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This paper uses van Leeuwen’s (2008. Discourse and practice: New tools from critical discourse analysis. Oxford: Oxford University Press) Authority Legitimation framework to examine government posters published in the 1950s–1980s in Hong Kong, which serve as a means of shaping public opinion and legitimate social action. Martin and White’s (2005. The language of evaluation: Appraisal in english. London: Palgrave Macmillan) Appraisal framework is also applied to provide the study with relevant analytical tools by which to construct evaluatively coherent authorial reading positions propagated by the government in the posters as well as aligning viewers with these desired positions. The government posters being studied are concerned with various aspects of social practices in the domain of public health communication. This paper argues that the representations of these social practices are realized as texts – both visual and verbal – in the posters, as part of a broader recontextualization process where legitimate ways of doing things as stipulated in the government guidelines are recontextualized in these posters and conveyed to members of the public. The aim is two-fold: (1) to provide a systematic analysis of how visual and verbal resources construe evaluation in the government posters and the consequent legitimation discourse as viewers are being persuaded to align with legitimate social practices; (2) to highlight various forms of legitimation, namely, role model authority legitimation, impersonal authority legitimation, and conformity authority legitimation, that are realized in these posters through visual-verbal articulation.

Screening a series of protected amine cationic ring-opening polymerization initiators revealed the commercially available N-(3-bromopropyl)phthalimide as the most suitable to achieve defined polymers with high degree of amine functionalization.

Elderly long-term care facility residents typically have musculoskeletal conditions that may lead to long-term disability and increased mortality. Our main objective was to explore the relationship between body mass index (BMI), albumin levels, and mortality in elderly individuals with limited performance status. Among 182 participants (mean age, 78.8 years; 57% women), 11%, 64%, and 25% had serum albumin levels of 3.5 g/dL, respectively. After multivariate adjustments, diastolic blood pressure >90 mmHg was associated with all-cause mortality [hazard ratio (HR) = 2.08, 95% confidence interval (CI) = 1.13-3.82; P = 0.018]. In addition, BMI 3.5 g/dL (HR = 1.80, 95% CI = 1.11-2.94 and HR = 2.54, 95% CI 1.22-5.30, respectively; P = 0.018 and 0.013, respectively). Highest mortality was noted in participants with albumin levels

Purpose: Directing nanoparticles to cancer cells without using antibodies is of great interest. Subtle changes to the surface chemistry of nanoparticles can significantly affect their biological fate, including their propensity to associate with different cell populations. For instance, nanoparticles functionalized with thiol-reactive groups can potentially enhance association with cells that over-express cell-surface thiol groups. The potential of such an approach for enhancing drug delivery for childhood acute lymphoblastic leukemia (ALL) cells has not been investigated. Herein, we investigate the impact of thiol-reactive star polymers on the cellular association and the mechanisms of uptake of the nanoparticles.Methods: We prepared fluorescently labeled star polymers functionalized with an mPEG brush corona and pyridyl disulfide to examine how reactivity to exofacial thiols impacts cellular association with ALL cells. We also studied how variations to the mPEG brush composition could potentially be used as a secondary method for controlling the extent of cell association. Specifically, we examined how the inclusion of shorter diethylene glycol brush moieties into the nanoparticle corona could be used to further influence cell association.Results: Star polymers incorporating both thiol-reactive and diethylene glycol brush moieties exhibited the highest cellular association, followed by those functionalized solely with thiol reactive groups compared to control nanoparticles in T and B pediatric ALL patient-derived xenografts harvested from the spleens and bone marrow of immunodeficient mice. Transfection of cells with an early endosomal marker and imaging with correlative light and electron microscopy confirmed cellular uptake. Endocytosis inhibitors revealed dynamin-dependent clathrin-mediated endocytosis as the main uptake pathway for all the star polymers.Conclusion: Thiol-reactive star polymers having an mPEG brush corona that includes a proportion of diethylene glycol brush moieties represent a potential strategy for improved leukemia cell delivery.

Purpose To assess the safety and the 3-year results of combined phase 1 and 2a randomized controlled trials of rAAV.sFLT-1 gene therapy (GT) for wet age-related macular degeneration. Design Phase 1/2a clinical trial. Methods Patients were prospectively randomized into control (n = 13) and GT (n = 24) groups. GT patients received 1X1011vg rAAV.sFLT-1 and were seen every month for 1 year then as needed every 1 to 2 months. They were given retreatment anti–vascular endothelial growth factor injections according to predetermined criteria. At 12 months, GT patients were divided into 2 groups: HD-1 (n = 14), requiring 2 retreatments. Results Between 1 year and 3 years there were 3 adverse events (AEs) and 33 serious AEs reported. Of these, 15 occurred in the 13 control subjects and 21 in the 24 GT patients. Except for 1 case of transient choroiditis in a control patient, serious AEs were deemed to be unrelated to the study. Control patients received a median of 7.0 retreatments and lost a median of 7.0 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, HD-1 patients received a median of 2.5 retreatments and lost a median of 4.0 ETDRS letters, and HD-2 patients received a median of 11.0 retreatments and lost a median of 7.0 ETDRS letters over 3 years. Center point thickness fluctuated. Thirty-three percent of control subjects, 44% of HD-2 patients, and 51% of HD-1 patients showed maintenance of baseline visual acuity. Four HD-1 patients (34%) maintained significant visual improvement at 3 years. None of these observations were statistically significant. Conclusions Given the small number of patients, this study was unable to unequivocally confirm the existence of a biologic efficacy signal; however, it confirmed that rAAV.sFLT-1 gene delivery was well tolerated among the elderly.

Water-soluble poly(cyclic imino ether)s (PCIEs) have emerged as promising biocompatible polymers for nanomedicine applications in recent years. Despite their generally accepted stealth properties, there has been no comprehensive evaluation of their interactions with primary immune cells in human blood. Here we present a library of core cross-linked micelles (CCMs) containing various PCIE shells. Well-defined high molar mass CCMs (Mn > 175 kDa, Ð

Protein aggregation into amyloid fibrils is a ubiquitous phenomenon across the spectrum of neurodegenerative disorders and type 2 diabetes. A common strategy against amyloidogenesis is to minimize the populations of toxic oligomers and protofibrils by inhibiting protein aggregation with small molecules or nanoparticles. However, melanin synthesis in nature is realized by accelerated protein fibrillation to circumvent accumulation of toxic intermediates. Accordingly, we designed and demonstrated the use of star-shaped poly(2-hydroxyethyl acrylate) (PHEA) nanostructures for promoting aggregation while ameliorating the toxicity of human islet amyloid polypeptide (IAPP), the peptide involved in glycemic control and the pathology of type 2 diabetes. The binding of PHEA elevated the β-sheet content in IAPP aggregates while rendering a new morphology of "stelliform" amyloids originating from the polymers. Atomistic molecular dynamics simulations revealed that the PHEA arms served as rodlike scaffolds for IAPP binding and subsequently accelerated IAPP aggregation by increased local peptide concentration. The tertiary structure of the star nanoparticles was found to be essential for driving the specific interactions required to impel the accelerated IAPP aggregation. This study sheds new light on the structure-toxicity relationship of IAPP and points to the potential of exploiting star polymers as a new class of therapeutic agents against amyloidogenesis.

Purpose To assess the safety of rAAV.sFlt-1 subretinal injection in neovascular age-related macular degeneration (wet AMD) over 36 months. Design Phase 1 dose escalation trial. Methods Eight subjects with advanced, treatment-experienced wet AMD were randomly assigned (3:1) to treatment and non–gene therapy control groups. Eligible subjects were ≥65 years, had wet AMD, and had best-corrected visual acuity (BCVA) 10/200 to 20/80 in the study eye and 20/200 or better in the other eye. Three of the treatment group subjects received low-dose (1 × 10 10 vector genomes) and 3 high-dose (1 × 10 11 vector genomes) rAAV.sFLT-1 via subretinal injection. Study monitoring was monthly to the primary endpoint at month 12 and then protocol-driven follow-up study visits were conducted at months 18 and 36. All subjects received intravitreal ranibizumab at baseline and at week 4, and retreatment injections at subsequent visits based on prespecified criteria for active wet AMD. The primary endpoint was ocular and systemic safety, but exploratory data including BCVA, retinal center point thickness, and the number of ranibizumab retreatments at and between study visits were also analyzed. Results Six of the 8 subjects completed the 36-month study. Subretinal injection with pars plana vitrectomy was well tolerated in this cohort. No ocular or systemic safety signals were observed during the long-term follow-up period. Exploratory data analysis suggests stability of wet AMD over the 36-month period. Conclusions Subretinal delivery of rAAV.sFLT-1 was well tolerated and demonstrated a favourable safety profile through month 36. Thus, rAAV.sFLT-1 could be safely considered for future evaluation in the treatment of wet AMD.

Background We present the results of a Phase 2a randomized controlled trial investigating the safety, and secondary endpoints of subretinal rAAV.sFLT-1 gene therapy in patients with active wet age-related macular degeneration (wAMD). Methods All patients (n = 32), (ClinicalTrials.gov; NCT01494805), received ranibizumab injections at baseline and week 4, and thereafter according to prespecified criteria. Patients in the gene therapy group (n = 21) received rAAV.sFLT-1 (1 × 1011 vg). All patients were assessed every 4 weeks to the week 52 primary endpoint. Findings Ocular adverse events (AEs) in the rAAV.sFLT-1 group were mainly procedure related and self-resolved. All 11 phakic patients in the rAAV.sFLT-1 group showed progression of cataract following vitrectomy. No systemic safety signals were observed and none of the serious AEs were associated with rAAV.sFLT-1. AAV2 capsid was not detected and rAAV.sFLT-1 DNA was detected transiently in the tears of 13 patients. ELISPOT analysis did not identify any notable changes in T-cell response. In the rAAV.sFLT-1 group 12 patients had neutralizing antibodies (nAb) to AAV2. There was no change in sFLT-1 levels in bodily fluids. In the rAAV.sFLT-1 group, Best Corrected Visual Acuity (BCVA) improved by a median of 1.0 (IQR: − 3.0 to 9.0) Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline compared to a median of − 5.0 (IQR: − 17.5 to 1.0) ETDRS letters change in the control group. Twelve (57%) patients in the rAAV.sFLT-1 group maintained or improved vision compared to 4 (36%) in the control group. The median number of ranibizumab retreatments was 2.0 (IQR: 1.0 to 6.0) for the gene therapy group compared to 4.0 (IQR: 3.5 to 4.0) for the control group. Interpretation rAAV.sFLT-1 combined with the option for co-treatment appears to be a safe and promising approach to the treatment of wAMD. Funding National Health and Medical Research Council of Australia (AP1010405), Lions Eye Institute, Perth Australia, Avalanche Biotechnologies, Menlo Pk, CA, USA., Highlights • Subretinal injection of rAAV.sFLT-1 was found to be safe in 21 patients with wet age-related macular degeneration. • Visual acuity was maintained in gene therapy treated patients over the 52 week period. • The gene therapy treated group of patients had a trend towards fewer ranibizumab retreatments than the control group. Wet age-related macular degeneration (wAMD) is a common cause of vision loss in the elderly. We propose to use gene therapy to treat this disease. This study reinforces the findings from our Phase 1 study examining the safety of the delivery of rAAV.sFLT-1 by subretinal injection as a form of treatment of wAMD. The findings from this trial demonstrate that the surgical subretinal administration of rAAV.sFLT-1 has a favorable safety profile and that it can potentially be used in conjunction with current therapies to provide an improved outcome in the treatment of wAMD.

The average age at menarche in the Taiwanese population is falling. Contrarily, the prevalence of metabolic syndrome (MetS) showed a worldwide increase in the past two decades. The aim of this study was to examine the association between age at menarche and MetS.A total of 3292 women aged 19-91 years old were enrolled in two databases from 2004 to 2008. MetS was defined according to American Heart Association's criteria. Age at menarche was obtained from self-reported questionnaires. Multiple logistic regression analyses were used to estimate the association between age at menarche and MetS with adjustment for potential confounding variables.The prevalence of MetS increased with age. After adjusting age, lifestyle status, and reproductive factors as variables, subjects who had menarche at a younger age showed significantly higher risk of MetS. The adjusted odds ratio of having MetS in12 and 12-14 years old menarche age groups were 1.71 (1.07-2.71) and 1.22 (1.00-1.50), respectively. The significant increase in odds ratio for MetS in early age menarche also reveals a dose-response effect.Early onset of menarche is an important risk factor of MetS and may help identify women at risk of MetS.

Objective To investigate the association between mid-upper arm circumference (MUAC), calf circumference (CC) and all-cause mortality in a Chinese population. Design Prospective cohort study. Setting Eight long-term care facilities in central Taiwan. Participants A total of 329 residents age 60 years and older (median 79.0 years, range 60–101; 139 men, 190 women) were enrolled. Methods Anthropometrics and metabolic parameters were measured at the time of enrolment to the study. Mean MUAC and CC were 24.2±3.4 cm and 27.5±4.3 cm, respectively. Mortality data were obtained from the Department of Health in Taiwan. Main outcome measure To identify the association between all-cause mortality and MUAC or CC. Results There were 255 deaths during the 7-year follow-up period. After adjusting for age, sex, cigarette smoking, betel nut chewing, alcohol use, Karnofsky Performance Status Scale score, serum albumin level, hypertension and diabetes mellitus, subjects in the highest tertile of MUAC (27.8±2.2 cm) and CC (32.1±2.6 cm) had a significantly lower mortality rate than did subjects in the lowest tertile (MUAC 20.6±1.7 cm; CC 22.8±1.9 cm). The adjusted HR for all-cause mortality in the highest versus lowest MUAC tertile was 0.64 (95% CI 0.45 to 0.90). The adjusted HR for all-cause mortality in the highest versus lowest CC tertile was 0.51 (95% CI 0.35 to 0.74). Conclusions MUAC and CC are negative predictors for all-cause mortality in older Chinese adults living in long-term care facilities. Participants with higher MUAC and CC had lower all-cause mortality.

Summary Background Neovascular, or wet, age-related macular degeneration causes central vision loss and represents a major health problem in elderly people, and is currently treated with frequent intraocular injections of anti-VEGF protein. Gene therapy might enable long-term anti-VEGF therapy from a single treatment. We tested the safety of rAAV.sFLT-1 in treatment of wet age-related macular degeneration with a single subretinal injection. Methods In this single-centre, phase 1, randomised controlled trial, we enrolled patients with wet age-related macular degeneration at the Lions Eye Institute and the Sir Charles Gairdner Hospital (Nedlands, WA, Australia). Eligible patients had to be aged 65 years or older, have age-related macular degeneration secondary to active subfoveal choroidal neovascularisation, with best corrected visual acuity (BCVA) of 3/60–6/24 and 6/60 or better in the other eye. Patients were randomly assigned (3:1) to receive either 1 × 10 10 vector genomes (vg; low-dose rAAV.sFLT-1 group) or 1 × 10 11 vg (high-dose rAAV.sFLT-1 group), or no gene-therapy treatment (control group). Randomisation was done by sequential group assignment. All patients and investigators were unmasked. Staff doing the assessments were masked to the study group at study visits. All patients received ranibizumab at baseline and week 4, and rescue treatment during follow-up based on prespecified criteria including BCVA measured on the Early Treatment Diabetic Retinopathy Study (EDTRS) scale, optical coherence tomography, and fluorescein angiography. The primary endpoint was ocular and systemic safety. This trial is registered with ClinicalTrials.gov, number NCT01494805. Findings From Dec 16, 2011, to April 5, 2012, we enrolled nine patients of whom eight were randomly assigned to receive either intervention (three patients in the low-dose rAAV.sFLT-1 group and three patients in the high-dose rAAV.sFLT-1 group) or no treatment (two patients in the control group). Subretinal injection of rAAV.sFLT-1 was highly reproducible. No drug-related adverse events were noted; procedure-related adverse events (subconjunctival or subretinal haemorrhage and mild cell debris in the anterior vitreous) were generally mild and self-resolving. There was no evidence of chorioretinal atrophy. Clinical laboratory assessments generally remained unchanged from baseline. Four (67%) of six patients in the treatment group required zero rescue injections, and the other two (33%) required only one rescue injection each. Interpretation rAAV.sFLT-1 was safe and well tolerated. These results support ocular gene therapy as a potential long-term treatment option for wet age-related macular degeneration. Funding National Health and Medical Research Council of Australia, Richard Pearce Bequest, Lions Save Sight Foundation, Brian King Fellowship, and Avalanche Biotechnologies, Inc.

Journal of MCU Peace Studies, 5, 2

Objective: The study aims to investigate the incidence of first ischemic stroke in patients with benign cardiac tumors who did or did not undergo operations. Methods: We used the National Health Insurance Research Database of Taiwan to conduct the research. The exposure cohort comprised 587 adult patients with benign cardiac tumors. Each patient was randomly frequency matched by age, index month, and index year with 10 participants from the general population who exhibited no history of benign cardiac tumors before the index date (control group). Cox's proportion hazard regression analyses were conducted to determine the relation between benign cardiac tumors and the risk of ischemic stroke. Results: Based on clinical diagnoses, the prevalence of benign cardiac tumors was 0·004%. Patients with benign cardiac tumors exhibited an increased risk of first ischemic stroke [adjusted hazard ratio: 1·77; (95% confidence interval, 1·20–2·63)], particularly at young ages (adjusted hazard ratio: 22·9, 95% confidence interval: 4·17–126·0). We observed no significant difference in the risk of ischemic stroke between men with and without benign cardiac tumors (adjusted hazard ratio: 1·29, 95% confidence interval: 0·63–2·63). Among patients with benign cardiac tumors, the adjusted hazard ratio of first ischemic stroke was 0·48 (95% confidence interval: 0·23–1·04) in the operation group compared with the nonoperation group. Conclusion: Younger patients (

Objective To estimate the risk of head injury or fracture requiring hospitalization in patients treated with zolpidem. Patients and Methods We identified 8188 patients 18 years and older who had received a first prescription for zolpidem between January 1, 2000, and December 31, 2009, and compared them with 32,752 age- and sex-matched patients who had not used sedative-hypnotic agents. Both cohorts were followed up for at least 1 year or until hospitalization for head injury or fracture (major injury). Hazard ratios (HRs) and 95% CIs were calculated by comparing the incidence of major injury requiring hospitalization between the zolpidem user and comparison cohorts, including age groups 18 to 54 and 55 years or more, using a Cox proportional hazards regression analysis. Results The adjusted HR for major injury in zolpidem users was 1.67 (95% CI, 1.19-2.34). The adjusted HR for major injury in zolpidem users in the younger cohort (aged 18-54 years) was 1.70 (95% CI, 1.15-2.51) and in the older cohort (aged ≥55 years) was 1.57 (95% CI, 0.78-3.13). The adjusted HR for major injury in zolpidem users increased when the zolpidem dosage increased (HR, 2.04; 95% CI, 1.32-3.13 for 71-800 mg/y; HR, 4.37; 95% CI, 2.12-9.01 for 801-1600 mg/y; and HR, 4.74; 95% CI, 2.38-9.42 for >1600 mg/y). Conclusion The long-term use of zolpidem is associated with a significantly greater risk of head injury or fracture requiring hospitalization than in patients who do not use sedative-hypnotic agents ( P

The preliminary report of the Malaysian Education Blueprint – 2013–2025 (Malaysia Ministry of Education, 2012. Preliminary education blueprint (2013–2025). Retrieved June 11, 2012 from http://www.moe.gov.my/userfiles/file/PPP/Preliminary-Blueprint-Eng.pdf) highlights the importance, in a globalised world, of producing future intellectual, social and human capital for Malaysia. It is paramount to note that adolescents are the future human capital of Malaysia. Literature indicates adolescents are confronted with an environment that is rapidly changing and the time spent on non-school-related activities has negatively impacted academic performance. This research investigated the contribution of time use among students to academic achievement. The sample of secondary school students was stratified to ensure balance of gender, school type and grade level. Correlation analyses were conducted to determine the associations among the variables identified in the study. Participants completed the Daily Record of How I Use My Time each day for seven consecutive days. Cooperating schools provided copies of the academic transcript of each participant. This information was used to establish the overall secondary school academic achievement of each participant. The data collected were subjected to bivariate comparison of means and t-test comparisons of means to yield correlations among the target variables. The findings of this research support those of some previous studies and contradict those of other studies, many conducted with non-Malaysian populations. In sum, this study may help to develop a conceptual framework for guiding efforts to improve academic performance, as it relates to time use, as a contribution to accomplishing the national agenda of Malaysia.

Hepatoblastoma is the most common malignant liver tumor of infancy and presents most frequently at a median age of 18 months. Presentation in the neonatal period is rare, and there are very few reports of an antenatal diagnosis of hepatoblastoma. We recently encountered a neonate who presented with hemoperitoneum after rupture of a congenital hepatoblastoma during vaginal delivery. After successful right hepatectomy and adjuvant cis-platinum-based chemotherapy, the child is doing well. We draw attention to rarity of this condition and difficulty in definitively establishing a diagnosis both in the antenatal and neonatal periods and discuss the management dilemmas in congenital presentations of hepatoblastoma.

We report on the long-term safety of AAV2.sFlt-1 (a recombinant adeno-associated virus serotype 2 carrying the soluble form of the Flt-1 receptor) injection into the subretinal space of non-human primates. Levels of sFlt-1 protein were significantly higher (P

To monitor retinal and vascular changes associated with neovascularization, which were generated through photoreceptor-specific overexpression of human vascular endothelial growth factor (hVEGF), in transgenic trVEGF029 (Kimba) mice.The Spectralis Heidelberg Retina Angiography and Optical Coherence Tomography (HRA+OCT) imaging device was used to track changes in the retina and retinal vasculature of Kimba mouse eyes (n = 32) and control C57Bl/6J mouse eyes (n = 20) at 4, 8, 12, 16, and 20 weeks of age.Retinal vascular leakage, focal dilated vessel, vessel tortuosity, attenuated vessel, venous beading, capillary dropout, retinal non-perfusion, neovascularization, and focal retinal detachment were observed in Kimba mouse eyes. Through track changes, we detected edema in the peripheral part of the retina of 2/32 Kimba mouse eyes examined. The retinae of the Kimba mice were significantly thinner than control mice retinae at all ages of the mice assessed (p 0.01).In vivo monitoring of retinal vascular and neural retinal changes in the Kimba mice using the Spectralis HRA+OCT imaging device allowed us to assess and track VEGF-induced damages in great detail and in real-time. Real-time monitoring of these changes can be used to study the interplay between VEGF overexpression and other molecular factors and to monitor dynamic retinal changes following therapeutic intervention.

Background This study investigates the relationship between serum concentration of RBP4 and visfatin and the metabolic syndrome. Methods Patients with metabolic syndrome were studied between October, 2004 and September, 2005. All study subjects were aged 40 and over and lived in Taichung city, Taiwan. The Third Report of the National Cholesterol Education Program's Adult Treatment Panel (ATP III, 2001) was used to define the metabolic syndrome. Serum RBP4 and visfatin levels were measured by enzyme-linked immunosorbent assay. Results Serum mean RBP4 levels in subjects who had all five abnormal components of metabolic syndrome (mean ± SD = 40.8 ± 18.6) and those who had all components except hyperglycemia (43.5 ± 23.5) were significantly higher than those in healthy controls (30.3 ± 14.0 μg/ml) (p

This paper examines the use of gei constructions in Mandarin Chinese and bei constructions in Cantonese within three corpora (of spoken and written Chinese and Hong Kong Cantonese). There are seven structural patterns in which gei/VLgei takes two objects. The order of these objects is determined by the principle of end-weight. Another four structural patterns see the co-occurrence of verb phrases with gei/V-gei. About four percent of gei constructions are used to mark a passivised verb. The study also reveals that the fronting of direct object marked by the preposition ba is a rather formal style. In the contrast between Mandarin gei constructions and Cantonese bei constructions, it was found that (i) the order of indirect object followed by direct object as in Mandarin Chinese reverses in Cantonese; (ii) when compared with Mandarin gei, Cantonese bei is more commonly used as a passive marker and as a verb meaning ‘allow’.

Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of diabetic retinopathy. We investigated whether transgenic mice with moderate VEGF expression in photoreceptors (trVEGF029) developed changes similar to diabetic retinopathy and whether retinopathy progressed with time.Human VEGF(165) (hVEGF(165)) expression was analysed using ELISA and quantitative RT-PCR; serum glucose levels were also measured. Fundus fluorescein angiography (FA) was used to screen the degree of retinopathy from 6 weeks. Dynamic changes in the density of retinal microvasculature, as well as other changes similar to diabetic retinopathy, including retinal leucostasis, capillary endothelial cell and pericyte loss, and numbers of acellular capillaries, were quantified.trVEGF029 mice were normoglycaemic and showed a moderate, short-term hVEGF(165) upregulation for up to 3 weeks. Changes in the retinal microvasculature not only mimicked those seen in diabetic retinopathy, but also showed similar pathological progression with time. FA at 6 weeks identified two phenotypes, mild and moderate, which were distinguished by the extent of vascular leakage. Quantitative analysis of diabetic retinopathy-like changes revealed that these parameters were tightly correlated with the initial degree of vascular leakage; low levels reflected slow and limited retinal microvascular changes in mild cases and high levels reflected more rapid and extensive changes in moderate cases.The data suggest that even an early short-term elevation in hVEGF(165) expression might set a train of events that lead to progressive retinopathy. Induction of many features characteristic of diabetic retinopathy in trVEGF029 enables mechanisms leading to the disease state to be examined, and provides a relevant animal model for testing novel therapeutics.

Objective: The purpose of this study was to assess the lipid-lowering effect of Monascus purpureus Went rice on serum lipids in patients with hyperlipidemia, and to assess its safety by reporting adverse events and clinical laboratory measurements. Design and methods: This was a randomized, double-blind, placebo-controlled study. In all, 79 patients (aged 23–65 years) with a mean baseline low-density lipoprotein cholesterol (LDL-C) level of 5.28 mmol/l (203.9 mg/dl) received a twice daily dose of placebo or Monascus purpureus Went rice (600 mg) for 8 weeks. Results: At week 8, Monascus purpureus Went rice therapy reduced LDL-C by 27.7%, total cholesterol by 21.5%, triglycerides by 15.8% and apolipoprotein B by 26.0%. High-density lipoprotein cholesterol and apolipoprotein A-I levels were increased by 0.9 and 3.4% respectively (not significant). No patient in the Monascus purpureus Went rice treatment group had an alanine aminotransferase (ALT), aspartate aminotransferase (AST) or creatine phosphokinase (CPK) measurement that was ≥ 3 times the upper limit of normal at week 4 and week 8. Conclusion: Monascus purpureus Went rice significantly reduced LDL-C, total cholesterol, triglycerides and apolipoprotein B levels, and was well tolerated in patients with hyperlipidemia. However, this study only provides data from an 8-week trial and long-term safety and efficacy data are needed.

Vascular endothelial growth factor (VEGF) is one of the major mediators of retinal ischemia-associated neovascularization. We have shown here that adeno-associated virus (AAV)-mediated expression of sFlt-1, a soluble form of the Flt-1 VEGF receptor, was maintained for up to 8 and 17 months postinjection in mice and in monkeys, respectively. The expression of sFlt-1 was associated with the long-term (8 months) regression of neovascular vessels in 85% of trVEGF029 eyes. In addition, it resulted in the maintenance of retinal morphology, as the majority of the treated trVEGF029 eyes (75%) retained high numbers of photoreceptors, and in retinal function as measured by electroretinography. AAV-mediated expression of sFlt-1 prevented the development of laser photocoagulation-induced choroidal neovascularization in all treated monkey eyes. There were no clinically or histologically detectable signs of toxicity present in either animal model following AAV.sFlt injection. These results suggest that AAV-mediated secretion gene therapy could be considered for treatment of retinal and choroidal neovascularizations.

Tight junctions (TJ) between retinal pigmented epithelial (RPE) and retinal endothelial cells maintain the outer and inner blood-retinal barrier, and the breakdown of these barriers is associated with retinal diseases. Vascular endothelial growth factor (VEGF) increases vascular permeability and is thought to be involved in age-related maculopathy. However, to date, little is known about the effect of VEGF on RPE cell junctions. We have investigated the effect of VEGF on TJ formation by examining two essential proteins, ZO-1alpha(+) and ZO-1alpha(-). Cultured vascular endothelial cells in the presence of 5 ng/ml VEGF significantly down-regulate ZO-1alpha(+) and ZO-1alpha(-) transcripts and proteins with significant loss of their trans-epithelial resistance (TER). Immunoconfocal analysis with an anti-ZO-1 antibody has confirmed the relocation of ZO-1 protein from membrane to cytoplasm. By contrast, in the presence of 5 ng/ml VEGF, cultured RPE cells (ARPE19 and RPE51) significantly up-regulate ZO-1alpha(+) and ZO-1alpha(-) transcripts and proteins resulting in a significant increase in their TER. Subsequent immunoconfocal analysis has demonstrated increased ZO-1 membrane assembly in VEGF-treated RPE cells. Thus, VEGF has a dual capability with respect to the regulation of the expression of some TJ proteins at the transcriptional and post-translational levels depending on cell type.