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Abstract We aimed to identify prognostic risk factors for visual deterioration in eyes with epiretinal membrane (ERM) and open-angle glaucoma (OAG) through long-term follow-up. In this retrospective observational case series, we examined consecutive eyes with ERM and OAG over a minimum follow-up of 2 years. Visual outcomes and prognostic factors were analyzed in patients’ eyes undergoing ERM peeling with pars plana vitrectomy (PPV) (peeling group) and only observation (observation group). Eyes followed for less than 2 years after PPV were excluded. Among 100 eyes from 84 patients, 31 and 69 eyes were classified into peeling and observation groups, respectively. Over the follow-up period, best-corrected visual acuity (BCVA) in the observation group worsened from 0.03 ± 0.19 to 0.14 ± 0.33 (P = 0.0003), whereas that in the peeling group remained stable. Multivariate analysis revealed microcystic macular edema (MME) (odds ratio: 4.97; 95% confidence interval [CI]: 1.52 to 16.2; P = 0.008) and thin central foveal thickness (CFT) (odds ratio: 0.99; 95% CI: 0.98 to 1.00; P = 0.033) as risk factors for visual acuity decay. The presence of MME and thin CFT were risk factors for long-term visual deterioration in eyes with ERM and concomitant OAG. Vitrectomy with ERM peeling for eyes with OAG may be considered to preserve BCVA.

Summary: In vertebrates, retinal neural circuitry for visual perception is organized in specific layers. The outer plexiform layer is the first synaptic region in the visual pathway, where photoreceptor synaptic terminals connect with bipolar and horizontal cell processes. However, molecular mechanisms underlying cone synapse formation to mediate OFF pathways remain unknown. This study reveals that Necl-1/CADM3 is localized at S- and S/M-opsin-containing cones and dendrites of type 4 OFF cone bipolar cells (CBCs). In Necl-1−/− mouse retina, synapses between cones and type 4 OFF CBCs were dislocated, horizontal cell distribution became abnormal, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors were dislocated. Necl-1−/− mice exhibited aberrant short-wavelength-light-elicited signal transmission from cones to OFF CBCs, which was rescued by AMPA receptor potentiator. Additionally, Necl-1−/− mice showed impaired optokinetic responses. These findings suggest that Necl-1 regulates cone synapse formation to mediate OFF cone pathways elicited by short-wavelength light in mouse retina.

Abstract 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 fivefold cross-validation was 0.91. When the fivefold 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.

Abstract Background Iris mammillation is a rare disease characterized by the distribution of multiple nodules on the iris surface. The course of uveitic glaucoma with iris mammillation has never been reported. Case presentation A 56-year-old woman, who presented with unilateral decreased vision, visited our hospital for treatment of uveitic glaucoma in the right eye. Multiple nodules were scattered over the iris surface in that eye. This case was diagnosed as iris mammillation on clinical findings. After excluding malignant tumors such as melanoma, trabeculectomy was performed. The resected iris had no pathologically malignant findings. The iris nodules evolved to a sand-like appearance, and the intraocular pressure remained stable without recurrent inflammation 7 years after trabeculectomy. Conclusions In a case of unilateral uveitic glaucoma with iris mammillation, filtration surgery was performed after excluding the presence of a malignancy, and the long-term postoperative course has been stable.

BackgroundThe gonio-endoscope is a novel device for use during minimally invasive glaucoma surgery (MIGS) to treat glaucomatous eyes with cloudy cornea. The MIGS procedure requires a surgical gonioprism lens for direct visualization of the angle, intraoperative manipulation of the surgical microscope and the patient’s head position, and the patient’s eye without a cloudy cornea. In cases with cloudy corneas or limitation of neck movement, MIGS cannot be safely performed. Gonio-endoscopy facilitates clear visualization of the trabecular meshwork (TM) to perform MIGS safely and easily even in a patient with corneal opacities or limitation of neck movement with no additional MIGS procedures. We report the first case in which we performed the newly developed a 10,000-pixel high-resolution 23-gauge gonio-endoscopic operation.Case presentationThe patient was a 58-year-old man with Down syndrome who had secondary glaucoma bilaterally after cataract surgery and long-time use of a steroid for atopic dermatitis and allergic conjunctivitis. His left eye had a cloudy cornea after penetrating keratoplasty for keratoconus with severe corneal residual scarring after prior resolved corneal hydrops. When the intraocular pressure (IOP) in his left eye increased to 41 mmHg despite the maximum use of anti-glaucoma eyedrops, he was referred to our hospital. Anterior-segment optical coherence tomography showed an open angle. We developed a new gonio-endoscope (MACHIDA Endoscope Co., Ltd., Chiba, Japan and NIPRO CORPORATION, Osaka, Japan), the probe of which is bent appropriately to aid visualization of and access to the TM. After obtaining clinical approval from the government and our institution, we could safely perform a high-resolution 23-gauge gonio-endoscopy-assisted microhook ab interno trabeculotomy (μLOT). The IOP decreased to 10 mmHg and the visual acuity has been preserved with no major complications for 1 year postoperatively.ConclusionThis new technique of clear gonio-visualization using a gonio-endoscope might be helpful for a safe and easy μLOT in patients with cloudy corneas. This device can apply to other types of MIGS procedures and cases with pathological diagnoses of glaucoma that are difficult to treat.

Abstract Objective To determine senescence‐associated changes in the gingival tissues of aged mice and gingival fibroblast cultures. Materials and Methods The production of senescence‐associated β‐galactosidase (SA‐β‐gal) and mRNA expression of p16, p21, interleukin (IL)‐1β, and tumor necrosis factor α (TNF‐α) were evaluated in gingival tissues, gingival fibroblasts of 10‐ and 20‐month‐old C57BL/6NCrl mice, and multiple‐passaged and hydrogen peroxide‐stimulated human gingival fibroblasts (HGFs). Changes in molecular expression in HGF cultures due to senescent cell elimination by the senolytic drug ABT‐263 (Navitoclax) were analyzed. Results Compared to 10‐week‐old mice, the 20‐month‐old mice had higher numbers of M1 macrophages. The proportion of cells expressing SA‐β‐gal were also higher in 20‐ month‐old mice than in 10‐week‐old‐mice. Gingival fibroblasts in 20‐month‐old mice expressed less collagen 1a1, collagen 4a1, and collagen 4a2 mRNA than those in 10‐week‐old mice. Compared to control cells, H2O2 treated HGF cells expressed higher levels of SA‐β‐gal and p16, p21, IL‐1β, and TNF‐α. Furthermore, ABT‐263 suppressed HGF cell expression of cytokines after senescence induction. Conclusions Senescence‐associated changes were observed in the gingival tissues of aged mice and HGF cultures. In addition, the potential of senolytic drugs to modify aging‐related changes in the gingiva was shown.

Abstract Age-related tooth loss impedes mastication. Epidemiological and physiological studies have reported that poor oral hygiene and occlusion are associated with cognitive decline. In the present study, we analyzed the mechanism by which decreased occlusal support following bilateral extraction of the maxillary first molars affects cognitive functions in young and aged mice and examined the expression of brain-function-related genes in the hippocampus and hypothalamus. We observed decreased working memory, enhanced restlessness, and increased nocturnal activity in aged mice with molar extraction compared with that in mice with intact molars. Furthermore, in the hypothalamus and hippocampus of molar-extracted aged mice, the transcript-level expression of Bdnf, Rbfox3, and Fos decreased, while that of Cdkn2a and Aif1 increased. Thus, decreased occlusal support after maxillary first molar extraction may affect cognitive function and activity in mice by influencing aging, neural activity, and neuroinflammation in the hippocampus and hypothalamus.

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.

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.

Abstract 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.

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.

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

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.

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.

Abstract Background Ultraviolet (UV) light is used for phototherapy in dermatology, and UVB light (around 310 nm) is effective for treatment of psoriasis and atopic dermatitis. In addition, it is known that UVC light (around 265 nm) has a bactericidal effect, but little is known about the bactericidal effect of UVB light. In this study, we examined the bactericidal effects of UVB-light emitting diode (LED) irradiation on oral bacteria to explore the possibility of using a 310 nm UVB-LED irradiation device for treatment of oral infectious diseases. Methods We prepared a UVB (310 nm) LED device for intraoral use to examine bactericidal effects on Streptococcus mutans, Streptococcus sauguinis, Porphyromonas gingivalis, and Fusobacterium nucleatum and also to examine the cytotoxicity to a human oral epithelial cell line (Ca9–22). We also examined the production of nitric oxide and hydrogen peroxide from Ca9–22 cells after irradiation with UVB-LED light. Results Irradiation with the 310 nm UVB-LED at 105 mJ/cm2 showed 30–50% bactericidal activity to oral bacteria, though 17.1 mJ/cm2 irradiation with the 265 nm UVC-LED completely killed the bacteria. Ca9–22 cells were strongly injured by irradiation with the 265 nm UVC-LED but were not harmed by irradiation with the 310 nm UVB-LED. Nitric oxide and hydrogen peroxide were produced by Ca9–22 cells with irradiation using the 310 nm UVB-LED. P. gingivalis was killed by applying small amounts of those reactive oxygen species (ROS) in culture, but other bacteria showed low sensitivity to the ROS. Conclusions Narrowband UVB-LED irradiation exhibited a weak bactericidal effect on oral bacteria but showed low toxicity to gingival epithelial cells. Its irradiation also induces the production of ROS from oral epithelial cells and may enhance bactericidal activity to specific periodontopathic bacteria. It may be useful as a new adjunctive therapy for periodontitis.

Purpose: To report a case of Mycobacterium chelonae keratitis that resulted in a transient reduction of anterior chamber depth. Observations: A 46-year-old man with keratoconus and reduced visual acuity (20/286) in his left eye presented with ciliary injection 16 months after femtosecond laser-assisted penetrating keratoplasty (PK). A slit-lamp examination showed a corneal ulcer with infiltrates and edema in both the host and graft between the 3 o'clock and 6 o'clock positions. Microbiologic tests confirmed the presence of M. chelonae. Topical arbekacin and moxifloxacin, erythromycin/colistin ointment, and oral clarithromycin were prescribed. We monitored anterior chamber depth by anterior segment optical coherence tomography (AS-OCT) throughout the recovery period. The anterior chamber depth was normal before treatment, with an intraocular pressure (IOP) of 7 mmHg. Although ciliary injection and infiltrates were gradually resolved, slit-lamp examination and AS-OCT revealed an extreme reduction of anterior chamber depth without corneal perforation, 1 month after beginning treatment. The IOP was 5 mmHg, and ciliochoroidal detachment (CCD) was present. The anterior chamber increased with the resolution of CCD and keratitis. Although hypotony continued despite the resolution of CCD and keratitis, the IOP eventually recovered to ≥10 mmHg at 1 month after remission. Onset and resolution of transient reduction of anterior chamber depth presumably occurred by anterior rotation and recovery of the ciliary body, respectively. Subsequent PK triple surgery enabled visual recovery to 20/100. Conclusions and importance: severe anterior segment inflammation due to infectious keratitis may cause CCD and subsequent reduction of anterior chamber depth due to anterior rotation. AS-OCT is a non-invasive and efficient tool for the evaluation of iridociliary structure and the anterior chamber in patients with infectious keratitis. Keywords: Mycobacterium chelonae keratitis, Ciliochoroidal detachment, Anterior segment optical coherence tomography

This study reviews the research of dementia, a pathology for which numerous studies have found associations with masticatory function in the elderly. These issues are presently major problems in geriatric medical and welfare settings, and we discuss the prospects for future research into mastication. Dementia and masticatory function have been examined in a range of epidemiological and neuroscientific studies, and associations between the two have been reported. However, a causal relationship has not been satisfactorily established. Biochemical studies have also clarified the basis of the association between dementia and periodontal disease, but have not yet yielded sufficient evidence. Studies offering a high level of evidence, such as intervention studies and meta-analyses, are expected to be undertaken in this area in the future. Maintenance and recovery of masticatory function is of great importance with respect to achieving healthy longevity. Dental science will have considerable obligations and will have to take on an important role in this regard. For dental treatment to take on such important roles in the fields of health, medicine and welfare, it is necessary to provide information that will be understood not just by other medical and healthcare professionals, but also by the general public.

The cytokine IL-33 is constitutively expressed in epithelial cells and it augments Th2 cytokine-mediated inflammatory responses by regulating innate immune cells. We aimed to determine the role of the periodontal pathogen, Porphyromonas gingivalis, in the enhanced expression of IL-33 in human gingival epithelial cells. We detected IL-33 in inflamed gingival epithelium from patients with chronic periodontitis, and found that P. gingivalis increased IL-33 expression in the cytoplasm of human gingival epithelial cells in vitro. In contrast, lipopolysaccharide, lipopeptide, and fimbriae derived from P. gingivalis did not increase IL-33 expression. Specific inhibitors of P. gingivalis proteases (gingipains) suppressed IL-33 mRNA induction by P. gingivalis and the P. gingivalis gingipain-null mutant KDP136 did not induce IL-33 expression. A small interfering RNA for protease-activated receptor-2 (PAR-2) as well as inhibitors of phospholipase C, p38 and NF-κB inhibited the expression of IL-33 induced by P. gingivalis. These results indicate that the PAR-2/IL-33 axis is promoted by P. gingivalis infection in human gingival epithelial cells through a gingipain-dependent mechanism.

Vinculin, a 116-kDa membrane cytoskeletal protein, is an important molecule for cell adhesion; however, little is known about its other cellular functions. Here, we demonstrated that vinculin binds to Rab5 and is required for Staphylococcus aureus (S. aureus) uptake in cells. Viunculin directly bound to Rab5 and enhanced the activation of S. aureus uptake. Over-expression of active vinculin mutants enhanced S. aureus uptake, whereas over-expression of an inactive vinculin mutant decreased S. aureus uptake. Vinculin bound to Rab5 at the N-terminal region (1-258) of vinculin. Vinculin and Rab5 were involved in the S. aureus-induced phosphorylation of MAP kinases (p38, Erk, and JNK) and IL-6 expression. Finally, vinculin and Rab5 knockdown reduced infection of S. aureus, phosphorylation of MAPKs and IL-6 expression in murine lungs. Our results suggest that vinculin binds to Rab5 and that these two molecules cooperatively enhance bacterial infection and the inflammatory response.

Aim: Appetite loss has been associated with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Among older people, decreased appetite can result in poor nutrition and subsequent loss of independent living. We examined the factors related to appetite loss in persons with AD and MCI to provide evidence for countermeasures to prevent appetite loss and progression of cognitive impairment. Methods: We included 1238 older adults undergoing outpatient treatment at the Center for Comprehensive Care and Research on Memory Disorders (Medical Center for Dementia) at the National Center for Geriatrics and Gerontology in Obu, Japan. The Council on Nutrition Appetite Questionnaire, an appetite questionnaire for older people, was used to evaluate appetite. Appetite loss in persons diagnosed with AD or MCI was divided into two groups according to the Council on Nutrition Appetite Questionnaire scores, and logistic regression analysis was carried out to identify independent factors associated with appetite loss. The following variables were used to evaluate for covariates: general information, functional evaluation and medications. Results: The AD and MCI groups contained 853 and 385 individuals, respectively. In both groups, depression and difficulty in maintaining attention while eating were significantly associated with poor appetite. Among persons with AD, lower vitality, more comorbidities, nonuse of antidementia drugs and use of psychotropic drugs were also significantly associated with poor appetite. Conclusions: The present study recognized possible factors individually associated with appetite loss among persons with AD or MCI. Future studies are required to examine supportive strategies to treat poor appetite in these populations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Experiments have previously demonstrated the therapeutic potential of mobilized dental pulp stem cells (MDPSCs) for complete pulp regeneration. The aim of the present pilot clinical study is to assess the safety, potential efficacy, and feasibility of autologous transplantation of MDPSCs in pulpectomized teeth. Methods: Five patients with irreversible pulpitis were enrolled and monitored for up to 24 weeks following MDPSC transplantation. The MDPSCs were isolated from discarded teeth and expanded based on good manufacturing practice (GMP). The quality of the MDPSCs at passages 9 or 10 was ascertained by karyotype analyses. The MDPSCs were transplanted with granulocyte colony-stimulating factor (G-CSF) in atelocollagen into pulpectomized teeth. Results: The clinical and laboratory evaluations demonstrated no adverse events or toxicity. The electric pulp test (EPT) of the pulp at 4 weeks demonstrated a robust positive response. The signal intensity of magnetic resonance imaging (MRI) of the regenerated tissue in the root canal after 24 weeks was similar to that of normal dental pulp in the untreated control. Finally, cone beam computed tomography demonstrated functional dentin formation in three of the five patients. Conclusions: Human MDPSCs are safe and efficacious for complete pulp regeneration in humans in this pilot clinical study. [ABSTRACT FROM AUTHOR]

Background Tumor necrosis factor alpha (TNF-α) plays a central role in the initiation and maintenance of immune responses to periodontopathic bacteria. However, excess TNF-α leads to dysregulated immune responses and progression of periodontitis. Porphyromonas gingivalis (P. gingivalis) invades gingival epithelial cells and then multiplies and survives for a long period. Additionally, increment of TNF-α in periodontal sites is associated with a high prevalence of gram-negative anaerobes such as P. gingivalis. However, it has not been determined whether TNF-α affects invasion of P. gingivalis in periodontal tissues. Results We examined the effect of TNF-α on invasion of P. gingivalis in gingival epithelial cells and clarified the mechanism by which TNF-α augments invasion of P. gingivalis. Invasion of P. gingivalis into Ca9-22 cells was augmented by stimulation with TNF-α and it was inhibited by treatment with an antibody to TNF receptor-1. TNF-α increased production of ICAM-1, and P. gingivalis invasion was inhibited by an antibody to ICAM-1 in Ca9-22 cells. Silencing of Rab5 mRNA inhibited P. gingivalis invasion. Furthermore, the JNK inhibitor SP600125 inhibited invasion of P. gingivalis and also decreased the active form of Rab5 in Ca9-22 cells. Conclusion TNF-α augments invasion of P. gingivalis in human gingival epithelial cells through increment of ICAM-1 and activation of Rab5. These phenomena may contribute to persistent infection of P. ginigvalis and prolongation of immune responses in periodontal tissues. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the peri-papillary distribution of retinal nerve fiber layer thickness (RNFLT) in normal eyes using spectral-domain optical coherence tomography and to study potentially related factors. Methods: In 7 institutes in Japan, RNFLT in 7 concentric Peri-papillary circles with diameters ranging from 2.2 to 4.0 mm were measured using spectral-domain optical coherence tomography in 251 ophthalmologically normal subjects. Multiple regression analysis for the association of RNFLT with sex, age, axial length, and disc area was performed. Results: Retinal nerve fiber layer thickness decreased linearly from 125 to 89 μm as the measurement diameter increased (P<.001, mixed linear model). Retinal nerve fiber layer thickness correlated with age in all diameters (partial correlation coefficient [PCC]=-0.40 to -0.32; P<.001) and negatively correlated with disc area in the 2 innermost circles but positively correlated in the 3 outermost circles (PCC=-0.30 to -0.22 and 0.17 to 0.20; P≤.005). Sex and axial length did not correlate with RNFLT (P<.08). The decay slope was smallest in the temporal and largest in the nasal and inferior quadrants (P<.001); positively correlated with disc area (PCC=0.13 to 0.51; P≤.04); and negatively correlated with RNFLT (PCC=-0.51 to -0.15; P≤.01). Conclusions: In normal Japanese eyes, RNFLT significantly correlated with age and disc area, but not with sex or axial length. Retinal nerve fiber layer thickness decreased linearly as the measurement diameter increased. The decay slope of RNFLT was steepest in the nasal and inferior quadrants and steeper in eyes with increased RNFLT or smaller optic discs. [ABSTRACT FROM AUTHOR]

Abstract Purpose  To investigate the age-related changes in a myopic shift under binocular conditions (phoria myopia) in patients with intermittent exotropia (IXT). Methods  Forty-five patients with IXT were studied: 21 were ≤9 years old (children), 11 were between 10 and 19 years (adolescents), and 13 were between 20 and 43 years (adults). The angle of strabismus was determined by the alternating prism cover test. The spherical refractive error was measured at 1 m using infrared video retinoscopy under monocular and binocular viewing conditions. Results  The change in the spherical refractive error (ΔR) between binocular and monocular conditions was significantly larger in adults (ΔR = −1.11 ± 1.01 diopters (D), average ± standard deviation) than in children (ΔR = −0.34 ± 0.34 D; P r = 0.55, P = 0.04). After strabismus surgery, ΔR decreased in adults (n = 3). Conclusions  Because a significant myopic shift under binocular conditions was detected in IXT patients older than 20 years, phoria myopia can occur after age 20 even if functional disturbances are not observed in children or adolescent IXT patients, a fact that specialists need to bear in mind when treating younger patients. [ABSTRACT FROM AUTHOR]

Abstract Purpose  To investigate the effect of electrical stimulation (ES) on the induction of insulin-like growth factor 1 (IGF-1) in cultured retinal Müller cells. Methods  Müller cells were isolated from rat retinas. ES was applied to Müller cells of passage 1 with biphasic pulses (duration, 1 ms; frequency, 20 Hz; current, 0–10 mA) for 30 min. The mRNA level of IGF-1 was determined by reverse transcription-polymerase chain reaction (RT-PCR) immediately to 2 h after ES. The change of intracellular calcium concentration ([Ca2+]) induced by ES was monitored by Ca2+ imaging with Fura 2-AM. Ca2+ imaging and RT-PCR were performed with and without the application of l μM nifedipine, an L-type calcium channel blocker. Results  The mRNA level of IGF-1 was increased significantly (P 2+] began to increase immediately after the start of ES, reached a maximum of approximately 1.8-fold, and continued to increase until about 20 min after the ES. The inductions of IGF-1 transcription and Ca2+ influx were suppressed by nifedipine. Conclusions  These results indicate that the enhancement of IGF-1 transcription by ES in cultured Müller cells depends largely on Ca2+ influx through L-type Ca2+ channels. [ABSTRACT FROM AUTHOR]

Abstract Background  To determine the efficient parameters to evoke electrical phosphenes is essential for the development of a retinal prosthesis. We studied the efficient parameters in normal subjects and investigated if suprachoroidal-transretinal stimulation (STS) is effective in patients with advanced retinitis pigmentosa (RP) using these efficient parameters. Methods  The amplitude of pupillary reflex (PR) evoked by transcorneal electrical stimulation (TcES) was determined at different frequencies in eight normal subjects. The relationship between localized phosphenes elicited by transscleral electrical stimulation (TsES) and the pulse parameters was also examined in six normal subjects. The phosphenes evoked by STS were examined in two patients with RP with bare light perception. Biphasic pulses (cathodic first, duration: 0.5 or 1.0 ms, frequency: 20 Hz) were applied through selected channel(s). The size and shape of the phosphenes perceived by the patients were recorded. Results  The maximum PR was evoked by TcES with a frequency of 20 Hz. The brightest phosphene was elicited by TsES with a pulse train of more than 10 pulses, duration of 0.5–1.0 ms and a frequency of 20 to 50 Hz. In RP patients, localized phosphenes were elicited with a current of 0.3–0.5 mA (0.5 ms) in patient 1 and 0.4 mA (1.0 ms) in patient 2. Two isolated or dumbbell-shaped phosphenes were perceived when the stimulus was delivered through two adjacent channels. Conclusion  Biphasic pulse trains (≥10 pulses) with a duration of 0.5–1.0 ms and a frequency of 20–50 Hz were efficient for evoking phosphenes by localized extraocular stimulation in normal subjects. With these parameters, STS is a feasible method to use with a retinal prosthesis even in advanced stages of RPs. [ABSTRACT FROM AUTHOR]

Osterix, a zinc-finger-containing transcription factor, is required for osteoblast differentiation and bone formation. Osterix is also expressed in dental mesenchymal cells of the tooth germ. However, transcriptional regulation by Osterix in tooth development is not clear. Genetic studies in osteogenesis place Osterix downstream of Runx2 (Runt-related 2). The expression of Osterix in odontoblasts overlaps with Runx3 during terminal differentiation in vivo. Runx3 down-regulates Osterix expression in mouse DPCs (dental pulp cells). Therefore the regulatory role of Runx3 on Osterix expression in tooth development was investigated. Enforced expression of Runx3 down-regulated the activity of the Osterix promoter in the human embryonic kidney 293 cell line. When the Runx3 responsive element on the Osterix promoter, located at −713 to −707 bp (site 3, AGTGGTT) relative to the cap site, was mutated, this down-regulation was abrogated. Furthermore, electrophoretic mobility-shift assay and chromatin immunoprecipitation assays in mouse DPCs demonstrated direct functional binding of Runx3 to the Osterix promoter. These results demonstrate the transcriptional regulation of Osterix expression by Runx3 during differentiation of dental pulp cells into odontoblasts during tooth development. [ABSTRACT FROM AUTHOR]

Abstract

Neurofibrillar tangles caused by intracellular hyperphosphorylated tau inclusion and extracellular amyloid β peptide deposition are hallmarks of Alzheimer's disease. Tau contains one or two cysteine residues in three or four repeats of the microtubule binding region following alternative splicing of exon 10, and formation of intermolecular cysteine disulfide bonds accelerates tau aggregation. 8-Nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) acts as a novel second messenger of nitric oxide (NO) by covalently binding cGMP to cysteine residues by electrophilic properties, a process termed protein S-guanylation. Here we studied S-guanylation of tau and its effects on tau aggregation. 8-Nitro-cGMP exposure induced S-guanylation of tau both in vitro and in tau-overexpressed HEK293T cells. S-guanylated tau inhibited heparin-induced tau aggregation in a thioflavin T assay. Atomic force microscopy observations indicated that S-guanylated tau could not form tau granules and fibrils. Further biochemical analyses showed that S-guanylated tau was inhibited at the step of tau oligomer formation. In P301L tau-expressing Neuro2A cells, 8-nitro-cGMP treatment significantly reduced the amount of sarcosyl-insoluble tau. NO-linked chemical modification on cysteine residues of tau could block tau aggregation, and therefore, increasing 8-nitro-cGMP levels in the brain could become a potential therapeutic strategy for Alzheimer's disease. [ABSTRACT FROM AUTHOR]