Shih-Jen Chen

EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy.

Purpose: To assess the effects of verteporfin photodynamic therapy (PDT) combined with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Methods: In this multicenter, double-masked, primarily indocyanine green angiography–guided trial, 61 Asian patients were randomized to verteporfin PDT (standard fluence), ranibizumab 0.5 mg, or the combination. Patients were administered with verteporfin PDT/placebo and initiated with three consecutive monthly ranibizumab/sham injections starting Day 1, and re-treated (Months 3–5) as per predefined criteria. The primary endpoint was the proportion of patients with indocyanine green angiography–assessed complete regression of polyps at Month 6. Secondary endpoints included mean change in best-corrected visual acuity at Month 6 and safety. Results: At Month 6, verteporfin combined with ranibizumab or alone was superior to ranibizumab monotherapy in achieving complete polyp regression (77.8% and 71.4% vs. 28.6%; P < 0.01); mean change ± standard deviation in best-corrected visual acuity (letters) was 10.9 ± 10.9 (verteporfin PDT + ranibizumab), 7.5 ± 10.6 (verteporfin PDT), and 9.2 ± 12.4 (ranibizumab). There were no new safety findings with either drug used alone or in combination. Conclusion: Verteporfin PDT combined with ranibizumab 0.5 mg or alone was superior to ranibizumab monotherapy in achieving complete regression of polyps in this 6-month study in patients with symptomatic macular polypoidal choroidal vasculopathy. All treatments were well tolerated over 6 months.

The Prevalence of Age-Related Macular Degeneration in Asians : A Systematic Review and Meta-Analysis

OBJECTIVE To determine the prevalence of age-related macular degeneration (AMD) in Asian populations and to compare this with prevalence in white populations. DESIGN A clear understanding of AMD prevalence in Asians is essential to meet future demands for eye health care. METHODS We searched published literature reporting AMD prevalence in Asian populations. We limited studies examined to those using standardized grading systems (either the Wisconsin Age-Related Maculopathy Grading System or the international classification proposed by the International ARM Epidemiological Study Group). We used metaanalytical methods to calculate age-specific pooled prevalence of AMD using inverse-variance weighting in a random effect model. We also calculated pooled estimates of age-standardized prevalence. A metaregression model was used to examine gender differences and differences between Asian and white populations. RESULTS We identified 9 studies reporting AMD prevalence from 4 Asian populations. Pooled prevalence estimates of early and late AMD in Asian populations aged 40 to 79 years were 6.8% (95% confidence interval [CI], 4.6%-8.9%) and 0.56% (95% CI, 0.30%-0.81%), respectively; corresponding prevalence estimates in white populations were 8.8% (95% CI, 3.8%-13.8%) and 0.59% (95% CI, 0.35%-0.84%), respectively. Reliable prevalence estimates of AMD in Asian persons aged > or =80 years were not available owing to small subject numbers in this age category. CONCLUSIONS Among persons aged 40 to 79 years, the age-specific prevalence of late AMD in Asians was comparable with that reported from white populations, but early AMD signs were less common among Asians. Further studies in Asian populations are warranted to investigate whether certain specific AMD phenotypes or subtypes, such as polypoidal choroidal vasculopathy, are more common.

Polypoidal choroidal vasculopathy: evidence-based guidelines for clinical diagnosis and treatment.

Background: Polypoidal choroidal vasculopathy (PCV) is an exudative maculopathy affecting vision, with clinical features distinct from neovascular age-related macular degeneration. Currently, no evidence-based guidelines exist for its diagnosis and treatment. Methods: A panel of experts analyzed a systematic literature search on PCV together with results of the EVEREST trial, the only published randomized controlled clinical trial in PCV. At a subsequent Roundtable meeting, recommendations for the management of PCV were agreed based on this analysis and their own expert opinion. Results: Diagnosis of PCV should be based on early-phase nodular hyperfluorescence from choroidal vasculature visualized using indocyanine green angiography. Recommended initial treatment of juxtafoveal and subfoveal PCV is either indocyanine green angiography-guided verteporfin photodynamic therapy or verteporfin photodynamic therapy plus 3 × 0.5 mg ranibizumab intravitreal injections 1 month apart. If there is incomplete regression of polyps by indocyanine green angiography, eyes should be retreated with verteporfin photodynamic therapy monotherapy or verteporfin photodynamic therapy plus ranibizumab. If there is complete regression of polyps by indocyanine green angiography, but there is leakage on fluorescein angiography and other clinical or anatomical signs of disease activity, eyes should be retreated with ranibizumab. Conclusion: Practical guidance on the clinical management of PCV is proposed based on expert evaluation of current evidence.

Functional Improvement of Focal Cerebral Ischemia Injury by Subdural Transplantation of Induced Pluripotent Stem Cells with Fibrin Glue

Ischemic stroke is the leading cause of disability in the world. Cell transplantation has emerged in various neurological diseases as a potential therapeutic approach in the postacute stroke phase. Recently, inducible pluripotent stem (iPS) cells showed potential for multilineage differentiation and provide a resource for stem cell-based therapies. However, whether iPS transplantation could improve the function of stroke-like model is still an open question. The aim of this study is to investigate the therapeutic effects of subdural transplantation of iPS mixed with fibrin glue (iPS-FG) on cerebral ischemic rats induced by middle cerebral artery occlusion (MCAO). We demonstrated an efficient method to differentiate iPS into astroglial-like and neuron-like cells which display functional electrophysiological properties. In vivo study firstly showed that the direct injection of iPS into damaged areas of rat cortex significantly decreased the infarct size and improved the motor function in rats with MCAO. Furthermore, we found that the subdural iPS-FG can also effectively reduce the total infarct volume and greatly improve the behavior of rats with MCAO to perform rotarod and grasping tasks. Importantly, analysis of cytokine expression in iPS-FG-treated ischemic brains revealed a significant reduction of pro-inflammatory cytokines and an increase of anti-inflammatory cytokines. Taken together, these results suggest that iPS cells could improve the motor function, reduce infarct size, attenuate inflammation cytokines, and mediate neuroprotection after ischemic stroke. Subdural iPS-FG could be considered as a more safe approach because this method can avoid iatrogenic injury to brain parenchyma and enhance recovering from stoke-induced impairment.

Prevalence and Associated Risk Factors of Age-Related Macular Degeneration in an Elderly Chinese Population in Taiwan : The Shihpai Eye Study

PURPOSE To assess the prevalence and associated risk factors of age-related macular degeneration (AMD) in an elderly Chinese population in Taiwan. METHODS The Shihpai Eye Study was a survey of vision and ocular disease in an elderly Chinese population 65 years of age or older residing in Shihpai, Taipei, Taiwan. Of 2045 elderly residents randomly sampled from the household registration databank, 1361 (66.6%) underwent a detailed ophthalmic examination that included fundus color slides by fundus camera after pupil dilatation. Photographs were graded according to the Wisconsin Age-Related Maculopathy Grading System. RESULTS Fundus photographs were available for 1105 (54.0% in the eligible, 81.2% in the ocular examined) participants. The 47 (4.3%) participants who had ungradable fundus images were older and had more lens opacity. Of the 1058 gradable photographs, the prevalence of early AMD was 9.2% (95% confidence interval [CI], 7.8-10.8); of late AMD, 1.9% (95% CI, 1.3-2.7); of soft drusen, 42.2% (95% CI, 39.7-44.8); of soft indistinct drusen, 4.1% (95% CI, 3.1-5.2); and of any pigmentary change, 8.6% (95% CI, 7.2-10.2). Age was the most significant factor associated with both early and late AMD. The prevalence of early AMD rose from 5.0% in the 65- to 69-year age group to 24.4% in those 80 years of age and older; and for late AMD, from 1.0% to 9.0%. Those who currently drank alcohol had a lower rate of early AMD than did the nondrinker (adjusted odd ratio 0.32, 95% CI: 0.11-0.93, P = 0.037). CONCLUSIONS AMD is a common eye disease in the elderly Chinese people in Taiwan. The adjusted prevalence rate of exudative AMD is comparable to that in the Chinese people in the Multiethnic Study of Atherosclerosis (MESA) in the United States but is higher than in the Chinese people in the Beijing study in China. Further studies are needed to clarify the incidence and associated risk factors.

Resveratrol Promotes Osteogenic Differentiation and Protects Against Dexamethasone Damage in Murine Induced Pluripotent Stem Cells

Resveratrol is a natural polyphenol antioxidant that has been shown to facilitate osteogenic differentiation. A recent breakthrough has demonstrated that ectopic expression of four genes is sufficient to reprogram murine and human fibroblasts into induced pluripotent stem (iPS) cells. However, the roles of resveratrol in the differentiation and cytoprotection of iPS cells have never been studied. In this study, we showed that, in addition to cardiac cells, neuron-like cells, and adipocytes, mouse iPS cells could differentiate into osteocyte-like cells. Using atomic force microscopy that provided nanoscale resolution, we monitored mechanical properties of living iPS cells during osteogenic differentiation. The intensity of mineralization and stiffness in differentiating iPS significantly increased after 14 days of osteogenic induction. Furthermore, resveratrol was found to facilitate osteogenic differentiation in both iPS and embryonic stem cells, as shown by increased mineralization, up-regulation of osteogenic markers, and decreased elastic modulus. Dexamethasone-induced apoptosis in iPS cell-derived osteocyte-like cells was effectively prevented by pretreatment with resveratrol. Furthermore, resveratrol significantly increased manganese superoxide dismutase expression and intracellular glutathione level, thereby efficiently decreasing dexamethasone-induced reactive oxygen species (ROS) production and cytotoxicity. Transplantation experiments using iPS cell-derived osteocyte-like cells further demonstrated that oral intake of resveratrol could up-regulate osteopontin expression and inhibit teratoma formation in vivo. In sum, resveratrol can facilitate differentiation of iPS cells into osteocyte-like cells, protect these iPS cell-derived osteocyte-like cells from glucocorticoid-induced oxidative damage, and decrease tumorigenicity of iPS cells. These findings implicate roles of resveratrol and iPS cells in the stem cell therapy of orthopedic diseases.

Visual impairment in a Taiwanese population: Prevalence, causes, and socioeconomic factors

Abstract PURPOSE We sought to estimate the prevalence of visual impairment among an elderly population in urban Taiwan, determine the causes of visual impairment, and gain information about certain socioeconomic factors associated with visual impairment. METHODS A population-based survey of ocular diseases in residents aged 50 years or older was conducted in Peitou Precinct, Taipei, Taiwan. All participants underwent a comprehensive ophthalmic examination, including visual acuity measurement, using standardized protocols. Demographic data, marital status, employment status, and educational level were gathered through an interview. RESULTS A total of 2034 participants completed the visual acuity measurements. The prevalence of visual impairment (defined as best-corrected visual acuity in the better eye <6/18) among this population was 2.75% (95% confidence intervals: 2.04%–3.46%). Three major causes of visual impairment were cataract (30.4%), high myopic macular degeneration (25.0%), and age-related macular degeneration (14.3%). In multivariate analysis, age was positively correlated with visual impairment (P < 0.001), and higher education level was associated with a significant decrease in the odds of being visually impaired (P < 0.001). No relation was found between visual impairment and sex, or marital and employment status. CONCLUSIONS This study provides the first information about the prevalence and causes of visual impairment in Taiwan, and identifies age and educational level as the most important factors related to visual impairment. Additional educational programs should be developed to improve individual awareness of age-related ocular diseases and the availability of current ophthalmic intervention.

Corneal repair by human corneal keratocyte-reprogrammed iPSCs and amphiphatic carboxymethyl-hexanoyl chitosan hydrogel

Induced pluripotent stem cells (iPSCs) have promising potential in regenerative medicine, but whether iPSCs can promote corneal reconstruction remains undetermined. In this study, we successfully reprogrammed human corneal keratocytes into iPSCs. To prevent feeder cell contamination, these iPSCs were cultured onto a serum- and feeder-free system in which they remained stable through 30 passages and showed ESC-like pluripotent property. To investigate the availability of iPSCs as bioengineered substitutes in corneal repair, we developed a thermo-gelling injectable amphiphatic carboxymethyl-hexanoyl chitosan (CHC) nanoscale hydrogel and found that such gel increased the viability and CD44+proportion of iPSCs, and maintained their stem-cell like gene expression, in the presence of culture media. Combined treatment of iPSC with CHC hydrogel (iPSC/CHC hydrogel) facilitated wound healing in surgical abrasion-injured corneas. In severe corneal damage induced by alkaline, iPSC/CHC hydrogel enhanced corneal reconstruction by downregulating oxidative stress and recruiting endogenous epithelial cells to restore corneal epithelial thickness. Therefore, we demonstrated that these human keratocyte-reprogrammed iPSCs, when combined with CHC hydrogel, can be used as a rapid delivery system to efficiently enhance corneal wound healing. In addition, iPSCs reprogrammed from corneal surgical residues may serve as an alternative cell source for personalized therapies for human corneal damage.

Induction of Insulin-Producing Cells Derived from Endometrial Mesenchymal Stem-like Cells

Studies have demonstrated that mesenchymal stem-like cells can be isolated from endometrium. However, the potential of endometrial-derived stem cells to differentiate into insulin-positive cells and functionally secrete insulin remains undetermined. We isolated endometrial mesenchymal stem-like cells (EMSCs) from human endometrial tissue from six donors. The insulin-secreting function of EMSCs was further analyzed in vitro and in transplanted grafts in vivo. We successfully isolated EMSCs from human endometrium, and our results showed that EMSCs expressed high levels of stemness genes (Nanog, Oct-4, Nestin). Under specific induction conditions for 2 weeks, EMSCs formed three-dimensional spheroid bodies (SBs) and secreted C-peptide. The high insulin content of SB-EMSCs was confirmed by enzyme-linked immunosorbent assay, and glucose responsiveness was demonstrated by measuring glucose-dependent insulin secretion. Using cDNA microarrays, we found that the expression profiles of SB-EMSCs are related to those of islet tissues. Insulin and C-peptide production in response to glucose was significantly higher in SB-EMSCs than in undifferentiated EMSC controls. Furthermore, upon differentiation, SB-EMSCs displayed increased mRNA expression levels of NKx2.2, Glut2, insulin, glucagon, and somatostatin. Our results also showed that SB-EMSCs were more resistant to oxidative damage and oxidative damage-induced apoptosis than fibroblasts from the same patient. It is noteworthy that SB-EMSCs xenotransplanted into immunocompromised mice with streptozotocin-induced diabetes restored blood insulin levels to control values and greatly prolonged the survival of graft cells. These data suggest that EMSCs not only play a novel role in the differentiation of pancreatic progenitors, but also can functionally enhance insulin production to restore the regulation of blood glucose levels in an in vivo transplantation model.

Visual acuity and contrast sensitivity in different types of posterior capsule opacification

Purpose: To compare the visual acuity (VA) and contrast sensitivity in 2 types of posterior capsule opacification (PCO) in pseudophakic eyes before and after neodymium:YAG (Nd:YAG) capsulotomy and to evaluate vision test results after Nd:YAG capsulotomy. Setting: Department of Ophthalmology, Taipei Veterans General Hospital, National Yang‐Ming University, Taipei, Taiwan. Methods: Fourteen eyes with fibrosis‐type PCO and 15 eyes with Elschnig‐pearl‐type PCO were enrolled prospectively. Before and 1 week after Nd:YAG capsulotomy, VA and contrast sensitivity were assessed using the illiterate E version of the Bailey‐Lovie chart and the Vistech VCTS 6000 chart, respectively. Results: Before capsulotomy, the mean logMAR acuity in the group with Elschnig‐pearl‐type PCO was 0.47 ± 0.32 (SD) and in the group with fibrosis‐type PCO, 0.17 ± 0.07. The difference between the 2 groups was significant (P = .002). After capsulotomy, there was no significant between‐group difference (P gt; .05). Before capsulotomy, the contrast sensitivity was significantly worse (P < .01) at all spatial frequencies in the group with pearl‐type PCO, especially at 6 cycles per degree. After capsulotomy, there was no significant between‐group difference (P gt; .05) at any spatial frequency. Conclusions: After cataract surgery, patients with pearl‐type PCO had lower VA and contrast sensitivity than those with fibrosis‐type PCO. An Nd:YAG capsulotomy improved the VA and contrast sensitivity in patients with both types of PCO.