Diabetes and further risk of cancer: a nationwide population-based study.

BACKGROUND: Individuals with diabetes have a significantly higher risk of developing various forms of cancer, and the potential biological links between these two diseases are not completely understood. METHODS: This was a longitudinal retrospective nationwide cohort study, a study design that allows us to examine the natural course of cancer development over an extended period of time with a large sample size. Initially, 3,111,975 and 22,208,395 eligible patients aged ≥ 20 years with and without diabetes, respectively, were matched by age, sex, and the Charlson comorbidity index. Ultimately, 1,751,457 patients were selected from each group. Stratified populations for diabetic retinopathy (DR) (n = 380,822) and without DR (n = 380,822) as well as proliferative DR (PDR) (n = 141,150) and non-proliferative DR (NPDR) (n = 141,150) were analyzed in this study. The main outcome measure was the first-time diagnosis of cancer during the follow-up period. RESULTS: We observed a 20% higher risk of total cancer incidence [hazard ratios (HR), 1.20; p < 0.001] in the diabetes cohort compared to the non-diabetes cohort. The highest HR was observed for liver and pancreas cancers. Moderately increased risks were observed for oral, colon, gallbladder, reproductive (female), kidney, and brain cancer. Furthermore, there was a borderline significantly increased risk of stomach, skin, soft tissue, female breast, and urinary tract (except kidney) cancers and lymphatic and hematopoietic malignancies. The stratified analysis revealed that the total cancer incidence was significantly higher in the DR cohort compared to the non-DR cohort (HR, 1.31; p < 0.001), and there was a borderline increased risk in the PDR cohort compared to the NPDR cohort (HR, 1.13; p = 0.001). CONCLUSIONS: This study provides large-scale, nationwide, population-based evidence that diabetes is independently associated with an increased risk of subsequent development of total cancer and cancer at specific sites. Notably, this risk may further increase when DR develops.

A real-world study for timely assessing the diabetic macular edema refractory to intravitreal anti-VEGF treatment.

Background: Early Identifying and characterizing patients with diabetic macular edema (DME) is essential for individualized treatment and outcome optimization. This study aimed to timely investigate optical coherence tomography (OCT) biomarkers of DME refractory to intravitreal anti-vascular endothelial growth factor (VEGF) therapy. Methods: We retrospective reviewed 72 eyes from 44 treatment-naïve patients who were treated with intravitreal anti-VEGF for DME. OCT scans prior to anti-VEGF were evaluated for serous retinal detachment (SRD), size of outer nuclear layer cystoid changes, diffuse retinal thickening, integrity of the inner segment-outer segment (IS-OS) junction, quantity and location of hyperreflective foci, vitreomacular interface abnormalities, and epiretinal membrane (ERM). The Baseline best-corrected visual acuity (BCVA) and central macular thickness was recorded at baseline and 4 months after treatment with anti-VEGF. The main outcome measure was the correlation between spectral-domain OCT measurements and BCVA response at baseline and after anti-VEGF treatment (mean change from baseline; ≥ 10 Early Treatment Diabetic Retinopathy Study letters in BCVA). Results: Partially continuous IS-OS layers (partially vs. completely continuous: ß, -0.138; Wald chi-square, 16.392; P<0.001) was predictor of better response to anti-VEGF treatment. In contrast, ERM (present vs. absent ERM: ß, 0.215; Wald chi-square, 5.921; P=0.015) and vitreomacular traction (vitreomacular traction vs. posterior vitreous detachment: ß=0.259; Wald chi-square=5.938; P=0.015) were the predictors of poor response. The improvement of BCVA trended toward the OCT predictive value of central macular thickness reduction; however, this was not significant. Conclusion: Partially continuous IS-OS layers is predictive of better response to anti-VEGF therapy in DME. Meanwhile, ERM is a significant predictor of poor response.

LAWN TRIMMER-RELATED OPEN-GLOBE INJURIES IN TAIWAN.

PURPOSE: Work-related ocular trauma remains the leading cause of unilateral visual impairment worldwide. Many preventable work-related ocular injuries continue to occur, even at home. This study describes the characteristics, surgical techniques, and prognostic factors of lawn trimmer-related open-globe injuries in eastern Taiwan. METHODS: This was a retrospective, consecutive case series study. Slit-lamp biomicroscopy, dilated fundoscopy, and orbital computed tomography (CT) images were collected. RESULTS: Twenty-six eyes of 26 patients were enrolled in the study. Fifteen patients (57.7%) had an intraocular foreign body (IOFB). The IOFB was metallic in 13 cases and glass and stone in the other 2 cases. Seven IOFBs (46.7%) were retained in the anterior chamber, 7 (46.7%) in the posterior segment, and 1 (6.7%) in the intraconal space. Univariate analysis showed that the presence of IOFB trended toward the development of endophthalmitis; however, this was not statistically significant (hazard ratio, 2.25; 95% confidence interval 0.35-14.61; P = 0.658). Eleven patients had metallic IOFBs noted on CT scans with metal artifacts, whereas two patients had small metallic IOFBs without metal artifacts. One patient had a glass IOFB mimicking metal artifacts on the CT scan. In one case, CT failed to reveal the IOFB, and an intralenticular metallic foreign body was incidentally found intraoperatively. CONCLUSION: Our study provides a broad characterization of lawn trimmer-related open-globe injuries. The informative and diverse findings of IOFBs on CT scans will help clinicians detect and recognize IOFBs more precisely and perform the surgery without causing further damage.

The Acanthamoeba SBDS, a cytoskeleton-associated gene, is highly expressed during phagocytosis and encystation.

BACKGROUND/PURPOSE: Shwachman-Bodian-Diamond syndrome (SBDS) protein is widely present in eukaryotes from vertebrates to protozoa. However, there are several variants within species, and previous studies have shown evidence that they may have additional functions. There are two SBDS-related proteins in Acanthamoeba. One is an rRNA metabolism protein of the SBDS family (ACA1_142090), and the other is SBDS (ACA1_204560). Although there is a conserved SBDS domain in the Acanthamoeba SBDS (ACA1_204560; AcSBDS), its function has not been reported. The aims of this study were to characterize the expression of AcSBDS during phagocytosis and encystation. METHODS: AcSBDS-specific primer was designed to amplify the genomic AcSBDS of Acanthamoeba ATCC-30010. The AcSBDS expression was examined using reverse transcription polymerase chain reaction (RT-PCR) and immunostaining after phagocytosis and encystation treatment. RESULTS: In this study, we found that the mRNA expression level of AcSBDS increased rapidly and that alternative splice variants were detected during phagocytosis and encystation processes. The results of immunofluorescence staining showed that the AcSBDS proteins accumulated surrounding phagocytosed bacteria. CONCLUSION: Our results suggest that AcSBDS may not only have ribosomal maturation features but also have cytoskeleton-associated functions related to phagocytosis and encystation.

Systemic Alpha1-Adrenoceptor Antagonists and Increased Risk of Open-Angle Glaucoma: A Nationwide Population-Based Cohort Study.

Purpose: To examine the risk of open-angle glaucoma (OAG) among patients receiving alpha1-adrenoceptor (α1-AR) antagonists for lower urinary tract symptoms (LUTS). Methods: This was a nationwide, population-based, retrospective cohort study from Asia/Taiwan. One million beneficiaries were randomly sampled from among 27.38 million individuals enrolled in the National Health Insurance program, and subjects with a diagnosis of LUTS from 2001 to 2012 were identified (N = 105,341). After 1:1 propensity score matching by gender, age, comorbid medical diseases, number of all medical visits during the observational period, and index date, 4081 patients were enrolled in the study group, comprised of patients who had taken α1-AR antagonists, and 4081 patients were enrolled in the control group, comprised of patients who had never taken α1-AR antagonists. The incidence and risk of OAG (defined as two ambulatory visits with a ICD-9 diagnosis code 365, excluding ICD-9 diagnosis codes 365.2-365.6, 365.02, 365.03, 365.13, 365.14, and 365.8) were calculated. Results: Patients taking α1-AR antagonists had a higher incidence ratio of 1.86 (95% confidence interval [CI], 1.30-2.65) for developing OAG. After adjusting for age, gender, and comorbidities, the hazard ratio (HR) for OAG for patients taking α1-AR antagonists was 1.66 (95% CI, 1.16-2.39; P = 0.006). Among patients with hypertension, the hazard ratio for OAG associated with taking α1-AR antagonists increased to 1.79 (95% CI, 1.07-2.99; P = 0.003). On the other hand, the association of α1-AR antagonists with OAG was not significant among patients with diabetes mellitus, hyperlipidemia, or older age. Conclusions: The findings of our study suggest an increased risk for OAG among patients taking α1-AR antagonists for LUTS, especially in patients with hypertension.

Characterisation of the ß-lactam resistance enzyme in Acanthamoeba castellanii.

ß-Lactams are well known as the best antibiotics for inhibiting the cross-linking between adjacent polysaccharide chains and peptides in the peptidoglycan layer of bacterial cell walls, causing bacterial cell lysis. There are no reports on the action of and resistance mechanisms to ß-lactams in protozoa. Acanthamoeba castellanii is a free-living protozoan pathogen capable of causing blinding keratitis and fatal granulomatous encephalitis. When Acanthamoeba is exposed to harsh conditions, it differentiates into the cyst stage to avoid environmental stresses, such as drug treatment. In this study, it was shown that the mature encystation rate of A. castellanii is decreased by treatment with cefotaxime (CTX) and clavulanic acid (CLA); however, the drugs do not kill the amoeba. We hypothesise that ß-lactam antibiotics may disturb synthesis of the double cell wall during the encystation process of Acanthamoeba. Interestingly, CTX is considered a powerful ß-lactam, whereas CLA is considered a weak ß-lactam but an efficient ß-lactamase inhibitor. It was demonstrated that Acanthamoeba expresses ß-lactamases to prevent inhibition of the encystation process by ß-lactams. To reveal the functions of Acanthamoeba ß-lactamases, a recombinant Acanthamoeba ß-lactamase was produced in Escherichia coli that conferred resistance to ß-lactams such as CTX, cefuroxime, penicillin and meropenem. Consequently, we suggest that Acanthamoeba produces enzymes similar to ß-lactamases to avoid interference from the environment. Here we provide a new point of view on an important gene responsible for drug resistance and advocate for the development of more efficient treatment against Acanthamoeba infection.

Non-arteritic anterior ischemic optic neuropathy with Cilioretinal artery occlusion: a case report.

BACKGROUND: To describe a peculiar case of concurrent non-arteritic anterior ischemic optic neuropathy (NAION) and cilioretinal arteries occlusion (CLRAO) without other causative agents which responded well to intravenous and intravitreal injection of corticosteroids. CASE PRESENTATION: A 41-year-old woman presented with painless vision loss in the right eye for 1 week. Fundus examinations showed marked disc swelling, flame-shaped hemorrhage over the superior nerve fiber area, and well-demarcated retinal ischemia superior to the fovea in the right eye. Under the impression of NAION with branch retinal artery occlusion, the patient was treated with intravenous and intravitreal injection of corticosteroids. Two months later, as the disc swelling and retinal ischemia resolved, we found that the occluded artery was the cilioretinal artery and not the ordinary branch retinal artery. CONCLUSIONS: CLRAO may be concomitant with the setting of NAION, the physicians should be aware that CLRAO may be misinterpreted as BRAO owing to profound disc edema during the early stages of the disease.

The Association Between Diabetes and Age-Related Macular Degeneration Among the Elderly in Taiwan.

OBJECTIVE: To investigate the relationship between diabetes and future development of age-related macular degeneration (AMD). RESEARCH DESIGN AND METHODS: Longitudinal, retrospective cohort study data for the period between 1997 and 2012 were obtained from the Longitudinal Health Insurance Database (LHID) of Taiwan. The final available 71,904 patients with diabetes and 270,213 patients without diabetes ≥50 years of age were further matched by age, sex, and Charlson comorbidity index. In the end, 54,616 study subjects in each of the diabetes and nondiabetes groups were recruited. The stratified populations of patients with diabetes with diabetic retinopathy (DR) (n = 7,119) versus those with diabetes who do not have DR (n = 7,119) and populations of patients with proliferative DR (PDR) (n = 2,134) versus those with nonproliferative DR (NPDR) (n = 2,134) were also obtained. Competing risk regression models were used to assess the adjusted hazard ratio (HR) and 99% CI. The main outcome measures were the first-ever diagnosis of AMD during the observational period. RESULTS: The incidences of nonexudative AMD (HR 1.23; P = 0.108) and exudative AMD (HR 1.37; P = 0.023) were not significantly associated with cohorts of persons with diabetes compared with cohorts without diabetes. The stratified analysis showed that nonexudative AMD (HR 3.89; P = 0.001) and exudative AMD (HR 3.42; P < 0.001) were significantly correlated to diabetes with DR cohorts, compared with diabetes without DR cohorts. The incidences of nonexudative AMD (HR 0.53; P = 0.277) and exudative AMD (HR 2.27; P = 0.058) were not significantly different between PDR cohorts compared with NPDR cohorts. CONCLUSIONS: This study provides large-scale, population-based evidence that diabetes with retinopathy is independently associated with an increased risk of subsequent AMD development.

Varicella zoster virus-associated neuroretinitis.

Varicella zoster virus-associated neuroretinitis is rare. We report a patient who presented with blurred vision of the left eye and extraocular movement pain. A fundoscopic examination revealed disc edema, hyperemia, and macular edema. The impression was neuroretinitis. Intravenous methylprednisolone pulse therapy was administered. However, visual recovery was incomplete with optical coherence tomography (OCT) imaging showing photoreceptor layer disruption. The laboratory data were rechecked and demonstrated a high varicella zoster virus immunoglobulin G titer. Varicella zoster virus-associated neuroretinitis was suspected and oral acyclovir was prescribed. His visual acuity improved to 0.9 after 2 weeks of treatment, and OCT showed photoreceptor layer restoration. Spectrum-domain OCT provides useful information when evaluating the disease course of neuroretinitis.

Enhanced PKCδ and ERK signaling mediate cell migration of retinal pigment epithelial cells synergistically induced by HGF and EGF.

Proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR) are characterized by the development of epi-retinal membranes which may exert a tractional force on retina. A lot of inflammatory growth factors may disturb the local ocular cells such as retinal pigment epithelial (RPE) cells, causing them to migrate and proliferate in the vitreous cavity and ultimately forming the PVR membrane. In this study, the signal pathways mediating cell migration of RPE induced by growth factors were investigated. Hepatocyte growth factor (HGF), epidermal growth factor (EGF) or heparin-binding epidermal growth factor (HB-EGF) induced a greater extent of migration of RPE50 and ARPE19 cells, compared with other growth factors. According to inhibitor studies, migration of RPE cells induced by each growth factor was mediated by protein kinase C (PKC) and ERK (MAPK). Moreover, HGF coupled with EGF or HB-EGF had synergistic effects on cell migration and enhanced activation of PKC and ERK, which were attributed to cross activation of growth factor receptors by heterogeneous ligands. Furthermore, using the shRNA technique, PKCδ was found to be the most important PKC isozyme involved. Finally, vitreous fluids from PVR and PDR patients with high concentration of HGF may induce RPE cell migration in PKCδ- and ERK- dependent manner. In conclusion, migration of RPE cells can be synergistically induced by HGF coupled with HB-EGF or EGF, which were mediated by enhanced PKCδ activation and ERK phosphorylation.

PKCδ-dependent signaling mediates ethambutol-induced toxic effects on human retinal pigment cells.

PURPOSE: Our previous report demonstrated that ethambutol (EMB) might induce cytoplasmic vacuolization and reduce the uptake of photoreceptor rod outer segments (ROS) in retinal pigment epithelium (RPE) cells, which are mediated via a protein kinase C (PKC)-dependent pathway. In the present study, we sought to identify the PKC isozyme(s) involved. METHODS: EMB-induced cytoplasmic vacuolization and uptake of ROS were observed under a phase contrast microscope. Western blots were performed to observe the membrane translocation of PKC isozymes and cytoplasmic release of cathepsin D. Quantitative PCR were performed to analyze gene expression of PKCδ. Human RPE cell line RPE50 and ARPE19 cells were pretreated with specific inhibitors or transfected with shRNAs of various PKC isozymes, including PKCα, ß, ε, γ, and δ, to examine whether EMB-induced toxic effects were prevented. RESULTS: In RPE50 cells, gene expression of PKCδ on both mRNA and protein levels was induced by EMB within 30 min to 3 h. EMB-induced cytoplasmic vacuolization in both RPE50 and ARPE19 cells was prevented by pretreating the cells with a specific inhibitor of PKCδ, Rottlerin, or depletion of PKCδ by shRNA. EMB-triggered reduction of ROS uptake was also significantly suppressed by pretreatment with Rottlerin, or depletion of PKCδ by shRNA technology. In contrast, pretreatment of the cells with specific inhibitors of PKCα, ß, ε, or γ, or depletion of PKCα or ß didn't influence the aforementioned EMB-triggered toxic effects. In addition, in RPE50, EMB induced the release of lysosomal enzyme cathepsin D into cytosol within 30 min to 6 h, which was also prevented by Rottlerin. CONCLUSIONS: EMB-induced vacuole formation, cytoplasmic release of cathepsin D, and reduction of phagocytosis in RPE are intimately correlated and regulated by the PKCδ signal pathway.