To investigate the risk factors for myopia, including near work and outdoor activity, in Singapore Chinese preschool children.
A cross-sectional study, with disproportionate random sampling by 6-month age groups, of 3009 Singapore Chinese children aged 6–72 months was performed. Information on family history, near work and outdoor activity was obtained. Spherical equivalent refraction (SEA) was assessed.
Children with two myopic parents were more likely to be myopic (adjusted OR=1.91; 95% CI 1.38 to 2.63) and to have a more myopic SER (regression coefficient=−0.35; 95% CI −0.47 to −0.22) than children without myopic parents. For each 1 cm taller height, the SER was more myopic by 0.01 dioptres. Neither near work nor outdoor activity was associated with preschool myopia.
A family history of myopia was the strongest factor associated with preschool myopia. In contrast, neither near work nor outdoor activity was found to be associated with early myopia. These data suggest that genetic factors may play a more substantial role in the development of early-onset myopia than key environmental factors.
DNA repair genes that have been inactivated by promoter methylation offer potential therapeutic targets either by targeting the specific repair deficiency, or by synthetic lethal approaches. This study evaluated promoter methylation status for eight selected DNA repair genes (ATM, BRCA1, ERCC1, MGMT, MLH1, NEIL1, RAD23B and XPC) in 56 non-small cell lung cancer (NSCLC) tumours and 11 lung cell lines using the methylation-sensitive high resolution melting (MS-HRM) methodology. Frequent methylation in NEIL1 (42%) and infrequent methylation in ERCC1 (2%) and RAD23B (2%) are reported for the first time in NSCLC. MGMT methylation was detected in 13% of the NSCLCs. Contrary to previous studies, methylation was not detected in ATM, BRCA1, MLH1 and XPC. Data from The Cancer Genome Atlas (TCGA) was consistent with these findings. The study emphasises the importance of using appropriate methodology for accurate assessment of promoter methylation.
Glaucoma is a major cause of blindness in the world. To date, common genetic variants associated with glaucoma only explain a small proportion of its heritability. We performed a genome-wide association study of intra-ocular pressure (IOP), an underlying endophenotype for glaucoma. The discovery phase of the study was carried out in the TwinsUK cohort (N = 2774) analyzing association between IOP and single nucleotide polymorphisms (SNPs) imputed to HapMap2. The results were validated in 12 independent replication cohorts of European ancestry (combined N = 22 789) that were a part of the International Glaucoma Genetics Consortium. Expression quantitative trait locus (eQTL) analyses of the significantly associated SNPs were performed using data from the Multiple Tissue Human Expression Resource (MuTHER) Study. In the TwinsUK cohort, IOP was significantly associated with a number of SNPs at 9q33.3 (P = 3.48 × 10−8 for rs2286885, the most significantly associated SNP at this locus), within the genomic sequence of the FAM125B gene. Independent replication in a composite panel of 12 cohorts revealed consistent direction of effect and significant association (P = 0.003, for fixed-effect meta-analysis). Suggestive evidence for an eQTL effect of rs2286885 was observed for one of the probes targeting the coding region of the FAM125B gene. This gene codes for a component of a membrane complex involved in vesicular trafficking process, a function similar to that of the Caveolin genes (CAV1 and CAV2) which have previously been associated with primary open-angle glaucoma. This study suggests a novel association between SNPs in FAM125B and IOP in the TwinsUK cohort, though further studies to elucidate the functional role of this gene in glaucoma are necessary.
Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10−8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4–1.88, P = 2.7 × 10−10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29–1.68, P = 4.9 × 10−9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10−4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.
Combination blockade of human epidermal growth factor receptor (HER) family signaling may confer enhanced antitumor activity than single-agent blockade. We performed a single-arm study of pertuzumab, a monoclonal antibody that inhibits HER2 dimerization, and erlotinib in relapsed non-small cell lung cancer (NSCLC).
Patients received pertuzumab (840-mg loading dose and 420-mg maintenance intravenously every 3 weeks) and erlotinib (150-mg or 100-mg dose orally, daily). The primary endpoint was response rate (RR) by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) at day 56 in all patients and those with EGFR wild-type tumors.
Of 41 patients, 28 (68.3%) experienced treatment-related grade ≥3 adverse events, including pneumatosis intestinalis (3 patients), resulting in early cessation of enrollment. Tissue samples from 32 patients showed mutated EGFR status in 9 of 41 (22%) and wild-type EGFR in 23 of 41 (56%). The FDG-PET RR for patients with assessments at day 56 was 19.5% in all patients (n = 41) and 8.7% in patients with wild-type EGFR NSCLC (n = 23). Investigator-assessed computed tomography RR at day 56 was 12.2%.
FDG-PET suggests that pertuzumab plus erlotinib is an active combination, but combination therapy was poorly tolerated, which limits its clinical applicability. More research is warranted to identify drug combinations that disrupt HER receptor signaling but that exhibit improved tolerability profiles.
Keratoconus is a common complex corneal ectasia that can lead to severe visual impairment. Although a genetic component is well recognized, the genetic risk factors for keratoconus are yet to be fully elucidated. A recent genome-wide association study (GWAS) by Li et al. identified 15 potentially associated single nucleotide polymorphisms (SNPs). Here, we aimed to replicate these associations, and conduct a meta-analysis of the current and previous studies.
We genotyped the 15 reported associated SNPs in 524 Australian Caucasian cases with keratoconus and 2761 controls. Association analysis was conducted in PLINK. A meta-analysis of this study with the adjusted P values of the previously published GWAS was conducted using the method of Fisher to combine P values.
Our Australian cohort showed association (P < 0.003) at SNPs near RAB3GAP1, KCND3, IMMPL2, and in a gene desert on chromosome 13q33.3, providing evidence of replication of the published results. The meta-analysis showed SNP rs4954218 near RAB3GAP1 gene was associated significantly with keratoconus, with P = 9.26 × 10−9 passing the genome-wide significance level.
Although the mechanism of disease association is yet to be determined, SNP rs4954218 is associated consistently with keratoconus and likely tags a functional variant that contributes to disease susceptibility.
We describe the replication of published findings from a genome-wide association study of keratoconus. We show for the first time, to our knowledge, that SNPs near RAB3GAP1 are associated with keratoconus at genome-wide significance, and also provide further supportive evidence for association at other reported loci.
keratoconus; cornea; genetics; genome-wide association study; meta-analysis
In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10−9) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10−4–2.2 × 10−7. Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
Concurrent chemoradiotherapy (CCRT) has become the standard of care for patients with unresectable stage III non–small cell lung cancer (NSCLC). The comparative merits of two widely used regimens: carboplatin/paclitaxel (PC) and cisplatin/etoposide (PE), each with concurrent radiotherapy, remain largely undefined. Records for consecutive patients with stage III NSCLC treated with PC or PE and ≥60 Gy chest radiotherapy between 2000 and 2011 were reviewed for outcomes and toxicity. Survival was estimated using the Kaplan–Meier method and Cox modeling with the Wald test. Comparison across groups was done using the student's t and chi-squared tests. Seventy-five (PC: 44, PE: 31) patients were analyzed. PC patients were older (median 71 vs. 63 years; P = 0.0006). Other characteristics were comparable between groups. With PE, there was significantly increased grade ≥3 neutropenia (39% vs. 14%, P = 0.024) and thrombocytopenia (10% vs. 0%, P = 0.039). Radiation pneumonitis was more common with PC (66% vs. 38%, P = 0.033). Five treatment-related deaths occurred (PC: 3 vs. PE: 2, P = 1.000). With a median follow-up of 51.6 months, there were no significant differences in relapse-free survival (median PC 12.0 vs. PE 11.5 months, P = 0.700) or overall survival (median PC 20.7 vs. PE 13.7 months; P = 0.989). In multivariate analyses, no factors predicted for improved survival for either regimen. PC was more likely to be used in elderly patients. Despite this, PC resulted in significantly less hematological toxicity but achieved similar survival outcomes as PE. PC is an acceptable CCRT regimen, especially in older patients with multiple comorbidities.
Carboplatin/paclitaxel; cisplatin/etoposide; concurrent chemoradiotherapy; locally advanced; non–small cell lung cancer; stage III
Refractive error is the most common eye disorder worldwide, and a prominent cause of blindness. Myopia affects over 30% of Western populations, and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses including 37,382 individuals from 27 studies of European ancestry, and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in subjects of European ancestry, of which 8 were shared with Asians. Combined analysis revealed 8 additional loci. The new loci include genes with functions in neurotransmission (GRIA4), ion channels (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2, BMP2), and eye development (SIX6, PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for subjects with the highest genetic load. Our results, accumulated across independent multi-ethnic studies, considerably advance understanding of mechanisms involved in refractive error and myopia.
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.
To discover quantitative trait loci for intraocular pressure, a major risk factor for glaucoma and the only modifiable one, we performed a genome-wide association study on a discovery cohort of 2175 individuals from Sydney, Australia. We found a novel association between intraocular pressure and a common variant at 7p21 near to GLCCI1 and ICA1. The findings in this region were confirmed through two UK replication cohorts totalling 4866 individuals (rs59072263, Pcombined = 1.10 × 10−8). A copy of the G allele at this SNP is associated with an increase in mean IOP of 0.45 mmHg (95%CI = 0.30–0.61 mmHg). These results lend support to the implication of vesicle trafficking and glucocorticoid inducibility pathways in the determination of intraocular pressure and in the pathogenesis of primary open-angle glaucoma.
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.