 9 (17.3%) as Ib, 5 (9.6%) as Ic, 2 (3.8%) as IIb, 12 (23.1%) as IIc, and 11 (21.2%) as III. Five eyes (9.6%) were unclassifiable. There was a significant association between follow-up duration and LSCD severity (odds ratio per +1 year, 1.41; P < 0.001). CDVA significantly decreased as follow-up duration increased. Each increase of 1 year in the follow-up duration was associated with a mean difference of +0.021 logMAR (95% confidence interval [CI] 0.01–0.03; P < 0.001). Conclusions We quantitatively demonstrate that LSCD severity and visual impairment significantly progress as follow-up duration increases.

Alzheimer’s disease (AD) is the most common cause of dementia, and it exhibits pathological properties such as deposition of extracellular amyloid β (Aβ) and abnormally phosphorylated Tau in nerve cells and a decrease of synapses. Conventionally, drugs targeting Aβ and its related molecules have been developed on the basis of the amyloid cascade hypothesis, but sufficient effects on the disease have not been obtained in past clinical trials. On the other hand, it has been pointed out that chronic inflammation and microbial infection in the brain may be involved in the pathogenesis of AD. Recently, attention has been focused on the relationship between the periodontopathic bacterium Porphylomonas gingivalis and AD. P. gingivalis and its toxins have been detected in autopsy brain tissues from patients with AD. In addition, pathological conditions of AD are formed or exacerbated in mice infected with P. gingivalis. Compounds that target the toxins of P. gingivalis ameliorate the pathogenesis of AD triggered by P. gingivalis infection. These findings indicate that the pathological condition of AD may be regulated by controlling the bacteria in the oral cavity and the body. In the current aging society, the importance of oral and periodontal care for preventing the onset of AD will increase.

Summary: In the vertebrate retina, cone photoreceptors play crucial roles in photopic vision by transmitting light-evoked signals to ON- and/or OFF-bipolar cells. However, the mechanisms underlying selective synapse formation in the cone photoreceptor pathway remain poorly understood. Here, we found that Lrit1, a leucine-rich transmembrane protein, localizes to the photoreceptor synaptic terminal and regulates the synaptic connection between cone photoreceptors and cone ON-bipolar cells. Lrit1-deficient retinas exhibit an aberrant morphology of cone photoreceptor pedicles, as well as an impairment of signal transmission from cone photoreceptors to cone ON-bipolar cells. Furthermore, we demonstrated that Lrit1 interacts with Frmpd2, a photoreceptor scaffold protein, and with mGluR6, an ON-bipolar cell-specific glutamate receptor. Additionally, Lrit1-null mice showed visual acuity impairments in their optokinetic responses. These results suggest that the Frmpd2-Lrit1-mGluR6 axis regulates selective synapse formation in cone photoreceptors and is essential for normal visual function. : Ueno et al. finds that Lrit1 plays an important role in regulating the synaptic connection between cone photoreceptors and cone ON-bipolar cells. The Frmpd2-Lrit1-mGluR6 axis is crucial for selective synapse formation in cone photoreceptors and for development of normal visual function. Keywords: retina, circuit, synapse formation, cone photoreceptor cell, ON-bipolar cell, visual acuity

Atopic dermatitis (AD) is a chronic inflammatory skin disease. Corticosteroids, which are widely used for AD treatment, have adverse effects, and alternative treatments are urgently needed. This study examined the effect of topical application of high-dose glucose on inflamed skin in a murine model of AD. High-dose glucose treatment on the ear reduced dermatitis scores and ear thicknesses in mite antigen-treated NC/Nga mice. The levels of thymus and activation-regulated chemokine (TARC), Th cytokines (interleukin (IL)-4, IL-5, IL-12, IL-13, and (interferon) IFN-γ), and IgE were decreased in the serum of high-dose glucose-treated mice. Expression of claudin-1 and filaggrin was reduced in the ear epithelium in the NC/Nga mice. However, the reduced expression was restored by topical treatment with high-dose glucose. High-dose glucose also induced the expression of claudin-1 and filaggrin in cultured human skin keratinocytes. Co-stimulation with IL-4, IL-13, and thymic stromal lymphoprotein downregulated the expression of filaggrin in culture. However, high-dose glucose treatment restored the reduced expression of filaggrin. These results suggest that high-dose glucose treatment suppresses inflammation in the skin lesions by improving the skin barrier function.

Periodontitis is a localized infectious disease caused by periodontopathic bacteria, such as Porphyromonas gingivalis. Recently, it has been suggested that bacterial infections may contribute to the onset and the progression of Alzheimer’s disease (AD). However, we do not have any evidence about a causative relationship between periodontitis and AD. In this study, we investigated by using a transgenic mouse model of AD whether periodontitis evoked by P. gingivalis modulates the pathological features of AD. Cognitive function was significantly impaired in periodontitis-induced APP-Tg mice, compared to that in control APP-Tg mice. Levels of Amiloid β (Aβ) deposition, Aβ40, and Aβ42 in both the hippocampus and cortex were higher in inoculated APP-Tg mice than in control APP-Tg mice. Furthermore, levels of IL-1β and TNF-α in the brain were higher in inoculated mice than in control mice. The levels of LPS were increased in the serum and brain of P. gingivalis-inoculated mice. P. gingivalis LPS-induced production of Aβ40 and Aβ42 in neural cell cultures and strongly enhanced TNF-α and IL-1β production in a culture of microglial cells primed with Aβ. Periodontitis evoked by P. gingivalis may exacerbate brain Aβ deposition, leading to enhanced cognitive impairments, by a mechanism that involves triggering brain inflammation., Periodontal disease is a risk factor for Alzheimer’s disease Alzheimer’s disease is a scourge of longevity that will drain enormous resources from health budgets in the future. Unfortunately, the pathogenesis of the disease remains an enigma and there is no adequate treatment or prophylaxis for the disease. One key priority is to examine the modifiable risk factors that influence the development of dementia. A risk factor relationship between periodontal pathogens/periodontal disease and AD exists. In Alzheimer’s model mice infected with Porphromonas gingivalis, a type of periodontopathic bacterium, cognitive function was reduced and deposition of amyloid β peptide was increased. Moreover, inflammatory cytokines and bacterial endotoxin were increased in the serum and brain. Neuroinflammation may be caused by an increase in these inflammatory mediators, and the pathology of Alzheimer’s disease may be exacerbated. Since periodontal infections are treatable, treatment of periodontal diseases during this period may be effective for delaying the onset or progression of AD.

Respiratory syncytial virus (RSV) induces not only infantile recurrent wheezing but also potentially atopic asthma.To test the effect of RSV infection on development of subsequent atopic asthma, we evaluated whether palivizumab, an anti-RSV monoclonal antibody, by preventing severe RSV disease in the first year of life, could impact subsequent recurrent wheezing and atopic asthma at 6 years of age.During the 2007 to 2008 RSV season, the decision to administer palivizumab was made based on standard medical practice and an observational prospective multicenter (n = 52) case-control study in preterm infants with a gestational age between 33 and 35 weeks followed from 0 to 3 years (preceding Committee on Recurrent Wheezing study). The 52 investigators at hospitals then followed these subjects until 6 years of age, reported here (Effects of Preventive Treatment for Respiratory Syncytial [RS] Virus Infection During Infancy on Later Atopic Asthma in Preterm Infants; Scientific Committee for Elucidation of Infantile Asthma). Parents of study subjects reported the infants' physicians' assessment of recurrent wheezing, using a report card and a novel mobile phone-based reporting system using the Internet. The primary endpoint was the incidence of atopic asthma.Of 444 preterm infants enrolled, 349 received palivizumab during the first year of life. At 6 years, atopic asthma was not different in the groups: 15.3 and 18.2% of infants in the treated and untreated groups, respectively (P = 0.57). On the other hand, physician-diagnosed recurrent wheezing was observed in 15.3 and 31.6% in the treated and untreated groups, respectively (P = 0.003).Palivizumab prophylaxis administered to preterm infants did not suppress the onset of atopic asthma but resulted in a significantly lower incidence of recurrent wheezing during the first 6 years. Clinical trial registered with www.clinicaltrials.gov (NCT 01545245).

The morbidity of temporomandibular joint osteoarthritis (TMJOA) increases with age. Condylar articular cartilage degradation, which causes TMJOA, is known to be involved in articular chondrocyte metabolic imbalances in the temporomandibular joint (TMJ) and in other joints of the body. Epigenetic regulation, such as the chemical modification of DNA and histones, is implicated in cartilage homeostasis. However, few studies have been conducted on the epigenetic regulation of condylar articular cartilage degradation. The present study investigated the regulation of histone H3 lysine 9 (H3K9) methylation and its effects on the pathogenesis of degenerative TMJ cartilage disorders. The histone H3K9 methylation level was decreased in degenerated condylar articular cartilage in aged mice. Treatment with chaetocin (a selective H3K9 methylation inhibitor) reduced cell viability and promoted caspase‑3/7 activity in ATDC5 mouse chondroprogenitor cells. The inhibition of H3K9 methylation increased matrix metalloproteinase (Mmp)1 and Mmp13 mRNA expression in these cells. Furthermore, the expression levels of Sox9 and collagen α1(II) (Col2a1) mRNA, which are anabolic factors for chondrogenic differentiation, were also decreased by treatment with chaetocin, which is an inhibitor of histone methyltransferases. These results indicated that histone H3K9 methylation regulates chondrocyte homeostasis in terms of cell growth, apoptosis and gene expression, and highlighted a possible future therapy option for TMJOA.

A deep-learning (DL) based noise reduction algorithm, in combination with a vessel shadow compensation method and a three-dimensional (3D) segmentation technique, has been developed to achieve, to the authors best knowledge, the first automatic segmentation of the anterior surface of the lamina cribrosa (LC) in volumetric ophthalmic optical coherence tomography (OCT) scans. The present DL-based OCT noise reduction algorithm was trained without the need of noise-free ground truth images by utilizing the latest development in deep learning of de-noising from single noisy images, and was demonstrated to be able to cover more locations in the retina and disease cases of different types to achieve high robustness. Compared with the original single OCT images, a 6.6 dB improvement in peak signal-to-noise ratio and a 0.65 improvement in the structural similarity index were achieved. The vessel shadow compensation method analyzes the energy profile in each A-line and automatically compensates the pixel intensity of locations underneath the detected blood vessel. Combining the noise reduction algorithm and the shadow compensation and contrast enhancement technique, medical experts were able to identify the anterior surface of the LC in 98.3% of the OCT images. The 3D segmentation algorithm employs a two-round procedure based on gradients information and information from neighboring images. An accuracy of 90.6% was achieved in a validation study involving 180 individual B-scans from 36 subjects, compared to 64.4% in raw images. This imaging and analysis strategy enables the first automatic complete view of the anterior LC surface, to the authors best knowledge, which may have the potentials in new LC parameters development for glaucoma diagnosis and management.