The association of visual impairment and depression has been investigated in several studies based on a cross-sectional design, which cannot delineate temporal relationships. In the present study, we ...evaluated the influence of visual impairment on depression in all age groups using a longitudinal database of a national sample cohort from 2002 to 2013 provided by the Korean National Health Insurance Service. Of a total of 1,025,340 subjects, 5,846 participants who were registered as visually impaired persons without a previous diagnosis of depression were enrolled at a 1:4 ratio with 23,384 control participants matched for age, sex, income, and region of residence. The crude and adjusted (age, sex, income, region of residence, hypertension, diabetes, and dyslipidemia) hazard ratios (HRs) for the development of depression between the visually impaired and control groups were analyzed using a Cox proportional hazards model. Visual impairment increased the risk of depression after adjusting for age, sex, income, region of residence, hypertension, diabetes, and dyslipidemia (adjusted HR = 1.19, P = 0.002). The risk of depression increased significantly in both the non-blindness visual impairment (adjusted HR = 1.15, P = 0.036) and blindness subgroups (adjusted HR = 1.31, P = 0.016), with a higher HR in the blindness subgroup.
The influence of visual impairment and blindness on the risk of mortality has been reported in diverse cohort studies. However, the results reported have varied from nonsignificant to significant ...associations. In the present study, we evaluated the influence of blindness on the risk of mortality from 2002 to 2013 using a longitudinal database with a national sample cohort provided by the Korean National Health Insurance Service. Of a total of 1,125,691 subjects, 1,279 subjects who were registered as blind were enrolled, and 5,116 control participants were matched at a 1:4 ratio for age, sex, income, region of residence, and medical histories of hypertension, diabetes mellitus and dyslipidemia. The life/death information contained in this dataset was used for the analysis; this information was originally recorded by the medical doctors on the death certificates of the participants. The percentage of total deaths during the mean follow-up period of 111.0 ± 41.6 months was 28.1% in the blindness group and 19.7% in the matched control group. The risk of mortality was significantly higher in the blindness group than in the control group according to the Cox proportional hazards model with additional adjustments for ischemic heart disease, stroke, and depression (adjusted hazard ratio HR of mortality = 1.54, 95% confidence interval CI = 1.37-1.74, P < 0.001). In the subgroup analyses, the adjusted HRs for mortality were significantly higher in the blindness group than in the control group regardless of age (young defined as <60 years old vs old defined as ≥60 years old) and sex. The percentage of death due to metabolic diseases and genitourinary diseases was higher in the blindness group than in the matched control group.
Material surface engineering has attracted great interest in important applications, including electronics, biomedicine, and membranes. More recently, dopamine has been widely exploited in ...solution-based chemistry to direct facile surface modification. However, unsolved questions remain about the chemical identity of the final products, their deposition kinetics and their binding mechanism. In particular, the dopamine oxidation reaction kinetics is a key to improving surface modification efficiency. Here, we demonstrate that high O2 concentrations in the dopamine solution lead to highly homogeneous, thin layer deposition on any material surfaces via accelerated reaction kinetics, elucidated by Le Chatelier’s principle toward dopamine oxidation steps in a Michael-addition reaction. As a result, highly uniform, ultra-smooth modified surfaces are achieved in much shorter deposition times. This finding provides new insights into the effect of reaction kinetics and molecular geometry on the uniformity of modifications for surface engineering techniques.
We evaluated the influence of visual impairment (VI) on income change using the longitudinal database of a Korean National Health Insurance Service cohort. A total of 5292 participants ≥ 40 years old ...and registered as visually impaired persons were selected at a 1:4 ratio with 45,081 non-VI participants matched for age, sex, and income level. The income level of both the VI and non-VI groups increased over time. In the VI group, the income levels 3, 4 and 5 years were higher than the initial value, while the income levels from 1 through 5 years were increased each year in the non-VI group. The rate of change in income between time and VI were significant. In the subgroup analysis considering age, sex, and severity of VI, the rate of change in income were significant in < 65 years old subgroups. Regarding the severity of VI, a significant interaction was found for the mild-to-moderate VI subgroup. Although both the VI and non-VI groups showed increased income levels over 5 years, the degree of income increase in the VI group was relatively lower than that in the non-VI group. This finding was prominent in the middle-age subgroup. These results strongly suggested that VI induced an income inequality.
Accumulating evidence indicates that mesenchymal stem/stromal cell-derived extracellular vesicles (MSC-EVs) exhibit immunomodulatory effects by delivering therapeutic RNAs and proteins; however, the ...molecular mechanism underlying the EV-mediated immunomodulation is not fully understood. In this study, we found that EVs from early-passage MSCs had better immunomodulatory potency than did EVs from late-passage MSCs in T cell receptor (TCR)- or Toll-like receptor 4 (TLR4)-stimulated splenocytes and in mice with ocular Sjögren’s syndrome. Moreover, MSC-EVs were more effective when produced from 3D culture of the cells than from the conventional 2D culture. Comparative molecular profiling using proteomics and microRNA sequencing revealed the enriched factors in MSC-EVs that were functionally effective in immunomodulation. Among them, manipulation of transforming growth factor β1 (TGF-β1), pentraxin 3 (PTX3), let-7b-5p, or miR-21-5p levels in MSCs significantly affected the immunosuppressive effects of their EVs. Furthermore, there was a strong correlation between the expression levels of TGF-β1, PTX3, let-7b-5p, or miR-21-5p in MSC-EVs and their suppressive function. Therefore, our comparative strategy identified TGF-β1, PTX3, let-7b-5p, or miR-21-5p as key molecules mediating the therapeutic effects of MSC-EVs in autoimmune disease. These findings would help understand the molecular mechanism underlying EV-mediated immunomodulation and provide functional biomarkers of EVs for the development of robust EV-based therapies.
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With a strategy of comparative molecular profiling of MSC-derived extracellular vesicles (MSC-EVs), Kim et al. identified key molecules mediating immunosuppressive effects of MSC-EVs in autoimmune disease. These findings would help understand the molecular mechanism underlying EV-mediated immunomodulation and provide functional biomarkers of EVs for the development of robust EV-based therapies.
Current pharmacological treatments for Parkinson’s disease (PD) are focused on symptomatic relief, but not on disease modification, based on the strong belief that PD is caused by irreversible ...dopaminergic neuronal death. Thus, the concept of the presence of dormant dopaminergic neurons and its possibility as the disease-modifying therapeutic target against PD have not been explored. Here we show that optogenetic activation of substantia nigra pars compacta (SNpc) neurons alleviates parkinsonism in acute PD animal models by recovering tyrosine hydroxylase (TH) from the TH-negative dormant dopaminergic neurons, some of which still express DOPA decarboxylase (DDC). The TH loss depends on reduced dopaminergic neuronal firing under aberrant tonic inhibition, which is attributed to excessive astrocytic GABA. Blocking the astrocytic GABA synthesis recapitulates the therapeutic effect of optogenetic activation. Consistently, SNpc of postmortem PD patients shows a significant population of TH-negative/DDC-positive dormant neurons surrounded by numerous GABA-positive astrocytes. We propose that disinhibiting dormant dopaminergic neurons by blocking excessive astrocytic GABA could be an effective therapeutic strategy against PD.
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•Reactive astrocytes in SNpc produce excessive GABA via MAO-B in animal models of PD•Aberrant tonic inhibition causes reduced DA production in neurons and motor deficits•Dormant neurons are rescued by MAO-B inhibition or optogenetic neuronal activation
Heo et al. report that astrocytic GABA-mediated aberrant tonic inhibition of DA neurons leads to a reduction in TH expression and dopamine production, causing dormant DA neurons and motor deficits. Blocking astrocytic GABA synthesis by MAO-B inhibition or optogenetic activation of dormant DA neurons reverses PD pathology.
To report the long-term outcomes of enucleation and insertion of porous polyethylene (PP) orbital implant according to the evolving surgical techniques and implant in patients with paediatric ...retinoblastoma .
Patients with paediatric retinoblastoma who underwent enucleation and PP implant insertion from December 1998 to December 2014 were retrospectively reviewed and divided into four groups: group A, classic enucleation +PP implant; group B, enucleation +PP implant +anterior closure of the posterior Tenon's (ACPT) capsule; group C, enucleation +PP implant +free orbital fat graft +ACPT and group D, enucleation +smooth surface tunnel PP implant +ACPT. Survival analysis of implant exposure and eyelid malpositions was performed.
One hundred and ninety-eight eyes of 196 patients were included. The median follow-up period was 13.0 years (range, 5.0-21.1). A 20 mm implant was inserted for 149 eyes (75.3%). The 10-year exposure-free survival probabilities were 44.6% in group A, 96.4% in group B, 97.4% in group C and 97.7% in group D. ACPT was associated with significant reduction in implant exposure (p<0.001). The most common eyelid malposition was upper eyelid ptosis (24.2%). The eyelid malposition-free survival probability did not differ among the four groups. However, the insertion of a 20 mm implant was associated with significant reduction in upper eyelid ptosis and lower eyelid entropion (p=0.004 and 0.038, respectively).
The long-term postenucleation implant exposure was rare after PP implant insertion and ACPT, even with a 20 mm-diameter implant. A larger implant can be beneficial in long-term prevention of eyelid malposition.
We developed a simple dual signal (color and 'Off-On' fluorescent change) ensemble system based on the complex between a rhodamine derivative 1 and Al(3+) for the detection of pyrophosphate (PPi) in ...100% aqueous solutions. The complex between the rhodamine compound and Al(3+) was utilized as a chemosensing ensemble for the first time. The ensemble showed highly sensitive and selective fluorescent and colorimetric response to pyrophosphate among the anions in 100% aqueous solutions and no interference of the potent biological competitors including ATP, ADP, and phosphate for the detection of PPi in 100% aqueous solutions at pH 7.4.
Although the clinical activity score (CAS) is a validated scoring system for identifying disease activity of thyroid-associated orbitopathy (TAO), it may produce differing results depending on the ...evaluator, and an experienced ophthalmologist is required for accurate evaluation. In this study, we developed a machine learning (ML)-assisted system to mimic an expert's CAS assessment using digital facial images and evaluated its accuracy for predicting the CAS and diagnosing active TAO (CAS ≥ 3). An ML-assisted system was designed to assess five CAS components related to inflammatory signs (redness of the eyelids, redness of the conjunctiva, swelling of the eyelids, inflammation of the caruncle and/or plica, and conjunctival edema) in patients' facial images and to predict the CAS by considering two components of subjective symptoms (spontaneous retrobulbar pain and pain on gaze). To train and test the system, 3,060 cropped images from 1020 digital facial images of TAO patients were used. The reference CAS for each image was scored by three ophthalmologists, each with > 15 years of clinical experience. We repeated the experiments for 30 randomly split training and test sets at a ratio of 8:2. The sensitivity and specificity of the ML-assisted system for diagnosing active TAO were 72.7% and 83.2% in the test set constructed from the entire dataset. For the test set constructed from the dataset with consistent results for the three ophthalmologists, the sensitivity and specificity for diagnosing active TAO were 88.1% and 86.9%. In the test sets from the entire dataset and from the dataset with consistent results, 40.0% and 49.9% of the predicted CAS values were the same as the reference CAS, respectively. The system predicted the CAS within 1 point of the reference CAS in 84.6% and 89.0% of cases when tested using the entire dataset and in the dataset with consistent results, respectively. An ML-assisted system estimated the clinical activity of TAO and detect inflammatory active TAO with reasonable accuracy. The accuracy could be improved further by obtaining more data. This ML-assisted system can help evaluate the disease activity consistently as well as accurately and enable the early diagnosis and timely treatment of active TAO.
Recent studies have suggested that 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) increases macrophage phagocytosis through adenosine monophosphate-activated protein kinase (AMPK). ...However, little information is available on the effects of AICAR on the clearance of apoptotic cells by macrophages, known as efferocytosis, which is essential in maintaining tissue homeostasis and resolving inflammation. AICAR increased p38 MAPK activation and the phagocytosis of apoptotic cells by macrophages, which were inhibited by the p38 MAPK inhibitor, SB203580, the TGF-beta-activated kinase 1 (TAK1) inhibitor, (5Z)-7-oxozeaenol, and siRNA-mediated knock-down of p38α. AICAR increased phosphorylation of Akt, but the inhibition of PI3K/Akt activity using LY294002 did not affect the AICAR-induced changes in efferocytosis in macrophages. CGS15943, a non-selective adenosine receptor antagonist, did not affect AICAR-induced changes in efferocytosis, but dipyridamole, an adenosine transporter inhibitor, diminished the AICAR-mediated increases in efferocytosis. AICAR-induced p38 MAPK phosphorylation was not inhibited by the AMPK inhibitor, compound C, or siRNA-mediated knock-down of AMPKα1. Inhibition of AMPK using compound C or 5'-iodotubercidin did not completely block AICAR-mediated increases in efferocytosis. Furthermore, AICAR also increased the removal of apoptotic neutrophils or thymocytes in mouse lungs. These results reveal a novel mechanism by which AICAR increases macrophage-mediated phagocytosis of apoptotic cells and suggest that AICAR may be used to treat efferocytosis-related inflammatory conditions.
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