Risk Factors for Progression of Primary Open-Angle Glaucoma with Lower Normal Intraocular Pressure.

INTRODUCTION: This study aimed to investigate intraocular pressure (IOP)-independent factors associated with the progression of primary open-angle glaucoma (POAG) with IOP ≤15 mm Hg. METHODS: POAG patients with maximum IOP ≤15 mm Hg at the Kyoto University Hospital between January 2011 and August 2021 were retrospectively enrolled. We evaluated effects of various factors on the rate of mean deviation (MD) changes in the visual field (VF) examinations using a linear mixed model. These factors included hypertension, diabetes mellitus (DM), hyperlipidemia (HL), cardiovascular disease, arrhythmia, disc hemorrhage, sleep apnea syndrome, orthopedic diseases, and malignant tumors. RESULTS: In total, 98 eyes from 68 patients were included. The baseline MD was -9.74 ± 7.85 dB. The mean rate of MD change and IOP during the observation period were -0.28 ± 0.04 dB/year and 11.8 ± 1.0 mm Hg, respectively. Comorbidity of DM or HL showed a significant positive association with the rate of MD change (ß = 0.35, p = 0.0006 and ß = 0.18, p = 0.036, respectively) in the model adjusted for age, sex, axial length, mean IOP, and standard deviation of IOP during the observation period. However, no significant association of DM or HL was found after adjusting for central corneal thickness. CONCLUSION: This study suggests that DM or HL is associated with VF deterioration in glaucoma with lower IOP, but the association may be due to differences in IOP characteristics.

Characteristics of Eyes Requiring Trabeculotomy for Glaucoma With Steroid Treatment: Atopic Dermatitis and Factors Affecting Surgical Outcomes.

PURPOSE: The aim is to analyze the surgical outcomes of glaucomatous patients with steroid treatment and investigate the factors, including atopic dermatitis, associated with the surgical success rate. MATERIALS AND METHODS: We retrospectively enrolled participants who required first trabeculotomy for glaucoma with steroid treatment between May 2005 and February 2018 and then compared the postoperative outcomes according to the history of atopic dermatitis or surgical procedures. Surgical success was defined as postoperative IOP ≤ 21 mmHg, ≥20% reduction from baseline, and absence of reoperation. The factors influencing the surgical success rates were investigated using mixed-effects Cox regression. RESULTS: The study included 70 eyes of 46 patients (18 eyes of 12 patients with atopic dermatitis). Postoperative intraocular pressure was not significantly different between eyes with and without atopic dermatitis (12 months after the surgery: patients without atopic dermatitis, 15.4 ± 3.6 mmHg; patients with atopic dermatitis, 16.1 ± 3.9 mmHg; P = 0.65). Twelve months after the surgery, the number of postoperative medications was higher in patients with atopic dermatitis than in those without (2.8 ± 1.3 vs. 2.0 ± 1.7; P = 0.060). However, no significant differences were noted in surgical success rates between patients with atopic dermatitis and those without (P = 0.54). Mixed-effects Cox regression of surgical success rate indicated that only the number of preoperative medications significantly influenced surgical success (P = 0.03). CONCLUSIONS: Regardless of the presence of atopic dermatitis, patients taking many preoperative glaucomatous medications might require reoperation.

Influence of Trabeculectomy with Mitomycin C on Longitudinal Changes in the Visual Field in Glaucoma Patients with High Myopia.

Purpose: To evaluate the effect of trabeculectomy (Trab MMC) on visual field (VF) progression in eyes with glaucoma and high myopia. Patients and Methods: Patients diagnosed with primary open-angle glaucoma or exfoliation glaucoma who underwent Trab MMC as the first glaucoma surgery along with ≥3 VF tests preoperatively and postoperatively were enrolled. High myopia was defined as an axial length ≥26.5 mm. Postoperative reductions in intraocular pressure (IOP) were assessed by survival analysis using IOP measurements obtained preoperatively. The longitudinal trends of the outcome measures were evaluated using linear mixed models. Results: Thirty-five eyes of 32 patients were included in this study, including 22 eyes of 20 patients in non-highly myopic group and 13 eyes of 12 patients in highly myopic group. IOP decreased after Trab MMC, and the survival rate did not differ significantly in relation to axial length. Linear mixed-model analyses suggested that the inhibitory effects of Trab MMC on the rate of mean deviation (MD) changes were significant in the non-highly myopic group (-0.53 ± 0.15 dB/year preoperatively to -0.16 ± 0.13 dB/year postoperatively; P = 0.004), but not in the highly myopic group (-0.66 ± 0.19 dB/year preoperatively to -0.48 ± 0.18 dB/year postoperatively; P = 0.32). Conclusion: Trab MMC reduced IOP in both highly myopic and non-highly myopic eyes, and IOP reduction was very similar in both groups. The VF deterioration rate decreased in both groups, but the change was weaker and nonsignificant in the highly myopic group.

Branched Chain Amino Acids Promote ATP Production Via Translocation of Glucose Transporters.

Purpose: We have previously shown that maintenance of ATP levels is a promising strategy for preventing neuronal cell death, and that branched chain amino acids (BCAAs) enhanced cellular ATP levels in cultured cells and antagonized cell death. BCAAs attenuated photoreceptor degeneration and retinal ganglion cell death in rodent models of retinal degeneration or glaucoma. This study aimed to elucidate the mechanisms through which BCAAs enhance ATP production. Methods: Intracellular ATP concentration was measured in HeLa cells under glycolysis and citric acid cycle inhibited conditions. Next, glucose uptake was quantified in HeLa cells and in 661W retinal photoreceptor-derived cells under glycolysis inhibition, endoplasmic reticulum stress, and glucose transporters (GLUTs) inhibited conditions, by measuring the fluorescence of fluorescently labeled deoxy-glucose analog using flow cytometry. Then, the intracellular behavior of GLUT1 and GLUT3 were observed in HeLa or 661W cells transfected with enhanced green fluorescent protein-GLUTs. Results: BCAAs recovered intracellular ATP levels during glycolysis inhibition and during citric acid cycle inhibition. BCAAs significantly increased glucose uptake and recovered decreased glucose uptake induced by endoplasmic reticulum stress or glycolysis inhibition. However, BCAAs were unable to increase intracellular ATP levels or glucose uptake when GLUTs were inhibited. Fluorescence microscopy revealed that supplementation of BCAAs enhanced the translocation of GLUTs proteins to the plasma membrane over time. Conclusions: BCAAs increase ATP production by promoting glucose uptake through promotion of glucose transporters translocation to the plasma membrane. These results may help expand the clinical application of BCAAs in retinal neurodegenerative diseases, such as glaucoma and retinal degeneration.

Clinical Significance of Antinucleolar Antibodies: Biomarkers for Autoimmune Diseases, Malignancies, and others.

Nucleolar staining is one of the standard patterns in immunofluorescence antinuclear antibodies (ANA), seen in 5-9% of ANA in various conditions. Antinucleolar antibodies (ANoA) are classified into 3 patterns in the International Consensus on ANA Patterns (ICAP) classification; AC-8 homogeneous pattern, AC-9 clumpy pattern, and AC-10 punctate pattern. Specificities known to show AC-8 include anti-Th/To, -PM-Scl, -nucleophosmin/B23, -nucleolin/C23, -No55, and others. AC-9 is seen by anti-fibrillarin/U3RNP and AC-10 by anti-RNA polymerase I and hUBF/NOR-90. ANoA has been classically known to be associated with scleroderma (SSc) and the characterization of nucleolar antigens identified several autoantigens recognized by SSc autoantibodies. The clinical association of anti-Th/To, PM-Scl, fibrillarin/U3RNP, and RNA polymerase I with SSc or SSc-overlap syndrome is well established, and commercial assays are developed. Anti-hUBF/NOR90, nucleophosmin/B23, and nucleolin/C23 are known for decades and reported in systemic autoimmune rheumatic diseases (SARDs), malignancies, graft versus host disease (GVHD), and others; however, their clinical significance remains to be established.

Longitudinal changes in complete avascular area assessed using anterior segmental optical coherence tomography angiography in filtering trabeculectomy bleb.

Optical coherence tomography angiography (OCTA) is a new technique for non-invasive imaging of blood vessels, allowing combined evaluation of both deep and surface vessels. The purpose of this study was to evaluate the post-trabeculectomy longitudinal changes in complete avascular area (CAA) of filtering blebs using anterior segment (AS-) OCTA and their association with surgical outcomes. This study included 57 eyes of 53 patients who had undergone trabeculectomy with mitomycin C. AS-OCTA images of filtering bleb were acquired at 3 and 6 months after trabeculectomy, and at 1 month in possible cases. CAAs, regions where complete blood flow was not depicted in AS-OCTA images, were evaluated for their presence, extent, and change over time. CAAs were detected in 37 eyes (65%) and 33 eyes (58%) at 3 and 6 months postoperatively, respectively. The extent of CAAs reduced over time after surgery in most cases. No parameters related to CAAs were significantly associated with surgical success (i.e., intraocular pressure (IOP) ≤ 12 mmHg and IOP reduction > 20% without medication). In conclusion, although it is difficult to predict surgical success by CAA itself, AS-OCTA may be useful for the objective evaluation of the vascularity of filtering blebs.

Effect of smoking on macular function and retinal structure in retinitis pigmentosa.

Retinitis pigmentosa is an inherited neurodegenerative disease of the retina. We investigated smoking as a modifiable environmental factor for the progression of this currently untreatable disease. Clinical data, smoking history, macular function and morphology including visual acuity, visual field sensitivity, ellipsoid zone width and central retinal thickness were investigated. Association between pack × years and these parameters were evaluated using generalized estimating equation models to adjust confounding factors such as age and sex. A total of 410 patients with retinitis pigmentosa (≥20 years old; 209 female) were included, 164 had a smoking history. Patients without smoking history revealed a better visual acuity than smokers (0.39 versus 0.57, P = 0.001). The pack × years index was associated with worse visual acuity and thinner central retinal thickness after adjusting for age and sex (P = 0.0047 and 0.0099, respectively). Visual field and ellipsoid zone width showed a non-significant decline with increasing pack × years. This study indicates an association of smoking with worse macular function and structural integrity in retinitis pigmentosa patients, and hence a potential detrimental effect of smoking on the disease course.

Species differences in micronucleus induction of the clastogenic compounds associated with drug metabolic profile.

Genotoxicity and carcinogenicity profiles of drugs occasionally vary across species due to species difference in drug metabolic profile. To clarify the effect of species differences in the metabolic profile on micronucleus induction, we conducted an in vitro micronucleus test for seven clastogens (benzo[a]pyrene: BaP, cyclophosphamide monohydrate: CPA coumarin, diclofenac, piroxicam, lansoprazole, and chlorpheniramine) with rat, mouse, monkey, dog, or human liver S9. BaP, CPA, coumarin, diclofenac, piroxicam, and lansoprazole induced micronucleus formation with all species of S9s, whereas chlorpheniramine did not induce micronucleus formation in any of the S9s. BaP and CPA revealed remarkable species differences in micronucleus induction, whereas coumarin, diclofenac, piroxicam, and lansoprazole did not present any differences. Interestingly, the amounts of hydroxy-BaP-epoxides and phosphamide mustard, which might be associated with micronucleus induction by BaP and CPA, respectively, were correlated with the degree of micronucleus induction among the five species. In conclusion, the species difference in micronucleus induction by BaP and CPA was attributable to the differences in the metabolic profiles of these drugs among species. Our results indicate that it is crucial to understand the effect of species differences in the metabolic profile of drug candidates on genotoxicity and carcinogenicity potential and to predict their risk in human.

Preschool children's eating and sleeping habits: late rising and brunch on weekends is related to several physical and mental symptoms.

OBJECTIVE: As the relationships of sleep-wake schedule and mealtime with children's behaviors have not often been studied together, we investigated the relationships of these lifestyles variables with preschool children's well-being. METHODS: Using a network survey, we investigated several lifestyle variables of 1000 families with preschool children. RESULTS: Our previous articles reported that preschool children's bedtime was delayed by the compulsory nap routine in Japanese nursery schools. The present study revealed similar results. We conducted a cluster analysis with children's meal and sleep time data, which yielded five different lifestyle groups. Cluster 1 was characterized by "extremely late and irregular" meal and sleep times; similar to Cluster 1, Cluster 2 was a "late and irregular" lifestyle group. Cluster 3 was a "mildly late" lifestyle group. Cluster 4 was an "early bird and regular lifestyle" group, and Cluster 5 resembled the "early bird and regular lifestyle" group on weekdays, but was "late and irregular on weekends." It was found that the later and more irregular the children's meal and sleep times, the worse their physical and mental condition. Even for Cluster 5, the children who had early and regular meal and sleep times on weekdays, getting up and having breakfast late and irregularly on weekends showed worse physical and mental conditions. These problematic symptoms observed in children with late meal and sleep times on weekends might be partly associated with the irregularity of their habits and partly associated with delayed mealtime, especially for breakfast (brunch). CONCLUSION: A stable lifestyle, including a regular sleep and wake schedule and mealtime, is important for preschool children's mental and physical health.

Circadian transcription factor HSF1 regulates differential HSP70 gene transcription during the arousal-torpor cycle in mammalian hibernation.

Mammalian hibernation is a seasonal phenomenon. The hibernation season consists of torpor periods with a reduced body temperature (Tb), interrupted by euthermic arousal periods (interbout arousal, IBA). The physiological changes associated with hibernation are assumed to be under genetic control. However, the molecular mechanisms that govern hibernation-associated gene regulation are still unclear. We found that HSP70 transcription is upregulated in the liver of nonhibernating (summer-active) chipmunks compared with hibernating (winter-torpid) ones. In parallel, HSF1, the major transcription factor for HSP70 expression, is abundant in the liver-cell nuclei of nonhibernating chipmunks, and disappears from the nuclei of hibernating ones. Moreover, during IBA, HSF1 reappears in the nuclei and drives HSP70 transcription. In mouse liver, HSF1 is regulated by the daily Tb rhythm, and acts as a circadian transcription factor. Taken together, chipmunks similarly use the Tb rhythm to regulate gene expression via HSF1 during the torpor-arousal cycle in the hibernation season.

Long-term efficacy and safety of anti-VEGF therapy in retinitis pigmentosa: a case report.

BACKGROUND: Retinitis pigmentosa (RP), a neurodegenerative disease, is occasionally accompanied by choroidal neovascularization (CNV) and cystoid macular oedema. It is presently treated with repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents. However, there are concerns regarding long-term inhibition of VEGF by the use of these agents, especially in cases involving neurodegenerative diseases, since VEGFs have a neuroprotective effect. Currently, there are no reports on the long-term safety of anti-VEGF therapy in patients with RP. CASE PRESENTATION: In this report, we describe the case of a 56-year-old female patient with CNV associated with RP who was treated with anti-VEGF therapy for 8 years. She had autosomal dominant RP with a heterozygous PRPH2 mutation (c.410G > A) and complained of metamorphopsia in her left eye. Examinations revealed CNV with serous retinal detachment. She was treated with as-needed injections for 2 years; however, she experienced a recurrence. Therefore, we switched to a bimonthly regimen that was continued for 6 years. In total, the patient received 34 injections of various types of anti-VEGFs over 8 years. No recurrences were noted during that time, and we have not detected any negative effects concerning the progression of visual field loss in comparison with the fellow eye. CONCLUSIONS: No negative effects related to the progression of visual field loss were observed during continuous treatment with anti-VEGF agents for 8 years in our patient.

Optical Coherence Tomography Angiography to Estimate Retinal Blood Flow in Eyes with Retinitis Pigmentosa.

Ophthalmologists sometimes face difficulties in identifying the origin of visual acuity (VA) loss in a retinitis pigmentosa (RP) patient, particularly before cataract surgery: cataract or the retinal disease state. Therefore, it is important to identify the significant factors correlating with VA. Nowadays, retinal blood flow in superficial and deep layers can be estimated non-invasively using optical coherence tomography angiography (OCTA). We estimated blood flow per retinal layer by using OCTA; investigated the correlation between VA and other parameters including blood flow and retinal thickness; and identified the most associated factor with VA in patients with RP. OCTA images in 68 of consecutive 110 Japanese RP patients were analysable (analysable RP group). Thirty-two age- and axial length-matched healthy eyes (control group) were studied. In the analysable RP group, the parafoveal flow density in superficial and deep layers was 47.0 ± 4.9% and 52.4 ± 5.5%, respectively, which was significantly lower than that in controls. Using multivariate analysis, we found that the parafoveal flow density in the deep layer and superficial foveal avascular area were the factors associated with VA. Non-invasive estimation of retinal blood flow per retinal layer using OCTA is useful for predicting VA in RP patients.

Hair organ regeneration via the bioengineered hair follicular unit transplantation.

Organ regenerative therapy aims to reproduce fully functional organs to replace organs that have been lost or damaged as a result of disease, injury, or aging. For the fully functional regeneration of ectodermal organs, a concept has been proposed in which a bioengineered organ is developed by reproducing the embryonic processes of organogenesis. Here, we show that a bioengineered hair follicle germ, which was reconstituted with embryonic skin-derived epithelial and mesenchymal cells and ectopically transplanted, was able to develop histologically correct hair follicles. The bioengineered hair follicles properly connected to the host skin epithelium by intracutaneous transplantation and reproduced the stem cell niche and hair cycles. The bioengineered hair follicles also autonomously connected with nerves and the arrector pili muscle at the permanent region and exhibited piloerection ability. Our findings indicate that the bioengineered hair follicles could restore physiological hair functions and could be applicable to surgical treatments for alopecia.

Fully functional hair follicle regeneration through the rearrangement of stem cells and their niches.

Organ replacement regenerative therapy is purported to enable the replacement of organs damaged by disease, injury or aging in the foreseeable future. Here we demonstrate fully functional hair organ regeneration via the intracutaneous transplantation of a bioengineered pelage and vibrissa follicle germ. The pelage and vibrissae are reconstituted with embryonic skin-derived cells and adult vibrissa stem cell region-derived cells, respectively. The bioengineered hair follicle develops the correct structures and forms proper connections with surrounding host tissues such as the epidermis, arrector pili muscle and nerve fibres. The bioengineered follicles also show restored hair cycles and piloerection through the rearrangement of follicular stem cells and their niches. This study thus reveals the potential applications of adult tissue-derived follicular stem cells as a bioengineered organ replacement therapy.

Development of an antibody-lectin enzyme immunoassay for fucosylated α-fetoprotein.

BACKGROUND: Fucosylation is one of the most important types of glycosylations related to cancer. Our previous studies of the enzymatic basis and structural studies of α-fetoprotein (AFP) samples from liver cancer patients indicated that core-fucosylation by α1,6-fucosyltransferase (FUT8) resulted in the production of fucosylated AFP, and in fact fucosylated AFP allowed differential diagnosis in some types of liver cancer from liver cirrhosis. This served as a predictive biomarker for the development of liver cancer 3 to 18 months before it could be detected using imaging techniques. Fucosylated AFP is currently measured by means of a liquid-phase binding assay (LBA) or by an electrokinetic analyte transport assay (EATA). However, these methods require special instrumentation that is currently available only in major medical laboratories. To overcome this problem, we attempted to develop an enzyme immunoassay (EIA) based on the sandwich technique with specific antibody and lectin. RESULTS: Dilute solutions of highly fucosylated AFP in human sera were assayed using a microtiter plate coated with a periodate-oxidized anti-AFP antibody, a fucose-specific biotinylated Aleuria aurantia lectin (AAL), a peroxidase-conjugated streptoavidin, and a chemiluminescent detection system. The technique was able to measure highly fucosylated AFP diluted to 5 to 80ng/ml in human sera using the developed antibody-lectin EIA in combination with the enrichment of AFP. CONCLUSION: A simple method using an antibody-lectin EIA for quantifying fucosylated AFP that does not require special instrumentation was developed. GENERAL SIGNIFICANCE: The method can be generally applied to the quantitative measurement of various fucosylated glycoproteins using specific antibodies. This article is part of a Special Issue entitled Glycoproteomics.

Involvement of ST6Gal I in the biosynthesis of a unique human colon cancer biomarker candidate, alpha2,6-sialylated blood group type 2H (ST2H) antigen.

The alpha2,6-sialylated blood group type 2H (ST2H) antigen (Fucalpha1-2(NeuAcalpha2-6)Galbeta1-4GlcNAcbeta1-3Galbeta1-4Glc-Cer) is a fucoganglioside found in human colon cancer tissues. To elucidate an enzyme responsible for the ST2H antigen formation, we screened some partially purified candidate enzymes, alpha2,6-sialyltransferases, ST6Gal I and ST6Gal II, and alpha1,2-fucosyltransferases, FUT1 and FUT2 for their activities towards pyridylaminated type 2H (Fucalpha1-2Galbeta1-4GlcNAcbeta1-3Galbeta1-4Glc-PA) or LS-tetrasaccharide c (LST-c: NeuAcalpha2-6Galbeta1-4GlcNAcbeta1-3Galbeta1-4Glc-PA) as acceptor substrates. Here we show the ST6Gal I transfers NeuAc from the donor CMP-NeuAc to the terminal Gal of PA-type 2H, which formed the ST2H antigen, but the others could not synthesize it. Using a recombinant ST6Gal I, enzymatic reactions with two types of acceptors, PA-type 2H and PA-lacto-N-neotetraose (LNnT), were kinetically analysed. On the basis of catalytic efficiency (V(max)/K(m)), the specificity of ST6Gal I towards the PA-type 2H was estimated to be 42 times lower than that for PA-LNnT. The overexpression of ST6Gal I in human colon cancer DLD-1 cells effectively resulted in the ST2H antigen formation, as judged by LC-ESI-IT-MS. Many lines of evidence suggest the up-regulation of ST6Gal I in human colon cancer specimens. Collectively, these findings indicate that ST6Gal I is responsible for ST2H antigen biosynthesis in human colon cancer cells.

Potential cancer chemopreventive activity of simple isoquinolines, 1-benzylisoquinolines, and protoberberines.

Seventeen simple isoquinolines, 15 1-benzylisoquinolines, and 19 protoberberines were tested for their inhibitory activities against Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Among the tested alkaloids, the inhibitory activity of all 1-benzylisoquinolines and 11 protoberberines was higher than that of beta-carotene. The 1-benzylisoquinolines 19, 21, 22, 29, and 34 and protoberberines 41, 47-49, 51, 52, and 55 showed potent inhibitory effects on EBV-EA induction (96-100% inhibition at 1 x 10(3) mol ratio/TPA). These alkaloids were more active than the naturally occurring alkaloids, 23, 25, 33, 53, and 54. In addition, fifteen simple isoquinolines, eighteen 1-benzylisoquinolines and eight protoberberines were evaluated with respect to their ability to scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals. Nine simple isoquinolines, ten 1-benzylisoquinolines, and four protoberberines were more potent than alpha-tocopherol, and four 1-benzylisoquinolines, 20 and 28-30, exhibited potent activities (SC50 4.5-5.8 microM). Their activities were higher than the naturally occurring alkaloids, 23, 25, and 33. Therefore, some of the isoquinoline alkaloids indicating the high activity on both assays may be potentially valuable cancer chemopreventive agents. Structure-activity relationships are discussed for both tests.

Nursing diagnoses and interventions of Japanese patients with end-stage breast cancer admitted for different care purposes.

PURPOSE: To clarify actual nursing diagnoses for and interventions given to patients with end-stage breast cancer admitted for different care purposes. METHODS: Nursing diagnoses, defining characteristics, related/risk factors, and nursing interventions were analyzed in a convenience sample of 150 patient records. FINDINGS: A total of 539 nursing diagnoses (96 labels) were documented. Frequently listed diagnoses were chronic pain, risk for infection, and activity intolerance. The most frequently used nursing diagnosis for the chemotherapy group was risk for infection. The nurses in this study rarely report any diagnoses related to death and dying. CONCLUSIONS: Nursing diagnoses and interventions differed depending on the purpose of admission. PRACTICE IMPLICATIONS: Oncology nurses need to consider the reasons for admission when making nursing diagnoses and interventions for patients with end-stage breast cancer.