Evaluation of 1-year safety profile of intravitreal ranibizumab 0.5 mg in neovascular age-related macular degeneration (NV-AMD) within routine clinical practice.
The LUMINOUS programme comprises a prospective observational study assessing ranibizumab ‘real-world’ safety and clinical effectiveness across licensed indications worldwide and an annual retrospective pooled safety analysis from completed NV-AMD ranibizumab registries. 1-year data from four European registries are available. This retrospective pooled safety analysis assessed 1-year incidence rates for safety events of particular interest (key ocular or systemic events possibly related to the injection procedure or vascular endothelial growth factor inhibition) together with treatment exposure. Patients were treated according to local protocols within the ranibizumab licence.
Data of 4444 patients from registries in Germany (n=3470), the Netherlands (n=243), Belgium (n=260) and Sweden (n=471) were retrospectively pooled. Between 70.4% and 84.4% of enrolled patients completed 1 year of follow-up. Most frequent overall ocular events of particular interest were retinal pigment epithelial tears (27 patients; <1%) and intraocular pressure-related events (12 patients; <0.3%). Most frequent non-ocular event of particular interest was stroke (19 patients; 0.4%); annual incidence of stroke was low across all registries (0.0–0.5%).
Ranibizumab demonstrated favourable 1-year safety profile for NV-AMD in this routine clinical practice sample, consistent with previous reported trial data. Additional data from a larger patient population are needed to better describe the long-term safety profile of ranibizumab in routine clinical practice and further evaluate risk for infrequent but serious events in ‘real-life’ settings. The 5-year LUMINOUS prospective observational study will address this need.
Degeneration; Macula; Treatment Medical
Congenital cataract is the most common cause of treatable visual impairment in children worldwide. Mutations in many different genes lead to congenital cataract. Recently, mutations in the receptor tyrosine kinase gene, EPHA2, have been found to cause congenital cataract in six different families. Although these findings have established EPHA2 as a causative gene, the total contribution of mutations in this gene to congenital cataract is unknown. In this study, for the first time, a population-based approach was used to investigate the frequency of disease causing mutations in the EPHA2 gene in inherited cataract cases in South-Eastern Australia. A cohort of 84 familial congenital or juvenile cataract index cases was screened for mutations in the EPHA2 gene by direct sequencing. Novel changes were assessed for segregation with the disease within the family and in unrelated controls. Microsatellite marker analysis was performed to establish any relationship between families carrying the same mutation. We report a novel congenital cataract causing mutation c.1751C>T in the EPHA2 gene and the previously reported splice mutation c.2826-9G>A in two new families. Additionally, we report a rare variant rs139787163 potentially associated with increased susceptibility to cataract. Thus mutations in EPHA2 account for 4.7% of inherited cataract cases in South-Eastern Australia. Interestingly, the identified rare variant provides a link between congenital and age-related cataract.
Anemia is a frequent complication of Crohn’s disease (CD). The intestinal iron exporter ferroportin (FPN) is involved in both iron deficiency anemia and the anemia of chronic disease. To examine its role in CD, intestinal FPN expression was studied in subjects with and without CD.
Duodenal mucosal biopsies from 29 pediatric subjects with CD (n = 19) and without CD (n = 10) were obtained. FPN protein was measured using Western blot analysis and mRNA was assessed using quantitative real-time polymerase chain reaction (PCR).
Intestinal FPN protein was higher in anemic CD subjects than in nonanemic CD subjects (P = 0.01), while FPN mRNA levels were not different (P = 0.66). In nonanemic CD subjects, erythrocyte sedimentation rate (ESR) (P = 0.04), C-reactive protein (CRP) (P = 0.03), and interleukin-6 (IL-6) (P = 0.01) levels were elevated compared to controls. Nonanemic CD subjects had a lower median FPN protein than nonanemic controls, although it did not reach statistical significance (P = 0.07). Median FPN mRNA was similar between groups (P = 0.71). Although no correlation between FPN protein and IL-6 was noted, there was a strong negative correlation between serum iron and IL-6, both in subjects with CD (r = −0.88, P < 0.0001) and those without anemia (r = −0.58, P = 0.02).
Intestinal FPN protein is upregulated in anemic CD subjects, suggesting that iron deficiency or anemia is the driving force regulating FPN levels. A transporter distinct from FPN appears to be involved in the hypoferremia associated with the inflammatory process of CD.
Crohn’s disease; anemia; ferroportin; iron
Weight loss and changes in growth are noted in children treated with interferonα
To prospectively determine changes in weight, height, body mass index and body composition during and after treatment of children with hepatitis C.
Children treated with PEG-IFNα2a +/− ribavirin in the PEDS-C trial underwent anthropometric measurements, DXA scan, dietary and activity assessments during and after treatment.
114 (55% male) children mean age 11±3 years were randomized, and 107 received treatment for at least 24 weeks. Subjects were divided into 3 groups according to duration of treatment: 24 (N=14), 48 (N=82), or 72 (N=11) weeks. Decrements of up to 0.50 z score were observed for weight, height and BMI while on therapy among all groups (P≤0.01 compared to baseline). In the group treated for 48 weeks, 29 (33%) subjects had greater than 0.5 unit decrement in height-for-age Z score. While weight-for-age and BMI z scores returned to baseline after cessation of therapy, mean HAZ score was slower to rebound, still lower than baseline at 96 weeks post-therapy for the long treatment duration group (P=0.03) and lower than baseline in most children treated for 48 weeks. Percent body fat, fat-free mass z scores and triceps skinfold z scores decreased with therapy. Dietary energy intake and levels of physical activity did not change during treatment.
PEG-IFNα2a was associated with significant changes in body weight, linear growth, body mass index and body composition in children. These effects were generally reversible with cessation of therapy, although height-for-age z scores had not returned to baseline after 2 years of observation in many. Longer term growth data are needed among children treated for chronic HCV.
Cancer-Testis Antigens (CTAs) are immunogenic proteins that are poor prognostic markers in non-small cell lung cancer (NSCLC). We investigated expression of CTAs in NSCLC and their association with response to chemotherapy, genetic mutations and survival.
We studied 199 patients with pathological N2 NSCLC treated with neoadjuvant chemotherapy (NAC; n = 94), post-operative observation (n = 49), adjuvant chemotherapy (n = 47) or unknown (n = 9). Immunohistochemistry for NY-ESO-1, MAGE-A and MAGE-C1 was performed. Clinicopathological features, response to neoadjuvant treatment and overall survival were correlated. DNA mutations were characterized using the Sequenom Oncocarta panel v1.0. Affymetrix data from the JBR.10 adjuvant chemotherapy study were obtained from a public repository, normalised and mapped for CTAs.
NY-ESO-1 was expressed in 50/199 (25%) samples. Expression of NY-ESO-1 in the NAC cohort was associated with significantly increased response rates (P = 0.03), but not overall survival. In the post-operative cohort, multivariate analyses identified NY-ESO-1 as an independent poor prognostic marker for those not treated with chemotherapy (HR 2.61, 95% CI 1.28–5.33; P = 0.008), whereas treatment with chemotherapy and expression of NY-ESO-1 was an independent predictor of improved survival (HR 0.267, 95% CI 0.07–0.980; P = 0.046). Similar findings for MAGE-A were seen, but did not meet statistical significance. Independent gene expression data from the JBR.10 dataset support these findings but were underpowered to demonstrate significant differences. There was no association between oncogenic mutations and CTA expression.
NY-ESO-1 was predictive of increased response to neoadjuvant chemotherapy and benefit from adjuvant chemotherapy. Further studies investigating the relationship between these findings and immune mechanisms are warranted.
C-reactive protein (CRP) levels are associated with cardiovascular disease and systemic inflammation. We assessed whether CRP-associated loci were associated with serum CRP and retinal markers of microvascular disease, in Asian populations.
Genome-wide association analysis (GWAS) for serum CRP was performed in East-Asian Chinese (N = 2,434) and Malays (N = 2,542) and South-Asian Indians (N = 2,538) from Singapore. Leveraging on GWAS data, we assessed, in silico, association levels among the Singaporean datasets for 22 recently identified CRP-associated loci. At loci where directional inconsistencies were observed, quantification of inter-ethnic linkage disequilibrium (LD) difference was determined. Next, we assessed association for a variant at CRP and retinal vessel traits [central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE)] in a total of 24,132 subjects of East-Asian, South-Asian and European ancestry.
Serum CRP was associated with SNPs in/near APOE, CRP, HNF1A and LEPR (p-values ≤4.7×10−8) after meta-analysis of Singaporean populations. Using a candidate-SNP approach, we further replicated SNPs at 4 additional loci that had been recently identified to be associated with serum CRP (IL6R, GCKR, IL6 and IL1F10) (p-values ≤0.009), in the Singaporean datasets. SNPs from these 8 loci explained 4.05% of variance in serum CRP. Two SNPs (rs2847281 and rs6901250) were detected to be significant (p-value ≤0.036) but with opposite effect directions in the Singaporean populations as compared to original European studies. At these loci we did not detect significant inter-population LD differences. We further did not observe a significant association between CRP variant and CRVE or CRAE levels after meta-analysis of all Singaporean and European datasets (p-value >0.058).
Common variants associated with serum CRP, first detected in primarily European studies, are also associated with CRP levels in East-Asian and South-Asian populations. We did not find a causal link between CRP and retinal measures of microvascular disease.
Mitomycin C (MMC), which induces apoptosis in human Tenon's fibroblasts (HTF), is frequently used to retard wound healing after glaucoma surgery. The aim of this in vitro study was to examine whether adjunctive Verapamil and Cyclosporine could augment the cytotoxic effect of MMC on HTF.
Fibroblast cell lines were established by explant culture from human tissue biopsy samples obtained during trabeculectomy procedures. Cells were exposed to MMC at varying concentrations (0.01–0.4 mg/ml) for 3 minutes, prior to washing in the presence or absence of the following drugs: Staurosporine (0.003mg/ml), Verapamil (2.5–0.25 mg/ml), or Cyclosporine (50–0.5 mg/ml). Following exposure, cells were cultured for 6 hours and surviving cells quantitated by haemocytometer counts.
Both Verapamil and Staurosporine exhibited mild toxic effects on their own, but greatly enhanced the apoptotic effect of MMC. Staurosporine is too toxic to be considered clinically, so its augmentive effect on the activity of MMC was not studied further here. Doses as low as 0.25 mg/ml of Verapamil continued to show significant augmentation of the apoptotic effect of MMC Cyclosporine at a clinically used concentration (5 mg/ml) exhibited modest augmentation of the effect of MMC.
Verapamil and Cyclosporine in clinically acceptable concentrations potentiate the effect of MMC and may obviate the need for high dose antimetabolites in trabeculectomy; however, further preclinical study is required.
Adjunctive Verapamil or Cyclosporine may allow lower dose MMC to be used in glaucoma filtration surgery while maintaining the same antifibrotic effects.
wound healing; P-glycoprotein; Mitomycin C; human Tenon's fibroblasts
Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10−8. This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10−12 in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.
There is extensive evidence implicating the intestinal microbiota in inflammatory bowel disease [IBD], but no microbial agent has been identified as a sole causative agent. Bacteroidales are numerically dominant intestinal organisms that associate with the mucosal surface and have properties that both positively and negatively affect the host. To determine precise numbers and species of Bacteroidales adherent to the mucosal surface in IBD patients, we performed a comprehensive culture based analysis of intestinal biopsies from pediatric Crohn's disease [CD], ulcerative colitis [UC], and control subjects. We obtained biopsies from 94 patients and used multiplex PCR or 16S rDNA sequencing of Bacteroidales isolates for species identification. Eighteen different Bacteroidales species were identified in the study group, with up to ten different species per biopsy, a number higher than demonstrated using 16S rRNA gene sequencing methods. Species diversity was decreased in IBD compared to controls and with increasingly inflamed tissue. There were significant differences in predominant Bacteroidales species between biopsies from the three groups and from inflamed and uninflamed sites. Parabacteroides distasonis significantly decreased in inflamed tissue. All 373 Bacteroidales isolates collected in this study grew with mucin as the only utilizable carbon source suggesting this is a non-pathogenic feature of this bacterial order. Bacteroides fragilis isolates with the enterotoxin gene [bft], previously associated with flares of colitis, were not found more often at inflamed colonic sites or within IBD subjects. B. fragilis isolates with the ability to synthesize the immunomodulatory polysaccharide A [PSA], previously shown to be protective in murine models of colitis, were not detected more often from healthy versus inflamed tissue.
Background: Plant natural products typically contain regiospecific modifications in their side chains that lead to different bioactivities.
Results: Only 3-O-methylated flavonols enhance IL-1β production in THP-1 cells costimulated with the Toll-like receptor 2 agonist Pam3CSK4.
Conclusion: Regiospecific methylation of flavonols controls their bioactivity as immunomodulators.
Significance: This study provides a platform to explore the use of regiospecific-modified natural products as novel immunomodulators.
It is now recognized that innate immunity to intestinal microflora plays a significant role in mediating immune health, and modulation of microbial sensing may underpin the impact of plant natural products in the diet or when used as nutraceuticals. In this context, we have examined five classes of plant-derived flavonoids (flavonols, flavones, flavanones, catechins, and cyanidin) for their ability to regulate cytokine release induced by the Toll-like receptor 2 (TLR2) agonist Pam3CSK4. We found that the flavonols selectively co-stimulated IL-1β secretion but had no impact on the secretion of IL-6. Importantly, this costimulation of TLR2-induced cytokine secretion was dependent on regiospecific methylation of the flavonol scaffold with a rank order of quercetin-3,4′-dimethylether > quercetin-3-methylether > casticin. The mechanism underpinning this costimulation did not involve enhanced inflammasome activation. In contrast, the methylated flavonols enhanced IL-1β gene expression through transcriptional regulation, involving mechanisms that operate downstream of the initial NF-κB and STAT1 activation events. These studies demonstrate an exquisite level of control of scaffold bioactivity by regiospecific methylation, with important implications for understanding how natural products affect innate immunity and for their development as novel immunomodulators for clinical use.
Interleukin; Natural Products; Signaling; Small Molecules; Toll-like Receptors (TLR); IL-1β; Plant Natural Products; TLR Signaling; Methylated Flavonols
Background and Purpose
We examined the relationship of age-related macular degeneration (AMD) with incident stroke, including stroke subtypes of cerebral infarction and intracerebral haemorrhage (ICH).
We included 12,216 participants with retinal photographs taken at the third examination visit (1993–1995) from the Atherosclerosis Risk in Communities Study (ARIC), a population-based cohort study in middle-aged persons. Images were evaluated for AMD signs according to a standardized protocol. Incident events of stroke and its subtypes were identified and validated via case record review over time.
AMD was diagnosed in 591 participants, of whom 576 had early and 15 late AMD. After a mean follow-up of 13.0 years (standard deviation: 3.3), 619 persons developed an incident stroke, including 548 cerebral infarction and 57 ICH. Participants with any AMD were at an increased risk of stroke (multi-variable adjusted hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.11–2.06), with a stronger association for ICH (HR: 2.64; 95% CI: 1.18–5.87) than cerebral infarction (HR: 1.42; 95% CI: 1.01–1.99).
Persons with AMD are at an increased risk of both cerebral infarction and ICH. These data provide further insights into common pathophysiological processes between AMD and stroke subtypes.
retinal imaging; age-related macular degeneration; cerebral infarction; intra-cerebral hemorrhage
Direct assessment of capability to function may be useful in healthcare settings, but poses many challenges. This paper reports a first investigation of the feasibility of individuals self-reporting their capabilities and the meaning of the responses. The study was conducted in 2010, using think-aloud interviews with participants in the UK. The findings of the study suggest that the majority of participants were able to comprehend questions about their capabilities, felt able to judge their own capability wellbeing and provided responses in line with this judgement. In a number of cases, for example in relation to ‘autonomy’, participants highlighted that their capability was potentially greater than their functioning. The findings also show varying interpretations of the capability concept, with some participants finding the capability concept unintuitive in relation to specific aspects of life (in particular, ‘attachment’). The findings suggest that guiding individuals in the process of identifying their capabilities may be important in generating consistent responses to capability questions.
•Think-aloud interviews were used, in the UK, to study the response to capability wellbeing questions.•Most people felt able to judge their capabilities and made few obvious ‘errors’ in doing so.•The capability concept was unintuitive for some people in some aspects of their life.•Occasional divergence between capability and functioning was reported.
Capability approach; EQ-5D; Health economics; ICECAP-A; Outcome measurement; Think-aloud; United Kingdom; Wellbeing
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
Adult-onset hearing loss is insidious and typically diagnosed and managed several years after onset. Often, this is after the loss having led to multiple negative consequences including effects on employment, depressive symptoms, and increased risk of mortality. In contrast, the use of hearing aids is associated with reduced depression, longer life expectancy, and retention in the workplace. Despite this, several studies indicate high levels of unmet need for hearing health services in older adults and poor use of prescribed hearing aids, often leading to their abandonment. In Australia, the largest component of financial cost of hearing loss (excluding the loss of well-being) is due to lost workplace productivity. Nonetheless, the Australian public health system does not have an effective and sustainable hearing screening strategy to tackle the problem of poor detection of adult-onset hearing loss. Given the increasing prevalence and disease burden of hearing impairment in adults, two key areas are not adequately met in the Australian healthcare system: (1) early identification of persons with chronic hearing impairment; (2) appropriate and targeted referral of these patients to hearing health service providers. This paper reviews the current literature, including population-based data from the Blue Mountains Hearing Study, and suggests different models for early detection of adult-onset hearing loss.
Although concurrent vision and hearing loss are common in older adults, population-based data on their relationship with mortality is limited. This cohort study investigated the association between objectively measured dual sensory impairment (DSI) with mortality risk over 10 years. 2812 Blue Mountains Eye Study participants aged 55 years and older at baseline were included for analyses. Visual impairment was defined as visual acuity less than 20/40 (better eye), and hearing impairment as average pure-tone air conduction threshold greater than 25 dB HL (500–4000 Hz, better ear). Ten-year all-cause mortality was confirmed using the Australian National Death Index. After ten years, 64% and 11% of participants with DSI and no sensory loss, respectively, had died. After multivariable adjustment, participants with DSI (presenting visual impairment and hearing impairment) compared to those with no sensory impairment at baseline, had 62% increased risk of all-cause mortality, hazard ratio, HR, 1.62 (95% confidence intervals, CI, 1.16–2.26). This association was more marked in those with both moderate-severe hearing loss (>40 dB HL) and presenting visual impairment, HR 1.84 (95% CI 1.19–2.86). Participants with either presenting visual impairment only or hearing impairment only, did not have an increased risk of mortality, HR 1.05 (95% CI 0.61–1.80) and HR 1.24 (95% CI 0.99–1.54), respectively. Concurrent best-corrected visual impairment and moderate-severe hearing loss was more strongly associated with mortality 10 years later, HR 2.19 (95% CI 1.20–4.03). Objectively measured DSI was an independent predictor of total mortality in older adults. DSI was associated with a risk of death greater than that of either vision loss only or hearing loss alone.
To examine the global prevalence and major risk factors for diabetic retinopathy (DR) and vision-threatening diabetic retinopathy (VTDR) among people with diabetes.
RESEARCH DESIGN AND METHODS
A pooled analysis using individual participant data from population-based studies around the world was performed. A systematic literature review was conducted to identify all population-based studies in general populations or individuals with diabetes who had ascertained DR from retinal photographs. Studies provided data for DR end points, including any DR, proliferative DR, diabetic macular edema, and VTDR, and also major systemic risk factors. Pooled prevalence estimates were directly age-standardized to the 2010 World Diabetes Population aged 20–79 years.
A total of 35 studies (1980–2008) provided data from 22,896 individuals with diabetes. The overall prevalence was 34.6% (95% CI 34.5–34.8) for any DR, 6.96% (6.87–7.04) for proliferative DR, 6.81% (6.74–6.89) for diabetic macular edema, and 10.2% (10.1–10.3) for VTDR. All DR prevalence end points increased with diabetes duration, hemoglobin A1c, and blood pressure levels and were higher in people with type 1 compared with type 2 diabetes.
There are approximately 93 million people with DR, 17 million with proliferative DR, 21 million with diabetic macular edema, and 28 million with VTDR worldwide. Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with DR. These data highlight the substantial worldwide public health burden of DR and the importance of modifiable risk factors in its occurrence. This study is limited by data pooled from studies at different time points, with different methodologies and population characteristics.
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.
Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.
A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy.
No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, −1.3±0.23 (beta ± standard error), p = 6.6×10−9. Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r2 ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension.
This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.
The effects of habitual dairy consumption and the risk of 15-year cardiovascular disease (CVD) mortality in a cohort of older Australians were investigated. Participants (n = 2900) completed a validated 145-item semi-quantitative food frequency questionnaire. Cox proportional hazards regression models were used to investigate associations between tertiles of the dairy consumption, including low/reduced fat dairy, whole fat dairy and their ratio (ratioLF/WF), and risk of mortality from coronary heart disease (CHD), stroke or combined CVD. There were 548 recorded cases of CVD mortality in this cohort. For total dairy intake, a reduction in risk of CVD was only seen in tertile 2 (adjusted hazard ratio, AHR: 0.71; 95% CI: 0.55–0.93), and for CHD both tertile 2 and tertile 3 were associated with a reduced risk (both with AHR: 0.71). However there were no linear trends between total dairy consumption and any of the three outcomes. There were no associations or trends between low/reduced fat dairy or whole fat dairy consumption, or ratioLF/WF and any of the three outcomes in the fully adjusted model (all p > 0.05). This study found no consistent association between baseline consumption of dairy foods and the risk of CHD, stroke and combined CVD mortality.
dairy; cardiovascular disease; older Australian; Blue Mountains Eye Study; population
Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10−31) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10−24) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10−6) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10−6) and upstream of GLI2 (rs6721654; P = 6.5×10−6), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10−6), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.
The aim of the study was to prospectively determine risk factors for the development of parenteral nutrition–associated liver disease (PNALD) in infants who underwent surgery for necrotizing enterocolitis (NEC), the most common cause of intestinal failure in children.
Patients and Methods
From February 2004 to February 2007, we diagnosed 464 infants with NEC, of whom 180 had surgery. One hundred twenty-seven patients were available for full analysis. PNALD was defined as serum direct bilirubin ≥2 mg/dL or ALT ≥2× the upper limit of normal in the absence of sepsis after ≥14 days of exposure to PN. Median
Median gestational age was 26 weeks and 68% were boys. Seventy percent of the cohort developed PNALD and the incidence of PNALD varied significantly across the 6 study sites, ranging from 56% to 85% (P=0.05). Multivariable logistic regression analysis identified small-bowel resection or creation of jejunostomy (odds ratio [OR] 4.96, 95% confidence interval [CI] 1.97–12.51, P = 0.0007) and duration of PN in weeks (OR 2.37, 95% CI 1.56–3.60, P < 0.0001) as independent risk factors for PNALD. Preoperative exposure to PN was also associated with the development of PNALD; the risk of PNALD was 2.6 (95% CI 1.5–4.7; P = 0.001) times greater in patients with ≥4 weeks of preoperative PN compared with those with less preoperative PN use. Breast milk feedings, episodes of infection, and gestational age were not related to the development of PNALD.
The incidence of PNALD is high in infants with NEC undergoing surgical treatment. Risk factors for PNALD are related to signs of NEC severity, including the need for small-bowel resection or proximal jejunostomy, as well as longer exposure to PN. Identification of these and other risk factors can help in the design of clinical trials for the prevention and treatment of PNALD and for clinical assessment of patients with NEC and prolonged PN dependence.
intestinal failure; jejunostomy; necrotizing enterocolitis; parenteral nutrition–associated liver disease; short-bowel syndrome
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
We evaluated pharmacodynamic changes in tumour perfusion using positron emission tomography (PET) imaging with 15O-water to assess biological response to sunitinib, a multitargeted tyrosine kinase inhibitor.
Patients with advanced malignancies received sunitinib 50 mg/day orally, once daily for 4 weeks on treatment, followed by 2 weeks off treatment, in repeated 6-week cycles. Quantitative measurement of tumour perfusion was assessed using 15O-water-PET at baseline and after 2 weeks of treatment. At least one reference tumour lesion was included in the fields of view and assessed at both time points. Patients also underwent 18 F-fluorodeoxyglucose (FDG)-PET imaging at baseline and after 2 and 4 weeks of treatment. Radiological response of the reference tumour lesion and overall radiological response were assessed at week 12. Serum pharmacokinetic and biomarker analyses were also performed.
Data were available for seven patients. Compared with baseline, all patients experienced a decrease in reference tumour blood flow ranging from 20 % to 85 % and also a reduction in the FDG standard uptake value ranging from 29 % to 67 %. Six patients experienced a partial metabolic response based on FDG-PET criteria. Four patients had stable disease defined by radiological response (Response Evaluation Criteria in Solid Tumors) lasting between 4 and 12 cycles. An association between perfusion change and clinical benefit, and biomarker levels including vascular endothelial growth factor was observed.
Administering sunitinib to patients with advanced malignancies is associated with early biological responses, including decreased blood flow in secondary tumour deposits.
sunitinib; tumour perfusion; FDG-PET.
Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p = 1.4×10−8), and with rs7555523, located in TMCO1 at 1q24.1 (p = 1.6×10−8). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p = 2.4×10−2 for rs11656696 and p = 9.1×10−4 for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.
Glaucoma is a major eye disease in the elderly and is the second leading cause of blindness worldwide. The numerous familial glaucoma cases, as well as evidence from epidemiological and twin studies, strongly support a genetic component in developing glaucoma. However, it has proven difficult to identify the specific genes involved. Intraocular pressure (IOP) is the major risk factor for glaucoma and the only target for the current glaucoma therapy. IOP has been shown to be highly heritable. We investigated the role of common genetic variants in IOP by performing a genome-wide association study. Discovery analyses in 11,972 participants and subsequent replication analyses in a further 7,482 participants yielded two common genetic variants that were associated with IOP. The first (rs11656696) is located in GAS7 at chromosome 17, the second (rs7555523) in TMCO1 at chromosome 1. Both variants were associated with glaucoma in a meta-analysis of 4 case-control studies. GAS7 and TMCO1 are expressed in the ocular tissues that are involved in glaucoma. Both genes functionally interact with the known glaucoma disease genes. These data suggest that we have identified two genes involved in IOP regulation and glaucomatous neuropathy.
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.