Candidate Modifier Genes for the Penetrance of Leber's Hereditary Optic Neuropathy.

Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disease caused by mitochondria DNA (mtDNA) mutation. It is characterized by acute and subacute visual loss predominantly affecting young men. The mtDNA mutation is transmitted to all maternal lineages. However, only approximately 50% of men and 10% of women harboring a pathogenic mtDNA mutation develop optic neuropathy, reflecting both the incomplete penetrance and its unexplained male prevalence, where over 80% of patients are male. Nuclear modifier genes have been presumed to affect the penetrance of LHON. With conventional genetic methods, prior studies have failed to solve the underlying pathogenesis. Whole exome sequencing (WES) is a new molecular technique for sequencing the protein-coding region of all genes in a whole genome. We performed WES from five families with 17 members. These samples were divided into the proband group (probands with acute onset of LHON, n = 7) and control group (carriers including mother and relative carriers with mtDNSA 11778 mutation, without clinical manifestation of LHON, n = 10). Through whole exome analysis, we found that many mitochondria related (MT-related) nuclear genes have high percentage of variants in either the proband group or control group. The MT genes with a difference over 0.3 of mutation percentage between the proband and control groups include AK4, NSUN4, RDH13, COQ3, and FAHD1. In addition, the pathway analysis revealed that these genes were associated with cofactor metabolism pathways. Family-based analysis showed that several candidate MT genes including METAP1D (c.41G > T), ACACB (c.1029del), ME3 (c.972G > C), NIPSNAP3B (c.280G > C, c.476C > G), and NSUN4 (c.4A > G) were involved in the penetrance of LHON. A GWAS (genome wide association study) was performed, which found that ADGRG5 (Chr16:575620A:G), POLE4 (Chr2:7495872T:G), ERMAP (Chr1:4283044A:G), PIGR (Chr1:2069357C:T;2069358G:A), CDC42BPB (Chr14:102949A:G), PROK1 (Chr1:1104562A:G), BCAN (Chr 1:1566582C:T), and NES (Chr1:1566698A:G,1566705T:C, 1566707T:C) may be involved. The incomplete penetrance and male prevalence are still the major unexplained issues in LHON. Through whole exome analysis, we found several MT genes with a high percentage of variants were involved in a family-based analysis. Pathway analysis suggested a difference in the mutation burden of MT genes underlining the biosynthesis and metabolism pathways. In addition, the GWAS analysis also revealed several candidate nuclear modifier genes. The new technology of WES contributes to provide a highly efficient candidate gene screening function in molecular genetics.

Acute Invasive Fungal Rhinosinusitis-Related Orbital Infection: A Single Medical Center Experience.

BACKGROUNDS: Acute invasive fungal rhinosinusitis (AIFRS) is a hazardous infectious disease with rapid progression and high mortality and morbidities. Further orbital involvement is commonly seen. This study aims to analyze risk factors, clinical characteristics, and outcomes between patients with or without orbital involvement. METHODS: A retrospective review was performed in a single tertiary medical center over a span of 13 years (2005-2018). A total of 21 patients with diagnosis of AIFRS were enrolled. We reviewed the patients' basic characteristics, comorbidities, clinical presentations, image study findings, culture pathogens, and treatment outcomes and analyzed the differences between orbital-involved and orbital sparing disease. RESULTS: The most common comorbidities in AIFRS were diabetes mellitus (DM) and hematological malignancy. Nine the 21 AIFRS patients had orbital-involved disease. Patients with orbital involvement had a higher prevalence of DM (p < 0.05). Image studies revealed significant infection of the ethmoid sinus, sphenoid sinus, and frontal sinus in the group with orbital complication (p < 0.05). Mucor, Rhizopus, and Aspergillus were cultured in both groups. Five patients in the orbital involvement group expired, with all of them having an initial presentation of conscious disturbance (p < 0.01). Rhino-orbital-cerebral fungal infection was noticed in 3 of the 5 expired patients. CONCLUSION: In AIFRS patients, DM other than hematological malignancy was the main risk factor for orbital-involved disease. Patients with ethmoid, sphenoid, or frontal sinusitis had a higher possibility of orbital complication. Poor consciousness at initial presentation revealed highest possibility of rhino-orbital-cerebral fungal infection and led to death.

The association of dry eye syndrome and psychiatric disorders: a nationwide population-based cohort study.

BACKGROUND: Several previous studies reported a greater prevalence of dry eye syndrome (DES) among patients with psychiatric diseases. The aim of this study is to investigate the prevalence and risk factors of DES in patients with psychiatric disorders (PD) using nationwide population-based data in Taiwan. METHODS: This population-based cohort study retrospectively identified patients with PD from 1997 to 2011. Patients with both PD and DES served as the DES cohort, and PD patients without DES comprised the non-DES cohort. PD was defined as a diagnosis of PD (ICD-9-CM 290-319) made by psychiatrists only, with at least three consecutive outpatient visits or at least one inpatient visit. DES was defined as a diagnosis of DES (ICD-9-CM 375.15) and a prescription for an eye lubricant (anatomical therapeutic chemical code, ATC code: S01XA). The main outcome measures were the prevalence of DES in these patients and associated risk factors. RESULTS: A total of 75,650 patients with PD (3665 in the DES cohort and 71,985 in the non-DES cohort) were included in the final analysis. The majority of patients in the DES group were women (72.6%), compared the non-DES group (57.8%). The mean age of patients in the DES cohort was 62.2 ± 14.9, which was significantly older than those in the non-DES group (50.9 ± 17.5). The patients with DES had a significantly greater likelihood of having dementia, bipolar disorder, depression, and neurotic disorders. Conditional regression analyses revealed that patients with dry eye disease were more likely to have schizophrenia (OR = 1.34), bipolar disorder (OR = 1.9), depression (OR = 1.54), and neurotic disorders (OR = 1.62). In addition, patients with DES were more likely to use 1st generation anti-psychotics (OR = 1.28) and had a lower risk of using 2nd generation anti-psychotics (OR = 0.64). CONCLUSION: The study demonstrated that among PD patients, DES is highly prevalence in certain subtypes of PD, such as depression, bipolar disorder, and neurotic disorders, after adjusting for the comorbidities.

Association between Metformin and a Lower Risk of Age-Related Macular Degeneration in Patients with Type 2 Diabetes.

PURPOSE: This population-based, retrospective cohort study was to investigate whether metformin is associated with a lower risk of subsequent age-related macular degeneration (AMD) in patients with type 2 diabetes. METHODS: Using the Taiwan National Health Insurance Research Database from 2001 to 2013, 68205 subjects with type 2 diabetes were enrolled in the study cohort. Among them, 45524 were metformin users and 22681 were nonusers. The metformin and nonmetformin groups were followed until the end of 2013. Cox regression analyses were used to estimate hazard ratios (HRs) for AMD development associated with metformin use. Confounders included for adjustment were age, sex, and comorbidities (hypertension, hyperlipidemia, coronary artery disease, obesity, diabetic retinopathy, chronic kidney disease, and insulin treatment). Furthermore, propensity score (PS) matching method was used to choose the matched sample, and PS-adjusted Cox regression was performed. Finally, how HRs changed according to metformin treatment duration and dose was also evaluated in the metformin group. RESULTS: After adjusting for confounders, the metformin group had a significantly lower risk of AMD (adjusted HR = 0.54; 95% confidence interval [CI], 0.50-0.58). In the PS-matched sample, the significance remained (adjusted HR = 0.57; 95% CI, 0.52-0.63). In the metformin group, the adjusted HRs for the second (1.5-4 years) and third (≥4 years) tertiles of metformin treatment duration were 0.52 and 0.14, respectively, compared with the first tertile (<1.5 years). We also found significant trends of lower HRs (all p-value for trend <0.05) with increasing total and average doses. CONCLUSIONS: Among patients with type 2 diabetes, those who use metformin are at a significantly lower risk of developing AMD relative to individuals who do not use metformin. Also, the trend of a significantly lower AMD risk was found with a higher dose of metformin.

Association between normal tension glaucoma and the risk of Alzheimer's disease: a nationwide population-based cohort study in Taiwan.

OBJECTIVES: To investigate a possible association between normal tension glaucoma (NTG) and an increased risk of developing Alzheimer's disease (AD). DESIGN: Retrospective cohort study. SETTING: NTG group and the comparison group were retrieved from the whole population of the Taiwan National Health Insurance Research Database from 1 January 2001 to 31 December 2013. PARTICIPANTS: A total of 15 317 subjects with NTG were enrolled in the NTG group, and 61 268 age-matched and gender-matched subjects without glaucoma were enrolled in the comparison group. PRIMARY AND SECONDARY OUTCOME MEASURES: Kaplan-Meier curves were generated to compare the cumulative hazard of AD between the two groups. A multivariable Cox regression analysis was used to estimate the adjusted hazard ratios (HRs) of AD, adjusted for diabetes, hypertension, hyperlipidaemia, coronary artery disease and stroke. Furthermore, risk factors for developing AD among the NTG group were investigated. RESULTS: The mean age of the cohort was 62.1±12.5 years. Patients with NTG had significantly higher proportions of diabetes, hypertension, hyperlipidaemia, coronary artery disease and stroke than the comparisons. Patients with NTG had a significantly higher cumulative hazard for AD than the comparisons (p<0.0001). In the multivariable Cox regression after adjustment for confounders, the NTG group had a significantly higher risk of AD (adjusted HR 1.52; 95% CI 1.41 to 1.63). Moreover, in the NTG group, when we compared the effects of different types of glaucoma eye drops, none of the eye drops used were significant risk factors or protective factors for AD. CONCLUSIONS: People with NTG are at a significantly greater risk of developing AD compared with individuals without glaucoma. Among patients with NTG, none of the glaucoma eye drops used significantly changed the risk of subsequent AD.

Analysis of the Interleukin-6 (-174) Locus Polymorphism and Serum IL-6 Levels with the Severity of Normal Tension Glaucoma.

PURPOSE: In normal tension glaucoma (NTG), factors other than elevated intraocular pressure are likely to have a role in the pathogenesis of optic neuropathy. Recent studies of glaucoma or retinal ganglion cells (RGCs) reveal that the cytokine interleukin-6 (IL-6) is linked to the pathogenesis of glaucoma and may regulate RGC survival or death. The IL-6 (-174) G allele has also been shown to increase the IL-6 protein. We hypothesized that the IL-6 (-174) polymorphism may be a predisposing genetic factor affecting the severity of glaucoma. The aim of the present study was to evaluate the IL-6 polymorphism and serum IL-6 levels as a potential risk factor related to the severity of NTG. METHODS: A total of 256 subjects with NTG in the Chinese population were enrolled. The patients were genotyped for the IL-6 (-174) C/G polymorphism. Genomic DNA was amplified by a polymerase chain reaction, followed by the enzymatic restriction fragment length polymorphism technique. Serum IL-6 levels were measured by ELISA. Patient age at diagnosis, cup/disc (C/D) ratio, rim area (RA), retinal nerve fiber layer (RNFL) thickness, and visual field (VF) were analyzed. The associations between genotypes of IL-6 (-174) C/G and the clinical parameters were calculated using a logistic regression. RESULTS: The IL-6 (-174) GC genotype in NTG patients was significantly associated with a smaller C/D ratio (p = 0.04), larger RA (p = 0.04), and thicker RNFL (p = 0.05) compared with IL-6 (-174) GG patients. The allele frequency of IL-6 (-174) C was significantly higher in the NTG patients at an early-moderate stage than at an advanced stage according to the C/D ratio (OR 0.55; 95% CI 0.31-0.99). Pattern standard deviation of VF was borderline lower in IL-6 (-174) GC patients (p = 0.06), and serum IL-6 levels were borderline higher in advanced stages than in early-moderate stages (7.66 ± 3.22 vs. 4.46 ± 3.83 pg/mL; p = 0.06). CONCLUSION: The IL-6 (-174) GC genotype is associated with a smaller C/D ratio, larger RA, and thicker RNFL compared with IL-6 (-174) GG in NTG patients. We found that the IL-6 (-174) G/C polymorphism and serum IL-6 levels may be associated with the severity of NTG.

Pharmacokinetics and safety of intravitreal caspofungin.

Caspofungin exhibits potent antifungal activities against Candida and Aspergillus species. The elimination rate and retinal toxicity of caspofungin were determined in this study to assess its pharmacokinetics and safety in the treatment of fungal endophthalmitis. Intravitreal injections of 50 µg/0.1 ml of caspofungin were administered to rabbits. Levels of caspofungin in the vitreous and aqueous humors were determined using high-performance liquid chromatography (HPLC) at selected time intervals (10 min and 1, 2, 4, 8, 16, 24, and 48 h), and the half-lives were calculated. Eyes were intravitreally injected with caspofungin to obtain concentrations of 10 µg/ml, 50 µg/ml, 100 µg/ml, and 200 µg/ml. Electroretinograms were recorded 4 weeks after injections, and the injected eyes were examined histologically. The concentrations of intravitreal caspofungin at various time points exhibited an exponential decay with a half-life of 6.28 h. The mean vitreous concentration was 6.06 ± 1.76 µg/ml 1 h after intravitreal injection, and this declined to 0.47 ± 0.15 µg/ml at 24 h. The mean aqueous concentration showed undetectable levels at all time points. There were no statistical differences in scotopic a-wave and b-wave responses between control eyes and caspofungin-injected eyes. No focal necrosis or other abnormality in retinal histology was observed. Intravitreal caspofungin injection may be considered to be an alternative treatment for fungal endophthalmitis based on its antifungal activity, lower retinal toxicity, and lower elimination rate in the vitreous. More clinical data are needed to determine its potential role as primary therapy for fungal endophthalmitis.

Pterygium is related to a decrease in corneal endothelial cell density.

PURPOSE: The aim of this study was to investigate the relationship between pterygium and a decrease in the corneal endothelial cell density (ECD) in patients with unilateral primary pterygium. METHODS: In this retrospective cross-sectional study, 90 consecutive patients with unilateral primary pterygium were enrolled from January 2010 to June 2012. Corneal ECD was measured in both eyes, and the fellow eyes were considered as controls. The relationship between the percentage of pterygium to cornea and a decrease in the ECD was analyzed. An increase in astigmatism in eyes with pterygium was evaluated for association with decreased ECD using the Pearson correlation test. RESULTS: The percentage of pterygium to cornea ranged from 3.5% to 65.2%, with a median of 12.35%. The difference in the corneal ECD between eyes with pterygium and control eyes ranged from +9.6% to -37.7%, with a median of -9.75%. The results of the Pearson correlation statistical test showed a strong logarithmic correlation between a decrease in the corneal ECD and the percentage of pterygium to cornea (R = 0.688, P < 0.001). An increase in astigmatism was correlated with a decrease in the ECD in eyes with pterygium. CONCLUSIONS: Pterygium is related to a decrease in corneal ECD. Surgical intervention should be considered in patients with extensive pterygium involvement in the cornea or a significant increase in astigmatism.

Receptor for advanced glycation end products is upregulated in optic neuropathy of Alzheimer's disease.

Although Alzheimer's disease (AD) has been shown to be associated with a true primary optic neuropathy, the underlying pathophysiology of this disease and in particular the optic nerve disorder is still poorly understood. The receptor for advanced glycation end products (RAGE) has been implicated in the pathogenesis of AD by mediating the transport of plasma amyloid-beta into the brain. Once ligated, RAGE can play a role in signal transduction, leading to amplification and perpetuation of inflammatory processes. As a key player in the reaction to CNS injury, astrocytes have been shown to associate with RAGE in a number of diseases, including AD. To investigate the role of RAGE and astrocytes in the pathogenesis of AD optic neuropathy, we conducted immunohistochemical studies to examine the presence of RAGE in donor eyes from patients with AD (n = 10) and controls (n = 3). Both qualitative observation and quantitative analyses using imaging software were used to document the extent of RAGE in the neural tissues. The intensity and extent of RAGE expression was more prominent in AD nerves compared to controls (P < 0.05). The RAGE immunoreactivity was observed in the microvasculature and in close proximity to astrocytic processes. While RAGE immunoreactivity increased with age, the increase was more precipitous in the AD group compared to the controls. The up-regulation of RAGE in the AD optic nerves indicates that RAGE may play a role in the pathophysiology of AD optic neuropathy.