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Many cells and soluble factors are involved in the wound healing process, which can be divided into inflammatory, proliferative, and remodeling phases. Fibroblasts play a crucial role in wound healing, especially during the proliferative phase, and show heterogeneity depending on lineage, tissue distribution, and extent of differentiation. Fibroblasts from tissue stem cells rather than from healthy tissues infiltrate wounds and proliferate. Some fibroblasts in the wound healing site express the mesenchymal stem cell marker, p75NTR. In the cell culture system, fibroblasts attached to collagen fibrils stop growing, even in the presence of protein growth factors, thus mimicking the quiescent nature of fibroblasts in healthy tissues. Fibroblasts in wound healing sites proliferate and are surrounded by collagen fibrils. These facts indicate presence of new growth-initiating factor for fibroblasts attached to collagen fibrils at the wound healing site, where the collagen-derived peptide, prolyl-hydroxyproline (Pro-Hyp), is generated. Pro-Hyp triggers the growth of p75NTR-positive fibroblasts cultured on collagen gel but not p75NTR-negative fibroblasts. Thus, Pro-Hyp is a low molecular weight growth-initiating factor for specific fibroblasts that is involved in the wound healing process. Pro-Hyp is also supplied to tissues by oral administration of gelatin or collagen hydrolysate. Thus, supplementation of gelatin or collagen hydrolysate has therapeutic potential for chronic wounds. Animal studies and human clinical trials have demonstrated that the ingestion of gelatin or collagen hydrolysate enhances the healing of pressure ulcers in animals and humans and improves delayed wound healing in diabetic animals. Therefore, the low molecular weight fibroblast growth-initiating factor, Pro-Hyp, plays a significant role in wound healing and has therapeutic potential for chronic wounds.

Prolyl-hydroxyproline (Pro-Hyp) levels increase in human blood on ingesting collagen hydrolysate and trigger proliferation of primary cultured fibroblasts attached on collagen. Such proliferative effects have been associated with the beneficial effects of collagen hydrolysate ingestion including enhancement of wound healing. However, some fibroblast cell lines do not respond to Pro-Hyp. In this study, we focused on the mesenchymal stem cell marker p75 neurotrophin receptor (p75NTR), because p75NTR-positive cells are increased at wound healing sites. Most fibroblasts that had migrated from the dissected mouse skin for 1–4 days expressed p75NTR. After prolonged cultivation, however, the ratio of p75NTR-positive fibroblasts dropped. The p75NTR-positive fibroblasts specifically incorporated fluorescein isothiocyanate (FITC)-labeled Pro-Hyp and Pro-Hyp significantly increased the number of p75NTR-positive fibroblasts grown on collagen gel. These results suggest that Pro-Hyp could enhance wound healing by stimulating p75NTR-positive fibroblasts at wound healing sites, while it has little effect on p75NTR-negative resident fibroblasts in normal tissues.

Prolyl-hydroxyproline (Pro-Hyp) and hydroxyprolyl-glycine (Hyp-Gly) appear in human blood after ingestion of collagen hydrolysate and trigger growth of fibroblasts attached on collagen gel, which has been associated with beneficial effects upon ingestion of collagen hydrolysate, such as improvement of skin and joint conditions. In the present study, inconsistent results were obtained by using different lots of fetal bovine serum (FBS). Fibroblasts proliferated in collagen gel without adding Pro-Hyp and Hyp-Gly and did not respond to addition of Pro-Hyp and Hyp-Gly, which raises doubts about conclusions from prior research. Unexpectedly high levels of hydroxyprolyl peptides, including Pro-Hyp, however, were present in the FBS (approximately 100 µM), and also in other commercially available forms of FBS (70−80 µM). After removal of low molecular weight (LMW, < 6000 Da) compounds from the FBS by size exclusion chromatography, Pro-Hyp and Hyp-Gly again triggered growth of fibroblasts attached on collagen and increased the number of fibroblasts migrated from mouse skin. These results indicate the presence of bioactive hydroxyprolyl peptides in commercially available FBS, which can mask effects of Pro-Hyp and Hyp-Gly supplementation; our work confirms that Pro-Hyp and Hyp-Gly do play crucial roles in proliferation of fibroblasts.

The tryptophan and kynurenine pathway is well-known to play an important role in nervous, endocrine, and immune systems, as well as in the development of inflammatory diseases. It has been documented that some kynurenine metabolites are considered to have anti-oxidative, anti-inflammatory, and/or neuroprotective properties. Importantly, many of these kynurenine metabolites may possess immune-regulatory properties that could alleviate the inflammation response. The abnormal activation of the tryptophan and kynurenine pathway might be involved in the pathophysiological process of various immune-related diseases, such as inflammatory bowel disease, cardiovascular disease, osteoporosis, and/or polycystic ovary syndrome. Interestingly, kynurenine metabolites may be involved in the brain memory system and/or intricate immunity via the modulation of glial function. In the further deliberation of this concept with engram, the roles of gut microbiota could lead to the development of remarkable treatments for the prevention of and/or the therapeutics for various intractable immune-related diseases.

Mitophagy/autophagy plays a protective role in various forms of liver damage, by renovating cellular metabolism linking to sustain liver homeostasis. A characterized pathway for mitophagy is the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)/Parkin-dependent signaling pathway. In particular, PINK1-mediated mitophagy could play an indispensable role in improving the metabolic dysfunction-associated fatty liver disease (MAFLD) which could precede to steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma. In addition, the PI3K/AKT/mTOR pathway might regulate the various characteristics of cellular homeostasis including energy metabolism, cell proliferation, and/or cell protection. Therefore, targeting mitophagy with the alteration of PI3K/AKT/mTOR or PINK1/Parkin-dependent signaling to eliminate impaired mitochondria might be an attractive strategy for the treatment of MAFLD. In particular, the efficacy of prebiotics for the treatment of MAFLD has been suggested to be useful via the modulation of the PI3K/AKT/mTOR/AMPK pathway. Additionally, several edible phytochemicals could activate mitophagy for the improvement of mitochondrial damages, which could also be a promising option to treat MAFLD with providing liver protection. Here, the potential therapeutics with several phytochemicals has been discussed for the treatment of MAFLD. Tactics with a viewpoint of prospective probiotics might contribute to the development of therapeutic interventions.

Immunotherapy strategies targeting immune checkpoint molecules such as programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) are revolutionizing oncology. However, its effectiveness is limited in part due to the loss of effector cytotoxic T lymphocytes. Interestingly, supplementation of vitamin D could abolish the repressive effect of programmed cell death-ligand 1 (PD-L1) on CD8 + T cells, which might prevent the lymphocytopenia. In addition, vitamin D signaling could contribute to the differentiation of T-regulatory (Treg) cells associated with the expression of Treg markers such as forkhead box P3 (FOXP3) and CTLA-4. Furthermore, vitamin D may be associated with the stimulation of innate immunity. Peroxisome proliferator-activated receptor (PPAR) and estrogen receptor (ESR) signaling, and even the signaling from phosphoinositide-3 kinase (PI3K)/AKT pathway could have inhibitory roles in carcinogenesis possibly via the modulation of immune checkpoint molecules. In some cases, certain small molecules including vitamin D could be a novel therapeutic modality with a promising potential for the better performance of immune checkpoint blockade cancer therapies., Competing Interests: The authors declare that they have no competing financial interests., (© The Author(s) 2023.)

Hepatocellular carcinoma (HCC) constitutes an extremely malignant form of primary liver cancer. Intricate connections linking to the immune system might be associated with the pathogenesis of HCC. Meanwhile, immunotherapy with immune checkpoint inhibitors has been established to be a favorable therapeutic possibility for advanced HCC. Although curative opportunities for advanced HCC are restricted, the immune checkpoint immunotherapy has developed as the main choice for treating HCC. However, patients with metabolic-associated fatty liver disease (MAFLD)-linked HCC might be less likely to benefit from the immunotherapy alone. The limitation of the effect of the immunotherapy might be owing to the impaired T cell activation in MAFLD patients, which could be well explained by a dysfunctional gut-liver axis. Gut microbiota and their metabolites including several bile acids could contribute to modulating the responses of the immune checkpoint immunotherapy. Roles of gut microbiota in the development of cancers have expected great interest in the latest studies. Here, an interplay between the gut and liver has been presented, which might suggest to affect the efficacy of immune checkpoint immunotherapy against HCC., Competing Interests: The authors declare that they have no conflicts of interest., (© The Author(s) 2023.)

The PI3K/AKT/mTOR signaling pathway may play crucial roles in the pathogenesis of obesity and diabetes mellitus, as well as metabolic syndromes, which could also be risk factors for cardio-metabolic disorders. Consistently, it has been shown that beneficial effects may be convoyed by the modulation of the PI3K/AKT/mTOR pathway against the development of these diseases. Importantly, the PI3K/AKT/mTOR signaling pathway can be modulated by probiotics. Probiotics have a variety of beneficial properties, with the potential of treating specific diseases such as immune-related diseases, which are valuable to human health. In addition, an increasing body of work in the literature emphasized the contribution of genetically modified probiotics. There now seems to be a turning point in the research of probiotics. A better understanding of the interactions between microbiota, lifestyle, and host factors such as genetics and/or epigenetics might lead to a novel therapeutic approach with probiotics for these diseases. This study might provide a theoretical reference for the development of genetically modified probiotics in health products and/or in functional foods for the treatment of cardio-metabolic disorders.

In March 2020, many schools were closed to prevent the spread of COVID-19 in Japan, and it is predicted that many children, especially those with neurodevelopmental disorders (NDDs), will be affected emotionally and behaviorally. Here, we examined the impact of school closures due to COVID-19 on school-aged children with NDDs using the Child Behavior Checklist. Totally, data on 121 children diagnosed with autism spectrum disorder, attention-deficit hyperactivity disorder, and/or intellectual disorder were analyzed and it was found that externalizing and aggressive behavior increased in all NDDs, regardless of the type of diagnosis. A clear prospect is important for children with NDDs children to lead a stable life, and more generous supports for children with NDDs and their families are needed., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: The gap between the numbers of organ donors and recipients is a common problem worldwide. This study was designed to investigate the importance of 'individual readiness', a here introduced novel concept in transplantation medicine and a measure of positive attitudes towards organ donation and transplantation., Design: A cross-sectional online survey was used to collect the research data., Participants: The participants were recruited by a Japanese research company and affiliates in South Korea and Taiwan and fulfilled the following criteria: (1) laypersons aged 18-75 years, (2) residents of the countries and (3) understood the questions in their native languages., Primary Outcome Measures: The survey investigated the interest and attitude of individuals regarding transplantation medicine by asking multiple choice questions. Based on answers concerning attitude, a positive group was identified as willing to be organ donors and recipients, and a non-positive group was identified as unwilling to be donors and recipients. The ratio between the positive and non-positive group, the P/N ratio, was introduced as an index of individual readiness., Results: 1500 samples were included in this analysis. Individuals with interest agreed more with statements on organ donation than those without interest, and the P/N ratio per country was compatible with the actual deceased organ donors rate per million population (ADODR)., Conclusions: Interest in transplantation medicine was associated with positive attitudes, and positive attitudes were associated with a higher ADODR. These results support that individual readiness is an important determinant for the number of donors. The P/N ratio can be used as an index to assess individual readiness in organ transplantation, at least in countries with minor to moderate popularisation. Further studies of individual readiness using the P/N ratio should be undertaken to develop policies and initiatives for increasing organ donations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Although genetic factors are involved in the etiology of autism spectrum disorder (ASD), the significance of genetic analysis in clinical settings is unclear. Forty-nine subjects diagnosed with non-syndromic ASD were analyzed by microarray comparative genomic hybridization (CGH) analysis, whole-exome sequencing (WES) analysis, and panel sequencing analysis for 52 common causative genes of ASD to detect inherited rare variants. Genetic analysis by microarray CGH and WES analyses showed conclusive results in about 10% of patients, however, many inherited variants detected by panel sequencing analysis were difficult to interpret and apply in clinical practice in the majority of patients. Further improvement of interpretation of many variants detected would be necessary for combined genetic tests to be used in clinical settings., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Although choriocapillaris flow deficit (CFD) around choroidal neovascularization (CNV) is less associated with CNV activity in myopic eyes, no reports are investigating its size as an indicator of CNV activity. We investigated the relationship between CFD and high myopia-related CNV. In this retrospective, observational study, patients underwent optical coherence tomography angiography (OCTA) with split-spectrum amplitude-decorrelation angiography for diagnosing pathological myopic CNV (mCNV); CFD features around CNV margins were evaluated. Of the 33 eyes (30 patients), 11 (33.3%) had active mCNV, and 22 (66.7%) had inactive CNV. Six eyes (18.2%) were treatment-naïve, while the remainder previously underwent anti-vascular endothelial growth factor therapy. On OCTA, blood flow signals were detected in CNV in the outer retinal layer in 28 (84.8%) eyes, including all active cases (11 cases) and 17 (77.3%) of 22 inactive cases. CNV flow signal size correlated significantly with activity (P < 0.001). CFD around CNV was observed in 24 eyes (72.7%), including all active cases (11 cases) and 13 (59.1%) of 22 inactive cases. CFD size correlated significantly with CNV activity (P < 0.001). The size of both the CFD area around CNV and CNV flow signal area are useful indicators of CNV activity in eyes with mCNV, which may help determine treatment timing., (© 2021. The Author(s).)

Purpose: To evaluate the relationship between peripapillary tilt and visual field (VF) defects in glaucomatous eyes with axial myopia., Study Design: Retrospective cross-sectional study., Patients and Methods: One hundred four eyes of 104 patients with primary open-angle glaucoma (POAG) with myopia were included (52 eyes with high myopia [HM], 26.5 mm ≤ axial length [AL] < 30.0 mm; and 52 eyes without HM, 24.0 mm < AL < 26.5 mm). The direction and magnitude of the peripapillary tilt were evaluated using optical coherence tomography. The eyes were divided into 12 groups according to the tilt directions defined by clock-hour sectors in a clockwise direction in the right eyes and in a counterclockwise direction in the left eyes. The mean deviation (MD) and central VF (CVF) values, ie, the mean threshold values of 4 paracentral points within 5 degrees of the Swedish Interactive Threshold Algorithm 30-2 test, were evaluated., Results: The direction of the tilt was toward sector 9 (47.1%) and sector 8 (34.6%). The MD and CVF values were significantly worse (P = 0.013 and P = 0.019, respectively) in the sector 9 group than in the sector 8 group. Furthermore, the smaller peripapillary tilt magnitude in the sector 9 group was negatively correlated (P = 0.0019) with the CVF but not with the MD (P = 0.1) among the POAG eyes with HM. In contrast, the ovality index in the sector 9 group was not significantly correlated with the MD (P = 0.4) or the CVF (P = 0.36)., Conclusion: A smaller temporal peripapillary tilt correlated with CVF defects in POAG eyes with HM. The peripapillary tilt direction and magnitude affect the CVF defect in POAG eyes with HM.

Purpose: To characterize the corneal biomechanical properties of glaucoma eyes by comparing the dynamic Scheimpflug biomechanical parameters between untreated glaucoma and control eyes., Methods: Cross-sectional observational data of dynamic Scheimpflug analyzer (Corvis ST) examinations were retrospectively collected from 35 eyes of 35 consecutive patients with untreated normal tension glaucoma and 35 eyes of 35 healthy patients matched on age and IOP. Ten biomechanical parameters were compared between the two groups using multivariable models adjusting for IOP, central corneal thickness, age, and axial length. The Benjamini-Hochberg method was used to correct for multiple comparison., Results: In multivariable models, glaucoma was associated with smaller applanation 1 time (P < 0.001, coefficient = -0.5865), applanation 2 time (P = 0.012, coefficient = -0.1702), radius (P = 0.006, coefficient = -0.5447), larger peak distance (P = 0.011, coefficient = 0.1023), deformation amplitude ratio at 1 mm (P < 0.001, coefficient = 0.072), and integrated radius (P < 0.001, coefficient = 1.094). These associations consistently indicate greater compliance of the cornea in glaucoma eyes., Conclusions: Untreated normal tension glaucoma eyes were more compliant than healthy eyes. The greater compliance (smaller stiffness) of normal tension glaucoma eyes may increase the risk of optic nerve damage. These results suggest the relevance of measuring biomechanical properties of glaucoma eyes.

Purpose: To evaluate the relationship between biomechanical parameters measured with a dynamic Scheimpflug analyzer and glaucoma., Patients and Methods: Cross-sectional observational data of 47 eyes of 47 consecutive subjects with medically controlled primary open-angle glaucoma and 75 eyes of 75 healthy subjects examined with a dynamic Scheimpflug analyzer (Corvis ST) were retrospectively investigated. Eight biomechanical parameters were compared between eyes with and without glaucoma using multivariable models adjusting for intraocular pressure (IOP), central corneal thickness, age, and axial length., Results: In multivariable models, glaucoma was negatively correlated with A1 time (P<0.001, coefficient=-0.5535), A2 time (P=0.008, coefficient=-0.1509), radius (P=0.011, coefficient=-0.4034), and whole eye movement (P<0.001, coefficient=-0.0622). Negative correlation between glaucoma and 3 parameters (A1 time, A2 time, and radius) consistently indicate larger deformability of the cornea and negative correlation between glaucoma and whole eye movement indicate smaller eye movement, in glaucoma eyes. There were significant correlations of many biomechanical parameters with other baseline factors (8 parameters with IOP, 2 with central corneal thickness, 4 with age, and 7 with axial length)., Conclusions: Eyes with medically controlled glaucoma were more deformable than healthy eyes, which may increase the risk of optic nerve damage through an underestimation of IOP and biomechanical vulnerability of the globe. Many parameters showed a significant correlation with baseline factors, suggesting the importance of adjustment for these confounding factors when evaluating the correlation between biomechanical parameters and ocular diseases. These results suggest the relevance of measuring biomechanical properties of glaucoma eyes for accurate IOP measurement and risk assessment.

Objectives of the present study were to evaluate amounts of collagen in Japanese daily dishes and contents of food-derived collagen peptides in human blood. The meat in one serving of most Japanese daily dishes contains 0.2-2.5 g of collagen, except for beef tendon, eel with skin, and skinned shark tail (7.6-13.3 g). After ingestion of cooked shark meat, nine collagen di- and tripeptides were detected in plasma and the area under the curve of most peptides, except for Hyp-Gly and Pro-Hyp-Gly, was ∼30% of that after ingestion of collagen hydrolysate containing an equivalent amount of collagen. Likewise, only ∼30% of the total collagen in the meat was liberated into solution by pepsin and pancreatin digestion. Thus, ingestion of collagen-rich meat increases the collagen peptides in blood, which depends on not only the collagen content in the meat but also the susceptibility of the collagen/gelatin to digestive endoproteinases.

Purpose: Recent studies have suggested that OCT-based classification of parapapillary atrophy (PPA) may be helpful in distinguishing glaucomatous from myopic optic disc changes. However, the pathologic implications of PPA may be different in highly myopic eyes that exhibit optic disc deformations distinct from low-to-moderate myopia. Therefore, we conducted the current study to investigate factors associated with OCT-defined PPA zones measured in en face reconstructed swept-source OCT (SS OCT) images in highly myopic eyes., Design: Retrospective, cross-sectional study., Participants: Seventy-seven eyes of 55 subjects with high myopia (spherical equivalent refractive error ≤ -8 diopters or axial length ≥26.5 mm) were included. Forty-nine eyes of 33 subjects had open-angle glaucoma (MG group), and 28 eyes of 22 did not (M group)., Methods: The beta zone and the gamma zone PPA areas were measured in en face images reconstructed from 3-dimensional SS OCT volumetric scans. Relationships between the PPA areas and patient characteristics such as glaucoma, axial length, and age were evaluated using multivariate mixed-effects models. The diagnostic capability of each PPA zone area for detecting glaucoma was assessed with the receiver operating characteristic (ROC) curve analysis. Main outcome measures were areas of the beta zone and the gamma zone PPA measured in en face OCT images and factors associated with each PPA area., Results: Average ± standard deviation area of the beta and the gamma zone was 1.1±1.1 and 1.1±1.1 mm 2 . The gamma zone was positively correlated with axial length (P = 0.006) and age (P = 0.04951) but not with glaucoma (P = 0.776). The beta zone was positively correlated with both axial length (P = 0.039) and glaucoma (P = 0.011). The areas under the ROC curve of the beta zone and the gamma zone areas were 0.686 and 0.560, respectively., Conclusions: The OCT-defined beta zone was associated with glaucoma and axial length, whereas the gamma zone was correlated with axial length but not with glaucoma, in highly myopic eyes. The OCT-based classification showed poor diagnostic performance for glaucoma. Relationships between PPA areas and baseline clinical factors may be different between high myopia and non-high myopia., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the corneal biomechanics in eyes with keratectasia following LASIK using a dynamic Scheimpflug analyzer., Design: Case-Control study., Method: The subjects in the study included 12 eyes with keratectasia after LASIK (KE), 24 eyes with keratoconus (KC), 17 eyes without keratectasia after LASIK (LASIK), and 34 eyes with normal corneas (Normal). Corneal biomechanics of the four groups were evaluated using a dynamic Scheimpflug analyzer., Results: Compared with Normal (7.06 ± 0.54), the radius at the highest concavity (radius, mm) of LASIK (5.96 ± 0.76), KE (4.93 ± 0.61) and KC (5.39 ± 1.02) were significantly small. The Deflection Amplitude (HCDLA, mm) of Normal (0.94 ± 0.07) was significantly lower than those of KE (1.11 ± 0.10) and KC (1.06 ± 0.16), and was not significantly different from that of LASIK (0.98 ± 0.07). There were significant differences between LASIK and KE in radius and HCDLA (P < 0.05), whereas KE and KC had no differences in these parameters., Conclusions: Corneal biomechanical features evaluated using the dynamic Scheimpflug analyzer suggest that biomechanical properties in eyes with keratectasia, keratoconus, and LASIK are different from those of normal eyes. Although the biomechanics in eyes with keratectasia differs from that in eyes with LASIK, it is similar to that in eyes with keratoconus.

Purpose: To evaluate the repeatability of corneal deformation parameters measured using a dynamic Scheimpflug analyzer and the impact of baseline clinical factors on the repeatability of each parameter., Study Design: Retrospective, cross-sectional study., Methods: Forty-eight eyes (48 healthy subjects; mean age, 49.0 ± 19.5 years) underwent repeated examinations with the Scheimpflug analyzer to evaluate the test-retest variability. The intraclass correlation coefficient (ICC) and repeatability coefficient as indicators of variability were computed for 35 parameters measured with the Scheimpflug analyzer. The associations between the magnitude of the test-retest variability and baseline factors, such as age, axial length (AL), intraocular pressure (IOP), and central corneal thickness (CCT), were analyzed., Results: The test-retest repeatability was excellent for 22 (62.9%) of 35 parameters (ICC ≥ 0.75), good for seven (20%), (ICC ≥ 0.6), fair for four (11.4%), (ICC ≥ 0.4), and poor for two (5.7%) parameters (ICC < 0.4). Age was associated positively with the magnitude of variability in 13 (37.1%) parameters; measurement variability was affected significantly by AL (5 parameters, 14.3%) and CCT (7 parameters, 20%) but, except for one parameter not by IOP., Conclusion: Most parameters of the dynamic Scheimpflug analyzer showed favorable measurement reliability in healthy subjects. However, six parameters showed poor-to-fair repeatability. Age, AL, and CCT significantly affected the repeatability of several parameters. These results should be considered when clinicians use this device in clinical practice.

Objective: To measure the parapapillary atrophy (PPA) area in en face images obtained with swept-source optical coherence tomography (SS-OCT), and to evaluate its relationship to glaucoma, myopia, and age in non-highly myopic subjects., Design: Retrospective, cross-sectional study., Participants: Fifty eyes of 30 subjects with open-angle glaucoma (G group) and forty-three eyes of 26 healthy control subjects (C group). Eyes with high myopia (spherical equivalent refractive error ≤ -8 diopters or axial length ≥ 26.5 mm) were excluded., Methods: Mean age ± standard deviation was 59.9 ± 12.4 years. The beta zone and the gamma zone PPA areas were measured in en face images reconstructed from three-dimensional SS-OCT images. Relationship between the PPA areas and patient characteristics such as glaucoma, axial length, and age was statistically evaluated using multivariate mixed-effects models., Main Outcome Measures: Areas of the beta zone and the gamma zone PPA measured on en face OCT images., Results: Average ± standard deviation area of the beta and the gamma zone was 0.64 ± 0.79 and 0.16 ± 0.30 mm2, respectively. In multivariate models, the gamma zone significantly correlated with axial length (P = 0.001) but not with glaucoma (P = 0.944). In contrast, the beta zone significantly correlated with age (P = 0.0249) and glaucoma (P = 0.014)., Conclusions: En face images reconstructed from 3D SS-OCT data facilitated measurements of the beta and the gamma PPA zones even in eyes with optic disc distortion. The OCT-defined beta zone is associated with glaucoma and age, whereas the gamma zone correlated with myopia but not with glaucoma. This study confirmed the clinical usefulness of OCT-based classification of the PPA zones in distinguishing glaucomatous damage of the optic nerve from myopic damage in non-highly myopic eyes.

Purpose: The purpose of this study was to clarify correlations between corneal deformation parameters measured with a dynamic Scheimpflug analyzer and baseline factors such as axial length, intraocular pressure (IOP), age, central corneal thickness (CCT), and corneal curvature., Methods: Ninety-six eyes of 96 healthy subjects (mean 55.2 ± 16.1 years of age) were examined using a dynamic Scheimpflug analyzer. Eighteen of 35 deformation parameters were selected for analyses based on measurement reliability and clinical relevance. The associations between corneal deformation parameters and axial length, IOP, age, CCT, and average corneal power were evaluated using multivariate regression analyses., Results: Deformation parameters were correlated significantly with axial length (n = 13), IOP (n = 13), age (n = 8), and CCT (n = 6) in the multivariate models. Longer axial length corresponded with greater corneal deformability, less viscous damping, and less movement of the entire eye. Higher IOP was associated with greater corneal resistance and less movement of the entire eye. Older age was associated with less corneal deformability and greater movement of the entire eye. Corneal curvature was correlated significantly with only three deformation parameters., Conclusions: This study clarified the substantial impact of axial length, age, and IOP on the biomechanical responses of the cornea and the entire eye. In contrast, corneal curvature did not affect most of the deformation parameters. The current results confirmed the importance of corneal biomechanics, especially in eyes with longer axial length and in older subjects.

Purpose: We measured the three-dimensional geometric profile around the optic nerve head (ONH) using swept-source optical coherence tomography (SS-OCT) in highly myopic eyes., Methods: We studied 114 highly myopic eyes (<-6.0 diopters [D]) of 114 patients without glaucoma. Eyes were examined using the prototype SS-OCT. The retinal pigment epithelium (RPE) and chorioscleral interface were traced, and the mean y-axis coordinates of 24 sectors were calculated in circular peripapillary (3.4-mm diameter) images. The peripapillary tilting index (PTI) was calculated by subtracting the mean y-axis coordinate of the RPE in a sector from the mean of all sectors. The main outcome measures were the PTI and its association with the staphyloma depth from the OCT images and the ovality index (OI) of the ONH and peripapillary atrophy (PPA) area from fundus photographs., Results: The PTI differed significantly (P < 0.0001) among the 24 sectors and was lowest at the inferotemporal sector (-1930.76 μm). The minimal PTI value was in the temporal to inferotemporal sectors in 88 (77.2%) eyes and was correlated significantly with the OI (P < 0.0001) and age (P < 0.001) but not with the equivalent refractive error or axial length. The minimal PTI was correlated significantly with the PPA area (P < 0.05), minimal choroidal thickness (P < 0.05), macular choroidal thickness (P < 0.0001), and staphyloma depth (P < 0.0001)., Conclusions: The peripapillary area is tilted inferotemporally in 77.2% of myopic eyes. Peripapillary tilting was markedly greater in older patients. Greater tilt was associated with a thinner choroid, more extensive PPA, and deeper staphyloma.

Background: The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) was published in May 2013. Autism spectrum disorder (ASD) has been structured for the three subtypes of pervasive developmental disorder (PDD), but the number of impairment in social and communication dimension is not stated., Methods: The subjects were 68 children who visited the Department of Psychology and Development at Nagoya City University Hospital for the first time between the ages of 6 and 15 years old. We retrospectively re-examined the subjects using DSM-IV-TR criteria and DSM-5 criteria with two rules (two of three and one of three on the social and communication dimension) and examined the concordance rate., Results: Forty subjects were diagnosed with PDD, and 28 were not. The mean PDD subject age was 9.4 years, and mean IQ was 84.0 on the Wechsler Intelligence Scale for Children III or 62.7 on the Tanaka-Binet test. Twenty-seven (68%) of the PDD subjects were classified with ASD using DSM-5 criteria when the two of three rule was applied, while 32 (80%) were classified with ASD when the one of three rule was applied. All subjects without PDD were not diagnosed with ASD on DSM-5 criteria., Conclusion: DSM-5 criteria may exclude high functioning and older subjects from ASD because they tend to be atypical. The diagnostic procedure for DSM-5 criteria is ambiguous, especially in high functioning subjects and those diagnosed at an older age., (© 2015 Japan Pediatric Society.)

Purpose: We evaluated the prevalence and characteristics of the defects of the lamina cribrosa (LC) in high myopia and glaucoma, and compared them with control eyes using swept-source optical coherence tomography (SS-OCT)., Methods: One hundred fifty-nine eyes of 108 participants were divided into four subgroups; high myopia with glaucoma (MG, 67 eyes of 46 subjects), glaucoma without high myopia (G, 22 eyes of 13 subjects), high myopia without glaucoma (M, 35 eyes of 29 subjects), and a control group with neither glaucoma nor high myopia (C, 35 eyes of 20 subjects). The LC defects were identified and located using a standardized protocol in serial horizontal OCT scans. The prevalence rates of the defects were compared among the groups. Demographic and ocular factors were compared between eyes with and without defects., Results: LC defects were observed in one eye (0.03%) in the C group, 8 eyes (22.9%) in the M group, 11 eyes (50%) in the G group, and 28 eyes (41.8%) in the MG group. The prevalence rates of the defects differed significantly among the groups (P = 0.0009). Most eyes with defects in the G and MG groups (79.5%) had damage in the corresponding visual hemifields. Other factors such as visual acuity, intraocular pressure, axial length, refractive error, disc ovality, or parapapillary atrophy area did not differ significantly between eyes with and without LC defects., Conclusions: High myopia and glaucoma significantly increased the risk of LC damage. The LC damage in non-glaucomatous highly myopic eyes may at least partly explain the increased risk of developing glaucoma in myopic eyes.

Low level laser therapy (LLLT) affects various biological processes, and it is said that the non-coherent light of the light-emitting diode (LED) has a similar action. The purpose of this study was to examine the effects of LED light on the proliferation and differentiation of osteoblasts-like MC3T3-E1 cells cultured in osteogenic differentiation medium (ODM) over the long term. Cells were irradiated with red LED light of 630 nm at three doses; 0.5J/cm², 1.5J/cm² or 3.0J/cm² for the cell proliferation activity assay, and at 0.5J/cm² for the osteogenic differentiation activity assay. The former activity was checked by counting the number of viable cells using Trypan blue dye. The latter activity was evaluated by alkaline phosphatase (ALP) staining and examining the mRNA expression of the osteopontin (OPN) gene using real-time quantitative PCR. The number of viable MC3T3-E1 cells showed a tendency to increase after the irradiation at all three energy densities in comparison with a non-irradiation group (control group). In particular, there was a remarkable 3.34-fold increase in the group irradiated with 3.0J/cm² on day 7 after starting the culture. On culture day 15, there was a tendency for the red LED irradiation group (0.5 J/cm²) to exhibit more staining for ALP than the control group, and the expression of OPN was significantly higher in the irradiation group on culture day 16. In conclusion, low level red LED light can enhance MC3T3-E1 cell proliferation and osteogenic differentiation when the cells are cultured for a relatively long time.

Objective: The purpose of this study is to make a clinical evaluation of vascular malformations in the oral region treated by photocoagulation with an Nd:YAG laser, to determine its effectiveness., Background Data: The Nd:YAG laser, with a wavelength of 1064 nm in the near-infrared part of the electromagnetic spectrum, has unique characteristics, such as absorption by oxygenated hemoglobin, negligible absorption by water, and a deep depth of penetration, all of which are ideal for performing the photocoagulation of vascular malformations., Methods: The subjects were 67 patients (69 cases) with vascular malformations in the oral region who visited our hospital from 2004 to 2011, and were treated by photocoagulation using an Nd:YAG laser. They consisted of 23 male patients and 44 female patients, ranging from 7 to 89 years of age. Lesion size was classified for convenience into two groups (<15 mm or ≥ 15 mm) for clinical analysis and evaluation. The lesions were located at sites including the lip, tongue, buccal mucosa, gingiva, mouth floor, and soft palate, and ranged in size from 3 to 42 mm along the major axis. Fifty patients (74.6%) were treated on an outpatient basis, whereas 17 patients (25.4%) were treated in the hospital. All patients were treated using an Nd:YAG laser at an output of 8-15 W under local anesthesia., Results: No patient developed serious complications from this treatment. However, it was necessary to irradiate the laser beam two or more times in cases of deep-seated lesions., Conclusions: We were able to obtain satisfactory results without clinical complications, using only external irradiation. These results suggest that the Nd:YAG laser is effective for the treatment of vascular malformations in the oral region.

Purpose: To investigate microstructural changes and visual prognosis in myopic subretinal hemorrhages (mSH) without choroidal neovascularization (CNV)., Methods: In this retrospective, observational case series, 13 consecutive eyes with mSH were followed for 6 months. The medical records, fluorescein angiography (FA), and spectral-domain optical coherence tomography (OCT) were reviewed. Fluorescein angiography confirmed the absence of CNV. The baseline and 6-month findings/parameters were investigated, including the maximal hemorrhagic height, intraretinal hyperscattering signal across the retina at 6 months (i.e., intraretinal hyperreflective sign), and integrity of the photoreceptor inner and outer segment (IS/OS) and external limiting membrane (ELM) lines., Results: The final visual acuity (VA) improved significantly (P = 0.001), and the hemorrhages resolved in 12 (92.3%) eyes by 6 months. The tops of the hemorrhages reached the outer nuclear layer (ONL) in three eyes (23.1%), internal limiting membrane (ILM) in five (38.5%), and between the two layers in five (38.5%). The intraretinal hyperreflective sign in all eyes extended into the ONL in five eyes (38.5%), to the ILM in four (30.8%), and between the two layers in four (30.8%). The location of the hyperreflective signs at 6 months coincided with the ruptured retinal layers at baseline in all eyes. The IS/OS line and the ELM were each intact in six (46.2%) eyes. The final VA was associated significantly with the IS/OS (P < 0.05) and ELM (P < 0.01) integrity., Conclusions: The intraretinal hyperreflective sign, presumed to be scarring that enters through the disrupted outer retina, is correlated closely with photoreceptor function.

Purpose: To investigate the rate of choroidal thinning in highly myopic eyes., Patients and Methods: A retrospective observational study of 37 eyes of 26 subjects (nine males and 17 females, mean age 39.6 ± 7.7 years) with high myopia but no pathologies who had undergone spectral domain optical coherence tomography and repeated the test 1 year later (1 ± 0.25 year) at Osaka University Hospital, Osaka, Japan. Patients older than 50 years with visual acuity worse than 20/40 or with whitish chorioretinal atrophy involving the macula were excluded. Two masked raters measured the choroidal thicknesses (CTs) at the fovea, 3 mm superiorly, inferiorly, temporally, and nasally on the images and averaged the values. The second examination was about 365 days after the baseline examination. The CT reduction per year (CTRPY) was defined as (CT 1 year after - baseline CT)/days between the two examinations × 365. The retinal thicknesses were also investigated., Results: The CTRPY at the fovea was -1.0 ± 22.0 μm (range -50.2 to 98.5) at the fovea, -6.5 ± 24.3 μm (range -65.8 to 90.2) temporally, -0.5 ± 22.3 μm (range -27.1 to 82.5) nasally, -9.7 ± 21.7 μm (range -40.1 to 60.1) superiorly, and -1.4 ± 25.5 μm (range -85.6 to 75.2) inferiorly. There were no significant differences in the CTRPY at each location (P = 0.34). The CT decreased significantly (P < 0.05) only superiorly. The superior CTRPY was negatively correlated with the axial length (P < 0.05). The retinal thickness at the fovea did not change. Stepwise analysis for CTRPY selected axial length (P = 0.04, R (2) = 0.13) and age (P = 0.08, R (2) = 0.21) as relevant factors., Conclusions: The highly myopic choroid might gradually thin and be affected by many factors. Location and axial length are key factors to regulate the rate of choroidal thinning in highly myopic eyes. Overall choroidal thickness was not found to change significantly. Longer follow-ups are needed.

Purpose: To investigate the results of small gauge vitrectomy for myopic macular complications., Methods: We reviewed 68 eyes which underwent vitrectomy with various needles (20 G, 27 eyes; sutureless 23 G, 15 eyes; sutured 23 G, 15 eyes; and 25 G, 11 eyes) for myopic macular pathologies. Surgical results and complications were compared., Results: Mean logMAR after 3 months was 0.85 for 20 G, 0.78 for sutureless 23 G, 0.43 for sutured 23 G, and 0.46 for 25 G (p < 0.05). However, there was no significant difference in visual acuity change between the groups 3 months after surgery (p = 0.21). Mean intraocular pressure 1 day after surgery was significantly different (20 G, 15.0 mmHg; sutureless 23 G, 11.4 mmHg; sutured 23 G, 18.7 mmHg; and 25 G, 14.2 mmHg, p < 0.05), but that significance was lost 7 days after surgery., Conclusion: The small gauge system produces favorable results in vitrectomy for myopic macular complications, similar to the conventional 20 G system.

We performed maxillary sinus floor elevation combined with a vertical onlay graft for a total of 11 sides of nine patients (1 woman and 8 men) in our Hospital. On CT, the preoperative minimum alveolar bone thickness with a mean of 1.8 mm was improved to 15.3 mm within a month after this surgery. A total of 20 dental implants were placed and there was only one failed implant. With the average follow-up of 15.6 months, an average of 3.4 mm of bone absorption was found in the site of the maxillary sinus and 1.1 mm in the site of the onlay graft. The crown-implant ratio in all cases was within the permissible range. Consequently, this bone augmentation surgery was considered to be useful.

Purpose: The purpose of this retrospective study was to determine the success of Brånemark System TiUnite implants (Nobel Biocare/Sweden) placed in partially or completely edentulous jaws restored with fixed or removable prostheses., Patients and Methods: A total of 131 jaws from 110 patients (64 maxillae and 67 mandibles) received 472 implants from July 2003 until March 2008. The patients included 57 men and 53 women, with a median age of 49.6 years and an age range of 16 to 90 years at the time of implant surgery. Twelve maxillae and 10 mandibles were completely edentulous, and 52 maxillae and 57 mandibles were partially edentulous. A single implant was placed in 21 jaws (10 maxillae and 11 mandibles), while multiple implants were placed in the other patients. Among the 131 jaws, removable prostheses were mounted in 10 maxillae and 8 mandibles, and the other jaws were restored with fixed prostheses., Results: Among the 472 implants, 6 maxillary implants and 5 mandibular implants were unsuccessful. The success rate for the implants was 96.56% (96.07% in the maxillae and 97.18% in the mandibles).

Asperger's syndrome is not accompanied with intellectual disability, however it has social impairments as well as autism and demonstrates failure to develop peer relationships according to each life stage. Social reciprocal behavior deficits are revealed typically during childhood. On the other hand, after school age these deficits are modified by environmental factors that may induce secondary disorders consequently. Hypersensitivity and coordination disorder, which are not included in diagnostic criteria for Asperger's syndrome, are often in presence. These symptoms are diminished and rarely interfere daily living as growth. However they may keep Asperger's syndrome individuals from adapting to others, so we need to take it into consideration.