David S.H. Wong

Human Pluripotent Stem Cell‐Derived Mesenchymal Stem Cells Prevent Allergic Airway Inflammation in Mice

We previously found that mesenchymal stem cells (MSCs) derived from human‐induced pluripotent stem cells (iPSCs) exerted immunomodulatory effects on Th2‐mediated allergic rhinitis in vitro. However, their contribution to the asthma and allergic rhinitis in animal models remains unclear. In this study, we developed a mouse model of ovalbumin (OVA)‐induced allergic inflammation in both the upper and lower airways and evaluated the effects of the systemic administration of human iPSC‐MSCs and bone marrow‐derived MSCs (BM‐MSCs) on allergic inflammation. Our results showed that treatments with both the iPSC‐MSCs and BM‐MSCs before the challenge phase protected the animals from the majority of allergy‐specific pathological changes. This protection included an inhibition of inflammatory cell infiltration and mucus production in the lung, a reduction in eosinophil infiltration in the nose, and a decrease in inflammatory cell infiltration in both the bronchoalveolar and nasal lavage fluids. In addition, treatment with iPSC‐MSCs or BM‐MSCs before the challenge phase resulted in reduced serum levels of Th2 immunoglobulins (e.g., IgE) and decreased levels of Th2 cytokines including interleukin (IL)‐4, IL‐5, or IL‐13 in the bronchoalveolar and/or nasal lavage fluids. Similar therapeutic effects were observed when the animals were pretreated with human iPSC‐MSCs before the sensitization phase. These data suggest that iPSC‐MSCs may be used as an alternative strategy to adult MSCs in the treatment of asthma and allergic rhinitis. STEM CELLS 2012;30:2692–2699

Mitochondrial transfer of mesenchymal stem cells effectively protects corneal epithelial cells from mitochondrial damage

Recent studies have demonstrated that mesenchymal stem cells (MSCs) can donate mitochondria to airway epithelial cells and rescue mitochondrial damage in lung injury. We sought to determine whether MSCs could donate mitochondria and protect against oxidative stress-induced mitochondrial dysfunction in the cornea. Co-culturing of MSCs and corneal epithelial cells (CECs) indicated that the efficiency of mitochondrial transfer from MSCs to CECs was enhanced by Rotenone (Rot)-induced oxidative stress. The efficient mitochondrial transfer was associated with increased formation of tunneling nanotubes (TNTs) between MSCs and CECs, tubular connections that allowed direct intercellular communication. Separation of MSCs and CECs by a transwell culture system revealed no mitochiondrial transfer from MSCs to CECs and mitochondrial function was impaired when CECs were exposed to Rot challenge. CECs with or without mitochondrial transfer from MSCs displayed a distinct survival capacity and mitochondrial oxygen consumption rate. Mechanistically, increased filopodia outgrowth in CECs for TNT formation was associated with oxidative inflammation-activated NFκB/TNFαip2 signaling pathways that could be attenuated by reactive oxygen species scavenger N-acetylcysteine (NAC) treatment. Furthermore, MSCs grown on a decellularized porcine corneal scaffold were transplanted onto an alkali-injured eye in a rabbit model. Enhanced corneal wound healing was evident following healthy MSC scaffold transplantation. And transferred mitochondria was detected in corneal epithelium. In conclusion, mitochondrial transfer from MSCs provides novel protection for the cornea against oxidative stress-induced mitochondrial damage. This therapeutic strategy may prove relevant for a broad range of mitochondrial diseases.

Systematic screening for diabetic retinopathy (DR) in Hong Kong: prevalence of DR and visual impairment among diabetic population

Purpose To determine the prevalence of diabetic retinopathy (DR), sight threatening DR (STDR), visual impairment and other eye diseases in a systematic DR screening programme among primary care Chinese patients with diabetes mellitus (DM) in Hong Kong. Methods Screening for DR was provided to all subjects with DM in public primary care using digital fundus photography according to the English national screening programme. STDR was defined as preproliferative DR (R2), proliferative DR (R3) and/or maculopathy (M1). The presence of other eye diseases was noted. Visual impairment was classified as none (visual acuity in the better eye of 6/18 or better), mild (6/18 to >6/60) and severe (6/60 or worse). Results Of 174u2005532 subjects screened, most had never been screened before. The prevalence of DR was 39.0% (95% CI 38.8% to 39.2%) and STDR 9.8% (95% CI 9.7% to 9.9%). The most common DR status was R1 (35.7%), followed by M1 (8.6%), R2 (3.0%) and R3 (0.3%). The prevalence of mild and severe visual impairment was 4.2% and 1.3%, respectively. Subjects with STDR had a higher prevalence (9.8%) of visual impairment than those without (3.5%). Conclusions DR was prevalent in this population and one in 10 had STDR. This suggests the need for systematic screening to ensure timely referral to an ophthalmologist for monitoring and/or treatment.

Screening for diabetic retinopathy with or without a copayment in a randomized controlled trial: Influence of the inverse care law

OBJECTIVEnTo examine whether the inverse care law operates in a screening program for diabetic retinopathy (DR) based on fee for service in Hong Kong.nnnDESIGNnRandomized controlled trial.nnnPARTICIPANTSnAll those with type 1 or 2 diabetes from 2 clinics were recruited.nnnINTERVENTIONnDiabetic retinopathy screening with a small copayment versus free access in a publicly funded family medicine service.nnnMAIN OUTCOME MEASURESnUptake of screening and severity of DR detected. Association between these outcome variables and independent variables were determined using multivariate logistic regression models and reported as odds ratios (ORs).nnnRESULTSnAfter randomization, 1387 subjects in the free group and 1379 subjects in the pay group were eligible for screening, and 94.9% (1316/1387) and 92.6% (1277/1379), respectively, agreed to participate in the study. The offer of screening was accepted by 94.8% (1247/1316) in the free group and 91.2% (1164/1277) in the pay group, and the final uptake ratios were 88.5% (1165/1316) and 82.4% (1052/1277), respectively (Pearson chi = 19.74, P<0.001). Being in the pay group was associated with a lower uptake of screening than being in the free group (OR, 0.59; confidence interval [CI], 0.47-0.74) and a lower detection rate of DR (OR, 0.73; CI, 0.60-0.90) after adjustment for potential confounding factors. Subjects with higher socioeconomic status were more likely to attend screening and had a lower prevalence of DR detected.nnnCONCLUSIONSnThe inverse care law seems to operate in a preventive intervention when a relatively small copayment is applied. There is a case for making effective preventive services free of charge.nnnFINANCIAL DISCLOSURE(S)nThe author(s) have no proprietary or commercial interest in any materials discussed in this article.

Is it necessary to cover the macular hole with the inverted internal limiting membrane flap in macular hole surgery? A case report

BackgroundTo report a case of late closure of idiopathic full-thickness macular hole (FTMH) after vitrectomy with the inverted internal limiting membrane (ILM) technique.Case presentationA 68-year-old lady with a stage IV FTMH underwent pars plana vitrectomy with 25 gauge plus transconjunctival system, ILM peeling and gas tamponade. The inverted ILM flap technique was adopted, except that no extra surgical manipulation was used to cover the macular hole with the ILM flap. Surgical outcome was monitored with serial optical coherence tomography (OCT).Complete closure of the FTMH with resolution of intraretinal cystic changes was confirmed on OCT at 16xa0months postoperatively. Visual acuity improved from a baseline level of 0.1 to 0.4.ConclusionIdiopathic macular hole closure could be delayed to beyond 1xa0year following the inverted ILM flap technique, especially if the macular hole was not covered with the ILM flap. Not all macular holes that fail to close in the early postoperative period need to be re-operated and there may be no risk of further visual deterioration.

Impact of Genetic Loci Identified in Genome-Wide Association Studies on Diabetic Retinopathy in Chinese Patients With Type 2 Diabetes

PurposenDiabetic retinopathy (DR) is a common microvascular complication of type 2 diabetes (T2DM). Genome-wide association studies (GWAS) had identified novel DR-susceptibility genetic variants in various populations. We examined the associations of these DR-associated single nucleotide polymorphisms (SNPs) with severe DR in a Chinese T2DM cohort.nnnMethodsnCross-sectional case-control studies on sight-threatening DR (STDR) and proliferative DR (PDR) were performed. We genotyped 38 SNPs showing top association signals with DR in previous GWAS in 567 STDR cases, including 309 with PDR and 1490 non-DR controls. Multiple logistic regression models with adjustment for conventional risk factors, including age, sex, duration of diabetes, and presence of hypertension, were employed.nnnResultsnThe strongest association was found at INSR rs2115386, an intronic SNP of INSR: Padjusted = 9.13 × 10-4 (odds ratio [OR],1.28; 95% confidence interval [95%CI], 1.11-1.48) for STDR, and Padjusted= 1.12 × 10-4 (OR [95%CI],1.44 [1.20-1.74]) for PDR. rs599019 located downstream of COLEC12 (Padjusted = 0.019; OR [95%CI],1.19 [1.03-1.38]) and rs4462262 located at an intergenic region between ZWINT and MRPS35P3 (Padjusted = 0.041; OR [95%CI],1.38[1.01-1.89]) also were significantly associated with STDR, but not with PDR alone. On the other hand, MYT1L-LOC729897 rs10199521 (Padjusted = 0.022; OR [95%CI],1.25 [1.03-1.51]) and API5 rs899036 (Padjusted = 0.049; OR [95%CI],1.36 [1.00-1.85]) showed significant independent associations only with PDR. Similar results were obtained when hemoglobin A1c also was included in the adjustment models.nnnConclusionsnWe demonstrated the significant and independent associations of several GWAS-identified SNPs with DR in Chinese T2DM patients with severe DR. The findings on INSR rs2115386 are supportive of the role of insulin resistance, or the compensatory hyperinsulinemia, in the pathogenesis of DR.

Novel 'heavy' dyes for retinal membrane staining during macular surgery: multicenter clinical assessment.

Purpose:u2002 To evaluate the feasibility of two novel ‘heavy’ dye solutions for staining the internal limiting membrane (ILM) and epiretinal membranes (ERMs), without the need for a prior fluid‐air exchange, during macular surgery.

Inhibition of NUCKS Facilitates Corneal Recovery Following Alkali Burn

Corneal wound healing involves a complex cascade of cytokine-controlled cellular events, including inflammatory and angiogenesis responses that are regulated by transcriptional chromatin remodeling. Nuclear Ubiquitous Casein and cyclin-dependent Kinase Substrate (NUCKS) is a key chromatin modifier and transcriptional regulator of metabolic signaling. In this study, we investigated the role of NUCKS in corneal wound healing by comparing its effects on corneal alkali burn in NUCKS knockout (NKO) and NUCKS wild-type (NWT) mice. Our data showed that following alkali-injury, inhibition of NUCKS (NKO) accelerated ocular resurfacing and suppressed neovascularization; the cytokine profile of alkali burned corneas in NKO mice showed suppressed expression of inflammation cytokines (IL1A & IL1B); upregulated expression of antiangiogenic factor (Pigment Epithelium-derived Factor; PEDF); and downregulated expression of angiogenic factor (Vascular Endothelial Growth Factor, VEGF); in vitro, following LPS-induced NFκB activation, NKO corneal cells showed reduced expression of IL6, IP10 and TNFα. In vitro, corneal epithelial cells showed reduced NF-κb activation on silencing of NUCKS and corresponding NFκB-mediated cytokine expression was reduced. Here, we illustrate that inhibition of NUCKS played a role in cytokine modulation and facilitated corneal recovery. This reveals a potential new effective strategy for ocular burn treatment.

Altered myocardial response in patients with diabetic retinopathy: An exercise echocardiography study

BackgroundType 2 diabetes mellitus (T2DM) complicated by retinopathy is associated with altered left ventricular (LV) structure and resting myocardial dysfunction unlike T2DM without retinopathy. The myocardial response to stress has not been compared in patients with and without diabetic retinopathy. The aim of this retrospective study was to determine the relationship between retinopathy and myocardial function in patients with T2DM at rest and during exercise echocardiography.Methods134 patients with T2DM and no evidence of underlying coronary artery disease were recruited. All patients underwent retinal photography to screen for diabetic retinopathy, and resting and exercise echocardiography. Resting echocardiography was analyzed by conventional echocardiographic parameters and speckle tracking derived global longitudinal strain (GLS). Exercise echocardiography parameters included diastolic function reserve index (DFRI) and stress GLS.ResultsThe mean age of participants was 60xa0years and 49xa0% were male. Diabetic retinopathy was identified in 43 patients (32xa0%). Resting echocardiography revealed that those with diabetic retinopathy had a higher prevalence of impaired diastolic function, higher E/E′ ratio (LV filling pressures) and impaired resting GLS compared with those without. Exercise echocardiography revealed that those with diabetic retinopathy also had more impaired DFRI and stress GLS. Multivariable analysis showed that the presence of diabetic retinopathy was independently associated with high resting E/E′, diastolic dysfunction grade, impaired resting GLS, low DFRI and impaired stress GLS.ConclusionsIn conclusion, the presence of diabetic retinopathy was independently associated with impaired resting myocardial function (diastolic and systolic function) and myocardial function during stress (evaluated by DFRI and stress GLS).

Cost-Effectiveness of Screening for Intermediate Age-Related Macular Degeneration during Diabetic Retinopathy Screening

PURPOSEnTo determine whether screening for age-related macular degeneration (AMD) during a diabetic retinopathy (DR) screening program would be cost effective in Hong Kong.nnnDESIGNnWe compared and evaluated the impacts of screening, grading, and vitamin treatment for intermediate AMD compared with no screening using a Markov model. It was based on the natural history of AMD in a cohort with a mean age of 62 years, followed up until 100 years of age or death.nnnPARTICIPANTSnSubjects attending a DR screening program were recruited.nnnMETHODnA cost-effectiveness analysis was undertaken from a public provider perspective. It included grading for AMD using the photographs obtained for DR screening and treatment with vitamin therapy for those with intermediate AMD. The measures of effectiveness were obtained largely from a local study, but the transition probabilities and utility values were from overseas data. Costs were all from local sources. The main assumptions and estimates were tested in sensitivity analyses.nnnMAIN OUTCOME MEASURESnThe outcome was cost per quality-adjusted life year (QALY) gained. Both costs and benefits were discounted at 3%. All costs are reported in United States dollars (