Relationship between long-term visual function and the ratio of foveal avascular zone area in eyes with macular hole and healthy fellow eyes.

PURPOSE: This study is to investigate the relationship between long-term changes in the foveal avascular zone (FAZ) and visual function of eyes with macular hole (MH) and compare the relationship between the FAZ of MH eyes and fellow eyes. METHODS: This study included 31 patients with unilateral MH who underwent vitrectomy and their fellow eyes. Best-corrected visual acuity (BCVA) and metamorphopsia were measured preoperatively and at 1, 3, 6, and 12 months postoperatively. We evaluated retinal parameters using optical coherence tomography (OCT) and the superficial FAZ using OCT angiography. The FAZ ratio was defined as follows: (preoperative FAZ area of the MH eye)/(FAZ area of the fellow eye). RESULTS: The preoperative FAZ area of MH eyes was 0.42 ± 0.08 mm2, which decreased to 0.24 ± 0.07 mm2 1 month postoperatively (p < 0.001) and slightly increased to 0.25 ± 0.06 mm2 12 months postoperatively (p = 1.000). The FAZ area did not differ significantly from that of fellow eyes (0.39 ± 0.06 mm2, p = 0.281). The FAZ area of MH eyes was not associated with visual function at any time point. The FAZ ratio showed a correlation with the preoperative, 6-month, and 12-month BCVA (r = 0.604, p < 0.001; r = 0.510, p = 0.003; and r = 0.475, p = 0.007, respectively). CONCLUSIONS: A larger FAZ in the MH eye than that in the fellow eye is associated with poorer long-term visual acuity. The preoperative comparison of the FAZ of the MH eye with that of the fellow eye may be a biomarker for predicting long-term visual acuity.

Altered Gut Microbiota Composition Is Associated with Difficulty in Explicit Emotion Regulation in Young Children.

Executive function (EF) consists of explicit emotion regulation (EER) and cognitive control (CC). Childhood EER in particular predicts mental and physical health in adulthood. Identifying factors affecting EER development has implications for lifelong physical and mental health. Gut microbiota (GM) has attracted attention as a potential biomarker for risk of physical and mental problems in adulthood. Furthermore, GM is related to brain function/structure, which plays a crucial role in emotional processing. However, little is known about how GM compositions are associated with the development of emotion regulation in early childhood. Therefore, in this study, we examined 257 children aged 3-4 to investigate links between GM and risk to EF. EF was measured using the Mother-Reported Behavior Rating Inventory of Executive Function-Preschool version. GM composition (alpha/beta diversity and genus abundance) was evaluated using 16S rRNA gene sequencing and compared between EF-risk and non-risk groups. Our results show that children with EER-risk (an index of inhibitory self-control) had a higher abundance of the genera Actinomyces and Sutterella. Although we have not established a direct link between GM and CC risk, our findings indicate that GM of preschoolers is closely associated with emotional processing and that EERrisk children have more inflammation-related bacteria.

A case of bilateral diffuse uveal melanocytic proliferation with secondary angle closure caused by ciliary body thickening.

Purpose: To describe a case of bilateral diffuse uveal melanocytic proliferation (BDUMP) with secondary angle closure caused by ciliary body thickening accompanied by intraocular pressure (IOP) elevation after mydriasis. Observations: A 55-year-old woman with a history of ovarian cancer had blurred vision in both eyes. Fundus examination revealed multiple patchy lesions in both eyes and a nevus-like elevated lesion in the right eye. Anterior segment optical coherence tomography (AS-OCT) and ultrasound biomicroscopy (UBM) demonstrated angle closure resulting from ciliary body thickening. After mydriasis, the IOP was elevated in both eyes. Instillation of a miotic drug successfully reversed the IOP to normal levels. Conclusions and Importance: BDUMP caused secondary angle closure in both eyes, presumably due to thickening of the entire ciliary body. AS-OCT and UBM were advantageous for analyzing the morphology of the anterior eye segment in BDUMP. Clinicians should be aware of the possibility of angle closure during the management of patients with BDUMP.

T Cell-Intrinsic Vitamin A Metabolism and Its Signaling Are Targets for Memory T Cell-Based Cancer Immunotherapy.

Memory T cells play an essential role in infectious and tumor immunity. Vitamin A metabolites such as retinoic acid are immune modulators, but the role of vitamin A metabolism in memory T-cell differentiation is unclear. In this study, we identified retinol dehydrogenase 10 (Rdh10), which metabolizes vitamin A to retinal (RAL), as a key molecule for regulating T cell differentiation. T cell-specific Rdh10 deficiency enhanced memory T-cell formation through blocking RAL production in infection model. Epigenetic profiling revealed that retinoic acid receptor (RAR) signaling activated by vitamin A metabolites induced comprehensive epigenetic repression of memory T cell-associated genes, including TCF7, thereby promoting effector T-cell differentiation. Importantly, memory T cells generated by Rdh deficiency and blocking RAR signaling elicited potent anti-tumor responses in adoptive T-cell transfer setting. Thus, T cell differentiation is regulated by vitamin A metabolism and its signaling, which should be novel targets for memory T cell-based cancer immunotherapy.

Evaluation of postoperative visual function based on the preoperative inner layer structure in the epiretinal membrane.

PURPOSE: To evaluate the postoperative visual function using a preoperative epiretinal membrane (ERM) classification based on the status of the inner layer structure. METHODS: We assessed 62 eyes, one from each patient undergoing vitrectomy with internal limiting membrane (ILM) peeling for unilateral ERM. The inclusion criteria were as follows: (1) the presence of idiopathic ERM based on optical coherence tomography and a healthy contralateral eye, (2) successful surgery after 25- or 27-gauge transconjunctival 3-port pars plana vitrectomy with ILM peeling, and (3) a minimum follow-up period of 12 months. We included patients with preoperative ERM morphology with no disruption of the inner retinal layer in group A (37 eyes) and those with disruption in group B (25 eyes) and compared the visual acuity, central visual-field sensitivity (CVFS) measured using the Humphrey field analyzer 10-2 program, and detection rate of micro-scotoma (< 10 dB) at baseline and 12 months postoperatively between the groups. RESULTS: Visual acuity at 12 months showed greater improvement in group A than in group B (P = .03). There was no significant difference in CVFS at baseline; however, that of the nasal area was substantially lower after surgery in group B than in group A (P = .02). The 12-month postoperative detection rate of micro-scotoma was significantly higher in group B than in group A (P = .002). CONCLUSION: ERM that has preoperatively disrupted the inner layer poses the risks of CVFS reduction and micro-scotoma formation after vitrectomy. Evaluating the inner layer could be an important prognostic factor in determining retinal function in ERM.

Optical coherence tomography angiography and Humphrey field analyser for macular capillary non-perfusion evaluation in branch retinal vein occlusion.

We non-invasively evaluated macular non-perfused areas (m-NPAs) of branch retinal vein occlusion (BRVO) using optical coherence tomography (OCT) angiography and the Humphrey visual field analyser 10-2 programme (HFA 10-2). We enrolled 30 patients (30 eyes) with macular oedema secondary to BRVO. OCT angiography was used to photograph the macula at 6 × 6-mm; sizes of m-NPAs in the superficial capillary plexus (SCP) and deep capillary plexus (DCP) were measured in four areas. For HFA 10-2, we divided the actual measurement threshold of 68 points into four areas and calculated the mean central visual field sensitivity (CVFS). The correlation between the mean m-NPA and mean CVFS (dB) in each area was examined. There was a strong correlation between the m-NPA of each region detected in SCP and DCP, and the mean CVFS of each corresponding area (SCP: r = - 0.83, r = - 0.64, r = - 0.73, and r = - 0.79; DCP: r = - 0.82, r = - 0.71, r = - 0.71, and r = - 0.70), p values were < 0.001 for all. m-NPAs were associated with decreased visual field sensitivity in BRVO. Non-invasive m-NPA evaluation was possible using OCT angiography and HFA 10-2.

Relationship between morphological changes in the foveal avascular zone of the epiretinal membrane and postoperative visual function.

OBJECTIVE: To investigate the relationship between the preoperative morphology of the foveal avascular zone (FAZ) and postoperative visual function in patients with idiopathic epiretinal membrane (ERM). METHODS AND ANALYSIS: This retrospective study enrolled 36 patients who underwent a unilateral internal limiting membrane peeling with vitrectomy for idiopathic ERM. We measured the area of superficial FAZ in the eyes with ERM and in the contralateral control eyes preoperatively and at 6 months postoperatively using optical coherence tomography (OCT) angiography. The ERM stage was measured using swept-source OCT. We evaluated the FAZ area ratio (preoperative FAZ of the ERM eye/FAZ of the control eye) to indicate the degree of FAZ contraction in the ERM eyes compared with the control eyes. The correlations between the FAZ area ratio and postoperative visual function and changes in macular morphology were assessed. RESULTS: Preoperative mean best-corrected visual acuity (BCVA) significantly improved from the logarithm of the minimum angle of resolution 0.20±0.24 to 0.01±0.13 at 6 months postoperatively (p<0.01). The mean area of the FAZ increased significantly from 0.06±0.07 mm2 preoperatively to 0.09±0.07 mm2 after vitrectomy (p<0.01). FAZ area ratio showed significant negative correlations with changes in BCVA (r=-0.44, p<0.01) and the ERM stages (r=-0.56, p<0.01). CONCLUSION: The FAZ is reduced as ERM progresses and enlarges after vitrectomy. The FAZ area ratio based on preoperative FAZ may predict postoperative visual acuity.

Restoration of the Ellipsoid Zone and Visual Prognosis at 1 Year after Surgical Macular Hole Closure.

Purpose. To evaluate the restoration of the ellipsoid zone (EZ) and its influence on visual prognosis 1 year after surgical macular hole (MH) closure. Method. Subjects were patients with stage 2, 3, or 4 idiopathic MH who underwent primary vitrectomy that resulted in successful hole closure. Nineteen eyes with both EZ disruption with foveal detachment and a continuous external limiting membrane on optical coherence tomography during the early postoperative period were included in this study. Result. EZ disruption was restored in 10 eyes (53%, Group A) and remained in 9 eyes (47%, Group B) at 1 year after surgery. In Group B, the diameter of the residual EZ disruption was 54.7 ± 33.1 µm. LogMAR visual acuity (VA) 1 year after surgery was significantly better than preoperative VA in each group (Group A: -0.007 ± 0.102; P < 0.001; Group B: 0.051 ± 0.148; P < 0.001), but there was no significant difference between the 2 groups (P = 0.332). There was no significant correlation between logMAR VA and EZ disruption diameter at 1 year after surgery. Conclusion. EZ was restored in 53% of eyes at 1 year after surgical closure of idiopathic MH. Mean residual EZ disruption diameter was 54.7 ± 33.1 µm. Neither resolved nor residual EZ disruption influenced postoperative VA.

Prenatal Nicotine Exposure Impairs the Proliferation of Neuronal Progenitors, Leading to Fewer Glutamatergic Neurons in the Medial Prefrontal Cortex.

Cigarette smoking during pregnancy is associated with various disabilities in the offspring such as attention deficit/hyperactivity disorder, learning disabilities, and persistent anxiety. We have reported that nicotine exposure in female mice during pregnancy, in particular from embryonic day 14 (E14) to postnatal day 0 (P0), induces long-lasting behavioral deficits in offspring. However, the mechanism by which prenatal nicotine exposure (PNE) affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that PNE disrupted the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and subventricular zones. In addition, using a cumulative 5-bromo-2'-deoxyuridine labeling assay, we evaluated the rate of cell cycle progression causing the impairment of neuronal progenitor proliferation, and uncovered anomalous cell cycle kinetics in mice with PNE. Accordingly, the density of glutamatergic neurons in the medial prefrontal cortex (medial PFC) was reduced, implying glutamatergic dysregulation. Mice with PNE exhibited behavioral impairments in attentional function and behavioral flexibility in adulthood, and the deficits were ameliorated by microinjection of D-cycloserine into the PFC. Collectively, our findings suggest that PNE affects the proliferation and maturation of progenitor cells to glutamatergic neuron during neurodevelopment in the medial PFC, which may be associated with cognitive deficits in the offspring.

In vitro alpha-glucosidase inhibitory effect of Zn(II) complex with 6-methyl-2-picolinmethylamide.

We found alpha-glucosidase inhibitory effect of Zn(II) complex with 6-methyl-2-picolinmethylamide (6mpa-ma) which showed the highest blood glucose lowering effect in Zn(II) complexes with picolinamide derivatives in KK-A(y) mice. The Zn(II) complex showed strong alpha-glucosidase inhibitory activity greater by about eighty times (substrate: maltose) and forty times (substrate: sucrose) compared with acarbose.

The action mechanism of zinc(II) complexes with insulinomimetic activity in rat adipocytes.

Zinc (Zn), an essential trace element, and its complexes have recently been known to exhibit insulinomimetic activities. However, the action mechanism of Zn(II) has yet been obscure. The purpose of the present study was to estimate the action mechanism of the Zn(II) complexes. We found first that Zn given in the chemical forms such as Zn(maltolate)2 and Zn(threoninate)2 complexes is highly uptaken in the isolated rat adipocytes compared with that of Zn(picolinate)2. Then, the action mechanism for the insulinomimetic activities was examined in terms of free fatty acid release from the adipocytes. Four Zn(II) compounds, ZnSO4, Zn(picolinate)2, Zn(maltolate)2, and Zn(threoninate)2, inhibited the free fatty acid release from the adipocytes treated with epinephrine (adrenaline). By using several inhibitors for fatty acids and glucose metabolisms in the adipocytes, the following results were obtained. (1) Zn(picolinic acid)2 complex acts on the insulin receptor and PI3-k, which relate to the glucose uptake, as indicated by the experiments using hydroxy-2-naphthalenylmethyl phosphonic acid tris acetoxy methyl ester (HNMPA-(AM)3) and wortmannin, respectively. (2) ZnSO4, and Zn(maltolate)2 and Zn(threoninate)2 complexes affect a glucose transporter 4 (GLUT 4), which is involved in the glucose uptake as indicated by the results using cytochalasin B. (3) Four Zn(II) compounds affect the activation of the phosphodiesterase as indicated by the experiments using cilostamide. These results indicate that the Zn(II) compounds promote the glucose uptake into the adipocytes by affecting at least three sites in the adipocytes, which in turn normalize the blood glucose levels in the experimental diabetic animals.

Insulinomimetic zinc(II) complexes with natural products: in vitro evaluation and blood glucose lowering effect in KK-Ay mice with type 2 diabetes mellitus.

In vitro insulinomimetic activities of Zn(II) complexes with three natural products, betaine, L-lactic acid, and D-(-)-quinic acid (qui), were found in rat adipocytes treated with epinephrine in terms of the inhibition of free fatty acid release. Based on the results, the blood glucose lowering effect in KK-A(y) mice with type 2 diabetes mellitus was observed by daily i.p. injections of a monomeric zinc(II) complex, Zn(qui)(2), for 13 d.

Anti-diabetes effect of Zn(II)/carnitine complex by oral administration.

A novel bis(L-carnitinato)Zn(II) complex, Zn(car)(2)Cl(2), was prepared, and its insulinomimetic and antidiabetic activities were examined. The complex showed a tendency to lower the high blood glucose levels of KK-A(y) mice with type 2 diabetes mellitus when given by oral administration at a dose of 20 mg Zn/kg body weight for 16 d. In addition, the complex improved glucose tolerance ability when examined by the oral glucose tolerance test (1 g glucose/kg body weight).

Potential insulinominetic agents of zinc(II) complexes with picolinamide derivatives: preparations of complexes, in vitro and in vivo studies.

Following the finding of in vitro insulinominetic activities of new prepared Zn(II) complexes with amide ligands (2-picolinamide (pa-a) and 6-methyl-2-picolinmethylamide (6mpa-ma)) in isolated rat adipocytes treated with epinephrine in terms of inhibition of free fatty acid release, their blood glucose normalizing effects were observed on daily intraperitoneal injections for 14 d in a type 2 diabetes mellitus model animal, KK-Ay mice. The blood glucose levels of KK-Ay mice were maintained in a normal range during the administration of both complexes. After the administration of each complex for 14 d, the improvement of glucose metabolism was confirmed as judged by the glucose tolerance test.

Development of new insulinomimetic zinc(II) picolinate complexes with a Zn(N2O2) coordination mode: structure characterization, in vitro, and in vivo studies.

Three zinc(II) complexes of picolinic acid and its derivatives with a Zn(N2O2) coordination mode were prepared and evaluated for their insulinomimetic activities by in vitro and in vivo studies. By introducing an electron-donating methyl group into the picolinate ligand (pic), bis(6- or 3-methylpicolinato)zinc(II) complexes [Zn(6-mpa)2 or Zn(3-mpa)2, respectively] were prepared. The Zn(6-mpa)(2) complex was crystallized as a water adduct [Zn(6-mpa)2(H2O)].H2O, in which two carboxylate oxygens and two pyridine nitrogens of 6-mpa and a water oxygen coordinate to a zinc(II) with a trigonal bipyramidal geometry. By in vitro evaluation of the inhibition of free fatty acid (FFA) release from isolated rat adipocytes in the presence of epinephrine, the insulinomimetic activities of Zn(pic)2, Zn(6-mpa)2, and Zn(3-mpa)2 (IC50=0.64 +/- 0.13, 0.31 +/- 0.05, and 0.40 +/- 0.07 mM, respectively) were found to be higher than those of VOSO(4) (IC50=1.00 mM) and ZnSO(4) (IC50=1.58 +/- 0.05 mM) in terms of IC50 value, the 50% inhibition concentrations for the FFA release from the adipocytes. Then, Zn(6-mpa)2, which exhibited the highest in vitro insulinomimetic activity among three complexes examined, was given at a dose of 3.0 mg (45.9 micromol) Zn/kg body weight to KK-A(y) mice with type 2 diabetes mellitus by daily intraperitoneal injections for 14 days and it was found that the hereditary high blood glucose levels were lowered during the administration of the complex. The improvement of diabetes mellitus was confirmed with the oral glucose tolerance test.

Blood glucose lowering and toxicological effects of zinc (II) complexes with maltol, threonine, and picolinic acid.

The blood glucose lowering effects in KK-Ay mice with type 2 diabetes mellitus (DM) receiving daily an intraperitoneal (i.p.) administration of Zn(II) complexes with maltol, L-threonine, and picolinic acid for 14 days were estimated under the same conditions, and dose-dependent blood glucose lowering effects in the dose range of 0.2-3.0 mg Zn/kg body weight were found. Among them, the bis(maltolato)Zn(II) complex exhibited the highest blood sugar lowering effect at the dose of 3.0 mg Zn/kg. The improvement of DM was confirmed with oral glucose tolerance tests as well as blood HbA1c levels after the administration of the three Zn(II) complexes at the dose of 3.0 mg Zn/kg. For the purpose of the clinical trial of the complexes in the future, we examined the toxic effects of these three Zn(II) complexes in regard of the LD50 values and hepatic cytochrome P450 levels. The LD50 values of the three Zn(II) complexes exhibited high values compared with that of ZnCl2. No changes of both CYP1A1 and CYP2E1 levels in the liver of KK-Ay mice treated with the three Zn(II) complexes were observed. The obtained results will be important when the complexes are tried for clinical use.