To determine the prevalence of cataract surgery and factors associated with post-surgical visual outcomes in migrant Indians living in Singapore.
Research Design and Methods
We conducted a population-based study in 3,400 Indian immigrants residing in Singapore−the Singapore Indian Eye Study (SINDI). All participants underwent comprehensive medical eye examination and a standardized interview. Post-operative visual impairment (VI) was defined as best-corrected or presenting visual acuity (BCVA or PVA) of 20/60 or worse.
The age- and gender-standardized prevalence of cataract surgery was 9.7% (95% confidence interval [CI]: 8.9%, 10.7%) in Singapore resident Indians. Post-operative VI defined by BCVA occurred in 10.9% eyes (87/795). The main causes of post-operative VI were diabetic retinopathy (20.7%), posterior capsular opacification (18.4%), and age-related macular degeneration (12.6%). Undercorrected refractive error doubled the prevalence of post-operative VI when PVA was used.
The rate of cataract surgery is about 10% in Indian residents in Singapore. Socioeconomic variables and migration had no significant impact on the prevalence of cataract surgery. Diabetic retinopathy was a major cause of post-operative VI in migrant Indians living in Singapore. Uncorrected postoperative refractive error remains an efficient way to improve vision.
The hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) and treponema pallidum (TP) are blood-borne pathogens. They can lead to nosocomial and occupational infections in health care settings. We aimed to identify the prevalence of and risk factors associated with HBV, HCV, HIV and TP infections among patients with eye diseases at a tertiary eye hospital in Southern China.
From July 2011 to June 2012, a total of 26,386 blood units were collected from eye patients, including inpatients and the day surgery patients at Zhongshan Ophthalmic Center, one of the biggest eye hospitals in China. Based on the primary diagnoses from this period, the subjects were classified into different ocular disease groups. All blood samples were tested for HBsAg, anti-HCV, anti-HIV and anti-TP.
The overall prevalence of HBV, HCV, TP and HIV was 9.79%, 0.99%, 2.43% and 0.11%, respectively. The prevalence of HBsAg was much lower among patients younger than 20 years compared to other age groups. In addition, the risk of HBsAg was associated with the male gender, ocular trauma and glaucoma. The prevalence of TP increased with age and the prevalence among patients older than 30 was higher than that in patients younger than 20 years.
The prevalence of HBV, HCV, HIV and TP in patients with eye diseases was identified. This information can be utilised to strengthen the health education and implementation of universal safety precautions to prevent the spread of blood-borne pathogens in health care settings.
This study aimed to assess the prevalence, awareness, treatment, and control of hypertension and their associated factors among Bai ethnic population in the rural China.
A population-based survey was conducted in 2010 with a randomly cluster sampling in rural communities in Dali, southwest China. A total of 2133 adults aged 50 or above were interviewed, and their blood pressure, height, weight and waist circumference were measured. Hypertension was defined as a mean SBP≥140 mmHg and/or DBP≥90 mmHg, and/or current use of antihypertensive medications.
The prevalence of hypertension was 42.1% (899/2133), and the age- and gender-adjusted prevalence was 40.0%. Among the hypertensive participants, 28.4% (255/899)were aware of their condition, while 24.6% (221/899) took antihypertensive medications, with only 7.5% (67/899) of those achieving blood pressure control (<140/90 mmHg). Risk factors for hypertension were older age, smoking, alcohol drinking, family history of HBP, overweight, and obesity, while protective factors included being lean, and having finished senior high school or above.
Hypertension prevalence is high among the population of Bai ethnic group in China, while the associated risk factors of hypertension include overweight/obesity, cigarette smoking, history of hypertension, and older age. The percentages of hypertensive participants aware of their hypertension and those taking antihypertensive medications were low with an incredibly low proportion of hypertensive patients who kept their hypertension under control. It is suggested that health education and hypertension screening programs be carried out in the area for the high blood pressure prevention and control.
HIV-1 integrase (IN) is a key viral enzyme during HIV-1 replication that catalyzes the insertion of viral DNA into the host genome. Recent studies have provided important insights into the multiple posttranslational modifications (PTMs) of IN (e.g., ubiquitination, SUMOylation, acetylation and phosphorylation), which regulate its multifaceted functions. A number of host cellular proteins, including Lens Epithelium‑derived Growth factor (LEDGF/p75), p300 and Ku70 have been shown to interact with IN and be involved in the PTM process of IN, either facilitating or counteracting the IN PTMs. Although previous studies have revealed much about the important roles of IN PTMs, how IN functions are fine-tuned by these PTMs under the physiological setting still needs to be determined. Here, we review the advances in the understanding of the mechanisms and roles of multiple IN PTMs.
HIV; integrase; posttranslational modification; ubiquitination; SUMOylation; acetylation; phosphorylation
To compare the visual performance of multifocal intraocular lenses (IOLs) and monofocal IOLs made of the same material.
The subjects included patients implanted with either Tecnis® monofocal IOLs (ZA9003 or ZCB00) or Tecnis® multifocal IOLs (ZMA00 or ZMB00) bilaterally. We conducted a retrospective study comparing the two types of IOLs. The multifocal group included 46 patients who were implanted with Tecnis® multifocal IOLs bilaterally. The monofocal group was an age- and sex-matched control group, and included 85 patients who were implanted with Tecnis® monofocal IOLs bilaterally. Lens opacity grading, the radius of corneal curvature, corneal astigmatism, axial length and the refractive status were measured preoperatively. Pupil size, ocular aberrometry, distance, intermediate and near visual acuity, contrast sensitivity with and without glare and the responses to a quality-of-vision questionnaire were evaluated pre- and postoperatively.
The uncorrected near visual acuity was significantly better in the multifocal group, whereas both the corrected intermediate and near visual acuity were better in the monofocal group. Contrast sensitivity (with and without glare) was significantly better in the monofocal group. The rate of spectacle dependency was significantly lower in the multifocal group. There were no significant differences between the two groups regarding most items of the postoperative quality-of-vision questionnaire (VFQ-25), with the exception that the patients in the monofocal group reported fewer problems with nighttime driving.
The multifocal IOLs used in this study reduced spectacle dependency more so than monofocal IOLs and did not compromise the subjective visual function, with the exception of nighttime driving.
Recently, we reported obtaining tomograms of meibomian glands from healthy volunteers using commercial anterior segment optical coherence tomography (AS-OCT), which is widely employed in clinics for examination of the anterior segment. However, we could not create 3D images of the meibomian glands, because the commercial OCT does not have a 3D reconstruction function. In this study we report the creation of 3D images of the meibomian glands by reconstructing the tomograms of these glands using high speed Fourier-Domain OCT (FD-OCT) developed in our laboratory. This research was jointly undertaken at the Department of Ophthalmology, Seoul St. Mary's Hospital (Seoul, Korea) and the Advanced Photonics Research Institute of Gwangju Institute of Science and Technology (Gwangju, Korea) with two healthy volunteers and seven patients with meibomian gland dysfunction. A real time imaging FD-OCT system based on a high-speed wavelength swept laser was developed that had a spectral bandwidth of 100 nm at the 1310 nm center wavelength. The axial resolution was 5 µm and the lateral resolution was 13 µm in air. Using this device, the meibomian glands of nine subjects were examined. A series of tomograms from the upper eyelid measuring 5 mm (from left to right, B-scan) × 2 mm (from upper part to lower part, C-scan) were collected. Three-D images of the meibomian glands were then reconstructed using 3D “data visualization, analysis, and modeling software”. Established infrared meibography was also performed for comparison. The 3D images of healthy subjects clearly showed the meibomian glands, which looked similar to bunches of grapes. These results were consistent with previous infrared meibography results. The meibomian glands were parallel to each other, and the saccular acini were clearly visible. Here we report the successful production of 3D images of human meibomian glands by reconstructing tomograms of these glands with high speed FD-OCT.
To evaluate the efficacy and tolerability of Ex-PRESS implantation (Ex-Press) compared with trabeculectomy (Trab) in the treatment of patients with uncontrolled glaucoma.
A comprehensive literature meta-analysis was performed according to the Cochrane Collaboration methodology to identify controlled clinical trials comparing Ex-Press with Trab. Efficacy estimates were measured by weight mean difference (WMD) for the percentage intraocular pressure (IOP) reduction from baseline to end-point, odds ratio (OR) for complete success, and qualified success rates. Tolerability estimates were measured by OR for adverse events. All outcomes were reported with a 95% confidence interval (CI). Data were synthesized by Stata 11.0 SE for Windows.
Eight controlled clinical trials meeting the predefined criteria were included in the meta-analysis. A total of 605 eyes from 559 patients with medically uncontrolled glaucoma were included. The weighted mean difference of the percentage IOP reduction from baseline was 2.33 (95% confidence interval: −2.59–7.24) when comparing Ex-Press with Trab. Ex-Press was associated with numerically greater, but nonsignificant, IOP lowering efficacy than Trab. The pooled odds ratio comparing Ex-Press with Trab were 0.93 (0.39, 2.23) for the complete success rate and 1.00 (0.39, 2.56) for the qualified success rate. Ex-Press was associated with a significantly lower frequency of hypotony and hyphema than Trab, with pooled ORs of 0.29 (0.13, 0.65) and 0.36 (0.13, 0.97), respectively.
Ex-Press was associated with equivalent efficacy to Trab in lowering IOP. Comparable proportions of patients reached the IOP target with Ex-Press and Trab. Ex-Press was better tolerated than Trab.
Our purpose was to examine the relationship of retinal vascular parameters with diabetes and retinopathy in an older Asian population.
Retinal photographs from participants of a population-based survey of Asian Malay persons aged 40–80 years were analyzed. Specific retinal vascular parameters (tortuosity, branching angle, fractal dimension, and caliber) were measured using a semiautomated computer-based program. Diabetes was defined as random plasma glucose ≥ 11.1 mmol/liter, the use of diabetes medication, or physician-diagnosed diabetes. Retinopathy signs were graded from photographs using the modified Airlie House classification system.
A total of 2735 persons were included in the study. Persons with diabetes (n = 594) were more likely to have straighter (less tortuous) arterioles and wider arteriolar and venular caliber than those without diabetes (n = 2141). Among subjects with diabetes, those with retinopathy had wider venular caliber than those without retinopathy (211.3 versus 204.9 mm, p = .001). Among nondiabetic subjects, however, those with retinopathy had more tortuous venules than those without retinopathy [5.19(×104) versus 4.27(×104), p < .001].
Retinal vascular parameters varied by diabetes and retinopathy status in this older Asian cohort. Our findings suggest that subtle alterations in retinal vascular architecture are influenced by diabetes.
diabetes; epidemiology; imaging; retinopathy
To investigate the prevalence and visual acuity (VA) outcomes of cataract surgery in adults of the Bai Nationality populations in rural China.
We conducted a population-based cross-sectional survey (from randomly selected block groups) of Chinese Bai Nationality aged ≥50 years in southwestern China. Presenting visual acuity (PVA), best corrected visual acuity (BCVA) were recorded and a detailed eye examination was carried out. For all aphakic and pseudophakic subjects identified, information on the date, setting, type, and complications of cataract surgery were recorded. In eyes with VA <20/63, the principal cause of visual impairment was identified.
Of 2133 (77.8% of 2742) subjects, 99 people (129 eyes) had undergone cataract surgery. The prevalence of cataract surgery was 4.6%. Surgical coverage among those with PVA <20/200 in both eyes because of cataract was 52.8%. Unoperated cataract was associated with older age. The main barrier to cataract surgery was lack of awareness and knowledge, cost, and fear. Among the 129 cataract-operated eyes, 22.5% had PVA of ≥20/32, 25.6% had PVA of 20/40 to 20/63, 23.3% had PVA <20/63 to 20/200, and 28.7% had PVA<20/200. With BCVA, the percentages were 42.6%, 23.3%, 10.9%, and 23.3%, respectively. Aphakia (odds ratio [OR], 8.49; P<0.001) and no education (OR, 10.18; P = 0.001) or less education (OR, 6.49; P = 0.014) were significantly associated with postoperative visual impairment defined by PVA, while aphakia (OR, 8.49; P<0.001) and female gender (OR, 4.19; P = 0.004) were significantly associated with postoperative visual impairment by BCVA. The main causes of postoperative visual impairment were refractive error, retinal disorders and glaucoma.
Half of those with bilateral visual impairment or blindness because of cataract remain in need of cataract surgery in Bai population. Surgical uptake and visual outcomes should be further improved in the future.
Cellular senescence may be a key factor in HIV-related premature biological aging. We assessed features of the corneal endothelium that are known to be associated with biological aging, and cellular senescence markers in HIV-infected adults.
Case-control study of 242 HIV-infected adults and 249 matched controls. Using specular microscopy, the corneal endothelium was assessed for features of aging (low endothelial cell density [ECD], high variation in cell size, and low hexagonality index). Data were analysed by multivariable regression. CDKN2A expression (a cell senescence mediator) was measured in peripheral blood leukocytes and 8-hydroxy-2′-deoxyguanosine (8-OHDG; an oxidative DNA damage marker) levels were measured in plasma.
The median age of both groups was 40 years. Among HIV-infected adults, 88% were receiving antiretroviral therapy (ART); their median CD4 count was 468 cells/µL. HIV infection was associated with increased odds of variation in cell size (OR = 1.67; 95% CI: 1.00–2.78, p = 0.04). Among HIV-infected participants, low ECD was independently associated with current CD4 count <200 cells/µL (OR = 2.77; 95%CI: 1.12–6.81, p = 0.03). In participants on ART with undetectable viral load, CDKN2A expression and 8-OHDG levels were higher in those with accelerated aging, as reflected by lower ECD.
The corneal endothelium shows features consistent with HIV-related accelerated senescence, especially among those with poor immune recovery.
Overweight and obesity are thought to significantly influence a person's risk of cardiovascular disease, possibly via its effect on the microvasculature. Retinal vascular caliber is a surrogate marker of microvascular disease and a predictor of cardiovascular events. The aim of this systematic review and meta-analysis was to determine the association between body mass index (BMI) and retinal vascular caliber.
Methods and Findings
Relevant studies were identified by searches of the MEDLINE and EMBASE databases from 1966 to August 2011. Standardized forms were used for data extraction. Among over 44,000 individuals, obese subjects had narrower arteriolar and wider venular calibers when compared with normal weight subjects, independent of conventional cardiovascular risk factors. In adults, a 1 kg/m2 increase in BMI was associated with a difference of 0.07 μm [95% CI: −0.08; −0.06] in arteriolar caliber and 0.22 μm [95% CI: 0.21; 0.23] in venular caliber. Similar results were found for children.
Higher BMI is associated with narrower retinal arteriolar and wider venular calibers. Further prospective studies are needed to examine whether a causative relationship between BMI and retinal microcirculation exists.
Glutathione S transferase (GST) polymorphisms have been considered risk factors for the development of glaucoma, including primary open angle glaucoma (POAG) and other types of glaucoma. However, the results remain controversial. In this study, we have conducted a meta-analysis to assess the association between polymorphisms of GSTM1, GSTT1 and GSTP1 and glaucoma risk.
Published literature from PubMed and other databases were retrieved. All studies evaluating the association between GSTM1, GSTT1 and GSTP1 polymorphisms and glaucoma risk were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random- or fixed-effects model.
Twelve studies on GSTM1 (1109 cases and 844 controls), ten studies on GSTT1 (709 cases and 664 controls) and four studies on GSTP1 (543 cases and 511 controls) were included. By pooling all the studies, either GSTM1 or GSTT1 null polymorphism was not associated with a POAG risk, and this negative association maintained in Caucasian. The GSTP1 Ile 105 Val polymorphism was significantly correlated with increased POAG risk among Caucasian in a recessive model (Val/Val vs. Ile/Ile+Ile/Val: OR, 1.62, 95%CI: 1.00–2.61). Interestingly, increased glaucoma risk was associated with the combined GSTM1 and GSTT1 null genotypes (OR, 2.20; 95% CI, 1.47–3.31), and with the combined GSTM1 null and GSTP1 Val genotypes (OR, 1.86; 95% CI, 1.15–3.01).
This meta-analysis suggests that combinations of GST polymorphisms are associated with glaucoma risk. Given the limited sample size, the associations between single GST polymorphism and glaucoma risk await further investigation.
Clinical studies implicate low cerebrospinal fluid pressure (CSFP) or a high translaminar pressure difference in the pathogenesis of primary open angle glaucoma (POAG) and normal tension glaucoma (NTG). This study was performed to examine the effect of age, sex, race and body mass index (BMI) on CSFP.
Electronic medical records from all patients who had a lumbar puncture (LP) performed at the Mayo Clinic from 1996–2009 were reviewed. Information including age, sex, race, height and weight, ocular and medical diagnoses, intraocular pressure (IOP) and LP opening pressure was obtained. Patients using medications or with medical diagnoses known to affect CSFP, and those who underwent neurosurgical procedures or where more than one LP was performed were excluded from analysis.
Electronic medical records of 33,922 patients with a history of having an LP during a 13-year period (1996–2009) were extracted. Of these, 12,118 patients met all entry criteria. Relative to mean CSFP at age group 20–49 (mean 11.5±2.8 mmHg), mean CSFP declined steadily after age 50, with percent reduction of 2.5% for the 50–54 age group (mean 11.2±2.7 mmHg, p<0.002) to 26.9% for the 90–95 group (mean 8.4±2.4 mmHg, p<0.001). Females had lower CSFP than males throughout all age groups. BMI was positively and independently associated with CSFP within all age groups.
There is a sustained and significant reduction of CSFP with age that begins in the 6th decade. CSFP is consistently lower in females. BMI is positively and independently associated with CSFP in all age groups. The age where CSFP begins to decline coincides with the age where the prevalence of POAG increases. These data support the hypothesis that reduced CSFP may be a risk factor for POAG and may provide an explanation for the mechanism that underlies the age-related increase in the prevalence of POAG and NTG.
To determine the prevalence and risk factors associated with idiopathic epiretinal membranes (iERM) in a Chinese population aged 60 years or older in Beixinjing Blocks, Shanghai.
This population-based study consisted of 3727 participants (89.7% of the eligible). It was performed to describe the prevalence of iERM and possible demographic, systemic, and ocular factors associated with iERM. Each participant underwent a standardized interview and comprehensive ophthalmic examination. iERM was identified and graded from retinal photographs. Then, a case-control study comparing the participants with vs. without iERM was performed to further study the associations between iERM and blood biochemical test results (including fasting plasma glucose, serum creatinine, total cholesterol, and triglyceride), ocular biological parameters (including the axial length, corneal curvature, refractive diopter, intraocular press, and anterior chamber depth), and the data of optical coherence tomography.
The prevalence of iERM was 1.02%. iERM was significantly associated with diabetes (OR: 2.457; 95% CI: 1.137, 5.309) and a higher level of education (OR: 1.48; 95% CI: 1.123, 1.952). Blood biochemical test results and ocular biological parameters showed no significant differences between the iERM and control groups, whereas the incidence of posterior vitreous detachment in the iERM group was much higher than in the control group (26.5% vs. 8.8%), but this difference was not statistically significant. Moreover, the eyes with iERM had poorer visual acuity than the eyes without iERM (P<0.05).
In Beixinjing Blocks, Shanghai, iERM was relatively rare, was associated with diabetes and a higher level of education, and caused a substantial decrease in visual acuity.
Multilevel analyses are ideally suited to assess the effects of ecological (higher level) and individual (lower level) exposure variables simultaneously. In applying such analyses to measures of ecologies in epidemiological studies, individual variables are usually aggregated into the higher level unit. Typically, the aggregated measure includes responses of every individual belonging to that group (i.e. it constitutes a self-included measure). More recently, researchers have developed an aggregate measure which excludes the response of the individual to whom the aggregate measure is linked (i.e. a self-excluded measure). In this study, we clarify the substantive and technical properties of these two measures when they are used as exposures in multilevel models.
Although the differences between the two aggregated measures are mathematically subtle, distinguishing between them is important in terms of the specific scientific questions to be addressed. We then show how these measures can be used in two distinct types of multilevel models—self-included model and self-excluded model—and interpret the parameters in each model by imposing hypothetical interventions. The concept is tested on empirical data of workplace social capital and employees' systolic blood pressure.
Researchers assume group-level interventions when using a self-included model, and individual-level interventions when using a self-excluded model. Analytical re-parameterizations of these two models highlight their differences in parameter interpretation. Cluster-mean centered self-included models enable researchers to decompose the collective effect into its within- and between-group components. The benefit of cluster-mean centering procedure is further discussed in terms of hypothetical interventions.
When investigating the potential roles of aggregated variables, researchers should carefully explore which type of model—self-included or self-excluded—is suitable for a given situation, particularly when group sizes are relatively small.
The opinion of application of indocyanine green (ICG) in the macular hole surgery was contradictory. Here we conducted a meta-analysis to evaluate the effect of in internal limiting membrane (ILM) peeling for macular hole surgery.
Methods and Findings
We searched electronic databases for comparative studies published before July 2012 of ILM peeling with and without ICG. Twenty-two studies including 1585 eyes were included. Visual acuity (VA) improvement, including the postoperative rate of ≥20/40 VA gained (OR, 0.65; 95% CI, 0.43 to 0.97; P = 0.033) and increased LogMAR (WMD, −0.09; 95% CI, −0.16 to −0.02; P = 0.011), was less in the ICG group. The risk of visual field defects was greater in the ICG group than in the non-ICG group. There was no significant difference in the rate of anatomical outcomes between ILM peeling procedures performed with and without ICG. RPE changes and other postoperative complications were not significantly different between the ICG and non-ICG groups. An additional analysis showed that the VA improvement of the ICG group was less than the non-ICG group only within the first year of follow up. A subgroup analysis showed that the rate of VA improvement was lower in the ICG group than in other adjuncts group. A higher rate of secondary closure and less VA improvement were observed in a high proportion (>0.1%) of the ICG group. A sensitivity analysis after the randomized-controlled trials were excluded from the meta-analysis demonstrated no differences compared with the overall results.
This meta-analysis demonstrated that there is no evidence of clinical superiority in outcomes for ICG-assisted ILM peeling procedure over the non-ICG one. The toxicity of ICG should be considered when choosing the various staining methods.
Language barrier is an important determinant of health care access and health. We examined the associations of English proficiency with type-2 diabetes (T2DM) and diabetic retinopathy (DR) in Asian Indians living in Singapore, an urban city where English is the predominant language of communication.
This was a population-based, cross-sectional study. T2DM was defined as HbA1c ≥6.5%, use of diabetic medication or a physician diagnosis of diabetes. Retinal photographs were graded for the severity of DR including vision-threatening DR (VTDR). Presenting visual impairment (VI) was defined as LogMAR visual acuity > 0.30 in the better-seeing eye. English proficiency at the time of interview was assessed.
The analyses included 2,289 (72.1%) English-speaking and 885 (27.9%) Tamil- speaking Indians. Tamil-speaking Indians had significantly higher prevalence of T2DM (46.2 vs. 34.7%, p < 0.001) and, among those with diabetes, higher prevalence of DR (36.0 vs. 30.6%, p < 0.001), VTDR (11.0 vs. 6.5%, p < 0.001), and VI (32.4 vs. 14.6%) than English speaking Indians. Oaxaca decomposition analyses showed that the language-related discrepancies (defined as the difference in prevalence between persons speaking different languages) in T2DM, DR, and VTDR could not be fully explained by socioeconomic measures.
In an English dominant society, Tamil-speaking Indians are more likely to have T2DM and diabetic retinopathy. Social policies and health interventions that address language-related health disparities may help reduce the public health impact of T2DM in societies with heterogeneous populations.
English proficiency; Asian indians; Diabetes; Diabetic retinopathy; Visual impairment
Diabetic retinopathy (DR), a major microvascular complication of diabetes, has a significant impact on the world's health systems. Globally, the number of people with DR will grow from 126.6 million in 2010 to 191.0 million by 2030, and we estimate that the number with vision-threatening diabetic retinopathy (VTDR) will increase from 37.3 million to 56.3 million, if prompt action is not taken. Despite growing evidence documenting the effectiveness of routine DR screening and early treatment, DR frequently leads to poor visual functioning and represents the leading cause of blindness in working-age populations. DR has been neglected in health-care research and planning in many low-income countries, where access to trained eye-care professionals and tertiary eye-care services may be inadequate. Demand for, as well as, supply of services may be a problem. Rates of compliance with diabetes medications and annual eye examinations may be low, the reasons for which are multifactorial. Innovative and comprehensive approaches are needed to reduce the risk of vision loss by prompt diagnosis and early treatment of VTDR.
Compliance; diabetic retinopathy; services
As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay adults. We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, β = −0.16 mm per minor allele, Pmeta = 2.69×10−10). The minor C allele of rs4373767 was also observed to significantly associate with decreased susceptibility to high myopia (per-allele odds ratio (OR) = 0.75, 95% CI: 0.68–0.84, Pmeta = 4.38×10−7) in 1,118 highly myopic cases and 5,433 controls. ZC3H11B and two neighboring genes SLC30A10 and LYPLAL1 were expressed in the human neural retina, retinal pigment epithelium, and sclera. In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1. This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.
Myopic individuals exhibit an increase in ocular axial length (AL). As a highly heritable ocular biometry of refractive error, identification of quantitative trait loci influencing AL variation would be valuable in informing the biological etiology of myopia. We have determined that a genetic locus on chromosome 1q41 containing zinc-finger pseudogene ZC3H11B is associated with AL and high myopia through a meta-analysis of three genome-wide association scans on AL in Chinese and Malays, with validation for high myopia association in two additional Japanese cohorts. In addition, variations in the expression of murine gene ZC3H11A and two neighboring genes SLC30A10 and LYPLAL1 in the retina and sclera in a myopic mouse model implicate the role of these genes in myopia onset. To our knowledge, this is the first genome-wide survey of single nucleotide polymorphism (SNP) variation of AL in Asians. Our results suggest that genetic variants at chromosome 1q41 have potential roles in both common and high myopia.
Health of migrants is a major public health challenge faced by governments and policy makers. Asian Indians are among the fastest growing migration groups across Asia and the world, but the impact of migration and acculturation on diabetes and diabetes-related eye complications among Indians living in urban Asia remains unclear.
We evaluated the influence of migration and acculturation (i.e., migration status and length of residence) on the prevalence of type-2 diabetes mellitus (T2DM) and diabetes-related eye complications (diabetic retinopathy (DR) and cataract), among first-generation (defined as participant born in India with both parents born in India, n = 781) and second-generation (participants born in Singapore with both parents born in India, n = 1,112) Indian immigrants from a population-based study of Adult Indians in Singapore. Diabetes was defined as HbA1c≥6.5%, use of diabetic medication or a physician diagnosis of diabetes. Retinal and lens photographs were graded for the presence of DR and cataract. Compared to first generation immigrants, second generation immigrants had a higher age- and gender-standardized prevalence of T2DM (34.4% versus 29.0%, p<0.001), and, in those with T2DM, higher age- and gender-standardized prevalence of DR (31.7% versus 24.8%, p<0.001), nuclear cataract (13.6% versus 11.6%, p<0.001), and posterior sub-capsular cataract (6.4% versus 4.6%, p<0.001). Among first generation migrants, longer length of residence was associated with significantly younger age of diagnosis of diabetes and greater likelihood of having T2DM and diabetes-related eye complications.
Second generation immigrant Indians and longer length of residence are associated with higher prevalence of diabetes and diabetes-related complications (i.e., DR and cataract) among migrant Indians living in Singapore. These data highlight potential worldwide impacts of migration patterns on the risk and burden of diabetes.
An ultrasound biomicroscopy study demonstrates that iridotrabecular contact was present in 80% of eyes with a gonioscopically narrow angle and in 40% of control eyes. Two thirds of the eyes had high ITC.
To describe the characteristics of the iridocorneal angle using ultrasound biomicroscopy (UBM) in Chinese people classified gonioscopically as having suspected primary angle-closure (PACS) glaucoma.
PACS were defined as not having visible posterior (usually pigmented) trabecular meshwork in two or more quadrants examined by static gonioscopy. The PACS and 1 of 10 those who did not meet this criterion were identified from a population-based survey. Iridotrabecular meshwork contact (ITC) was identified and further classified into low and high, according to standard UBM images. Those with high ITC were further classified according the configuration of ITC: B-type, with contiguous ITC from the base of the angle, and S-type, with ITC localized to the region of Schwalbe's line.
ITC was identified in 78.6% of the superior, 40.2% of the nasal, 59.8% of the inferior, and 25.6% of the temporal quadrants in the PACS (n = 117). These proportions were 43.9%, 15.8%, 29.8%, and 14.0% in the controls (n = 57), respectively. About two thirds of the eyes with ITC were classified as high. In those with high ITC, the number with B- and S-type ITC was very similar. The proportions of any high ITCs increased substantially from 15.4% in those with Shaffer angle grade 4 and 45.0% in grade 3, to 71.0% in grade 2, 70.2% in grade 1, and 86.4% in grade 0.
More ITC is identified on UBM imaging than by gonioscopy. Careful consideration should be given to the assessment modality regarded as the reference standard in defining anatomic risk factors for glaucomatous visual loss and the need for treatment.
HIV-1 employs the cellular nuclear import machinery to actively transport its preintegration complex (PIC) into the nucleus for integration of the viral DNA. Several viral karyophilic proteins and cellular import factors have been suggested to contribute to HIV-1 PIC nuclear import and replication. However, how HIV interacts with different cellular machineries to ensure efficient nuclear import of its preintegration complex in dividing and nondividing cells is still not fully understood. In this study, we have investigated different importin α (Impα) family members for their impacts on HIV-1 replication, and we demonstrate that short hairpin RNA (shRNA)-mediated Impα3 knockdown (KD) significantly impaired HIV infection in HeLa cells, CD4+ C8166 T cells, and primary macrophages. Moreover, quantitative real-time PCR analysis revealed that Impα3-KD resulted in significantly reduced levels of viral 2-long-terminal repeat (2-LTR) circles but had no effect on HIV reverse transcription. All of these data indicate an important role for Impα3 in HIV nuclear import. In an attempt to understand how Impα3 participates in HIV nuclear import and replication, we first demonstrated that the HIV-1 karyophilic protein integrase (IN) was able to interact with Impα3 both in a 293T cell expression system and in HIV-infected CD4+ C8166 T cells. Deletion analysis suggested that a region (amino acids [aa] 250 to 270) in the C-terminal domain of IN is involved in this viral-cellular protein interaction. Overall, this study demonstrates for the first time that Impα3 is an HIV integrase-interacting cofactor that is required for efficient HIV-1 nuclear import and replication in both dividing and nondividing cells.
During the early stage of HIV-1 replication, integrase (IN) plays important roles at several steps, including reverse transcription, viral DNA nuclear import, targeting viral DNA to host chromatin and integration. Previous studies have demonstrated that HIV-1 IN interacts with a cellular Lens epithelium-derived growth factor (LEDGF/p75) and that this viral/cellular interaction plays an important role for tethering HIV-1 preintegration complexes (PICs) to transcriptionally active units of host chromatin. Meanwhile, other studies have revealed that the efficient knockdown and/or knockout of LEDGF/p75 could not abolish HIV infection, suggesting a LEDGF/p75-independent action of IN for viral DNA chromatin targeting and integration, even though the underlying mechanism(s) is not fully understood.
In this study, we performed site-directed mutagenic analysis at the C-terminal region of the IN catalytic core domain responsible for IN/chromatin binding and IN/LEDGF/p75 interaction. The results showed that the IN mutations H171A, L172A and EH170,1AA, located in the loop region 170EHLK173 between the α4 and α5 helices of IN, severely impaired the interaction with LEDGF/p75 but were still able to bind chromatin. In addition, our combined knockdown approach for LEDGF/p75 also failed to dissociate IN from chromatin. This suggests that IN has a LEDGF/p75-independent determinant for host chromatin binding. Furthermore, a single-round HIV-1 replication assay showed that the viruses harboring IN mutants capable of LEDGF/p75-independent chromatin binding still sustained a low level of infection, while the chromatin-binding defective mutant was non-infectious.
All of these data indicate that, even though the presence of LEDGF/p75 is important for a productive HIV-1 replication, IN has the ability to bind chromatin in a LEDGF/p75-independent manner and sustains a low level of HIV-1 infection. Hence, it is interesting to define the mechanism(s) underlying IN-mediated LEDGF/p75-independent chromatin targeting, and further studies in this regard will help for a better understanding of the molecular mechanism of chromatin targeting by IN during HIV-1 infection.
HIV-1 integrase (IN) is a key viral enzymatic molecule required for the integration of the viral cDNA into the genome. Additionally, HIV-1 IN has been shown to play important roles in several other steps during the viral life cycle, including reverse transcription, nuclear import and chromatin targeting. Interestingly, previous studies have demonstrated that the expression of HIV-1 IN induces the lethal phenotype in some strains of Saccharomyces cerevisiae. In this study, we performed mutagenic analyses of the C-terminal region of the catalytic core domain of HIV-1 IN in order to delineate the critical amino acid(s) and/or motif(s) required for the induction of the lethal phenotype in the yeast strain HP16, and to further elucidate the molecular mechanism which causes this phenotype.
Our study identified three HIV-1 IN mutants, V165A, A179P and KR186,7AA, located in the C-terminal region of the catalytic core domain of IN that do not induce the lethal phenotype in yeast. Chromatin binding assays in yeast and mammalian cells demonstrated that these IN mutants were impaired for the ability to bind chromatin. Additionally, we determined that while these IN mutants failed to interact with LEDGF/p75, they retained the ability to bind Integrase interactor 1. Furthermore, we observed that VSV-G-pseudotyped HIV-1 containing these IN mutants was unable to replicate in the C8166 T cell line and this defect was partially rescued by complementation with the catalytically inactive D64E IN mutant.
Overall, this study demonstrates that three mutations located in the C-terminal region of the catalytic core domain of HIV-1 IN inhibit the IN-induced lethal phenotype in yeast by inhibiting the binding of IN to the host chromatin. These results demonstrate that the C-terminal region of the catalytic core domain of HIV-1 IN is important for binding to host chromatin and is crucial for both viral replication and the promotion of the IN-induced lethal phenotype in yeast.
APOBEC3G (A3G), a deoxycytidine deaminase, is a potent host antiviral factor that can restrict HIV-1 infection. During Vif-negative HIV-1 replication, A3G is incorporated into HIV-1 particles, induces mutations in reverse transcribed viral DNA and inhibits reverse transcription. However, HIV-1 Vif counteracts A3G's activities by inducing its degradation and by blocking its incorporation into HIV-1 particles. Thus, it is interesting to elucidate a mechanism that would allow A3G to escape the effects of Vif in order to rescue its potent antiviral activity and to provide a possible novel therapeutic strategy for treating HIV-1 infection.
Methods and Findings
In this study, we generated an R88-A3G fusion protein by fusing A3G to a virion-targeting polypeptide (R14-88) derived from HIV-1 Vpr protein and compared its antiviral effects relative to those of HA-tagged native A3G (HA-A3G). Our study showed that transient expression of the R88-A3G fusion protein in both Vif− and Vif+ HIV-1 producing cells drastically inhibited viral infection in HeLa-CD4-CCR5-cells, CD4+ C8166 T cells and human primary PBMCs. Moreover, we established CD4+ C8166 T cell lines that stably express either R88-A3G or HA-A3G by transduction with VSV-G-pseudotyped lentiviral vector that harbor expression cassettes for R88-A3G or HA-A3G, respectively, and tested their susceptibility to Vif+ HIV-1 infection. Our results clearly reveal that expression of R88-A3G in transduced CD4+ C8166 cells significantly blocked Vif+ HIV-1 infection. In an attempt to understand the mechanism underlying the antiviral activity of R88-A3G, we demonstrated that R88-A3G was efficiently incorporated into viral particles in the presence of Vif. Moreover, PCR analysis revealed that R88-A3G significantly inhibited viral cDNA synthesis during the early stage of Vif+ virus infection.
Our results clearly indicate that R88 delivers A3G into Vif+ HIV-1 particles and inhibits infectivity and spread of the virions among CD4+ T cells. This study provides evidence for an effective strategy to modify a host protein with innate anti-HIV-1 activity and rescue its potent anti-HIV potential in the presence of Vif. Further characterization and optimization of this system may lead to the development of an effective therapeutic approach against HIV-1 infection.