Microforceps-Assisted Transscleral Fixation of Intraocular Lens.

PURPOSE: We present a novel technique for intraocular lens (IOL) fixation. The technique can be used on single-piece acrylic IOLs and can manage the patients who are either aphakia or with a dislocated IOL. METHODS: One end of Gore-Tex suture is tied into the optic-haptic junction of the IOL. Another end is fixated in the scleral wall. The single sclerotomy and double sclerotomies settings can be applied to different situations. RESULTS: Twelve eyes received this procedure. After a follow-up period of up to 20 months, the IOLs were well centered. CONCLUSION: The technique is a reliable method for scleral fixation of IOLs, which can be applied on the widely used single-piece acrylic IOLs. In our experience, it is reproducible and rarely cause complications.

Orbital and conjunctival nontuberculous mycobacteria infection.

A 64-year-old female developed refractory red-eye with itching and watery discharge 2 weeks after being injured by a comb in the left eye. It presented as diffuse pinkish thickening of the bulbar conjunctiva. Biopsy and histological examinations revealed granulomatous inflammation with microgranuloma. Acid-fast-positive bacilli were found within the tissue, which was identified by culture 5 weeks later as Mycobacterium Abscessus. The orbital computed tomography with contrast medium showed irregular enhancement with an ill-defined margin along the inferior sclera. Due to symptomatic and recurrent bulbar conjunctival thickening and abscess-like lesion formations, wide excision of the conjunctival and orbital granuloma with amniotic membrane transplantation was performed twice. Conjunctiva inflammation subsided after the surgical treatment was combined with 4 months of topical and parenteral antimycobacterial treatment. The presentation, diagnosis, and treatment of ocular nontuberculous mycobacterial (NTM) infection will be discussed in this article. NTM can cause infections of all adnexal and ocular tissues in patients with ocular trauma or surgical history. The pathological findings were granulomatous inflammation without true caseating. Periocular cutaneous, adnexal, and orbital NTM infections remain rare and require surgical debridement and long-term parenteral antibiotic therapy.

Modulation of tooth regeneration through opposing responses to Wnt and BMP signals in teleosts.

Most vertebrate species undergo tooth replacement throughout adult life. This process is marked by the shedding of existing teeth and the regeneration of tooth organs. However, little is known about the genetic circuitry regulating tooth replacement. Here, we tested whether fish orthologs of genes known to regulate mammalian hair regeneration have effects on tooth replacement. Using two fish species that demonstrate distinct modes of tooth regeneration, threespine stickleback (Gasterosteus aculeatus) and zebrafish (Danio rerio), we found that transgenic overexpression of four different genes changed tooth replacement rates in the direction predicted by a hair regeneration model: Wnt10a and Grem2a increased tooth replacement rate, whereas Bmp6 and Dkk2 strongly inhibited tooth formation. Thus, similar to known roles in hair regeneration, Wnt and BMP signals promote and inhibit regeneration, respectively. Regulation of total tooth number was separable from regulation of replacement rates. RNA sequencing of stickleback dental tissue showed that Bmp6 overexpression resulted in an upregulation of Wnt inhibitors. Together, these data support a model in which different epithelial organs, such as teeth and hair, share genetic circuitry driving organ regeneration.

Beneficial effects of an endogenous enrichment in n3-PUFAs on Wnt signaling are associated with attenuation of alcohol-mediated liver disease in mice.

Alcohol-associated liver disease (ALD) is a major human health issue for which there are limited treatment options. Experimental evidence suggests that nutrition plays an important role in ALD pathogenesis, and specific dietary fatty acids, for example, n6 or n3-PUFAs, may exacerbate or attenuate ALD, respectively. The purpose of the current study was to determine whether the beneficial effects of n3-PUFA enrichment in ALD were mediated, in part, by improvement in Wnt signaling. Wild-type (WT) and fat-1 transgenic mice (that endogenously convert n6-PUFAs to n3) were fed ethanol (EtOH) for 6 weeks followed by a single LPS challenge. fat-1 mice had less severe liver damage than WT littermates as evidenced by reduced plasma alanine aminotransferase, hepatic steatosis, liver tissue neutrophil infiltration, and pro-inflammatory cytokine expression. WT mice had a greater downregulation of Axin2, a key gene in the Wnt pathway, than fat-1 mice in response to EtOH and LPS. Further, there were significant differences between WT and fat-1 EtOH+LPS-challenged mice in the expression of five additional genes linked to the Wnt signaling pathway, including Apc, Fosl1/Fra-1, Mapk8/Jnk-1, Porcn, and Nkd1. Compared to WT, primary hepatocytes isolated from fat-1 mice exhibited more effective Wnt signaling and were more resistant to EtOH-, palmitic acid-, or TNFα-induced cell death. Further, we demonstrated that the n3-PUFA-derived lipid mediators, resolvins D1 and E1, can regulate hepatocyte expression of several Wnt-related genes that were differentially expressed between WT and fat-1 mice. These data demonstrate a novel mechanism by which n3-PUFAs can ameliorate ALD.

Fungi.guru: Comparative genomic and transcriptomic resource for the fungi kingdom.

The fungi kingdom is composed of eukaryotic heterotrophs, which are responsible for balancing the ecosystem and play a major role as decomposers. They also produce a vast diversity of secondary metabolites, which have antibiotic or pharmacological properties. However, our lack of knowledge of gene function in fungi precludes us from tailoring them to our needs and tapping into their metabolic diversity. To help remedy this, we gathered genomic and gene expression data of 19 most widely-researched fungi to build an online tool, fungi.guru, which contains tools for cross-species identification of conserved pathways, functional gene modules, and gene families. We exemplify how our tool can elucidate the molecular function, biological process and cellular component of genes involved in various biological processes, by identifying a secondary metabolite pathway producing gliotoxin in Aspergillus fumigatus, the catabolic pathway of cellulose in Coprinopsis cinerea and the conserved DNA replication pathway in Fusarium graminearum and Pyricularia oryzae. The tool is available at www.fungi.guru.

Dermis-fat graft as treatment of early implant exposure in a postpenetrating keratoplasty patient with nontraumatic eyeball rupture.

Orbital implant exposure may be the most common complication after evisceration surgery with orbital implantation. Management of implant exposure is a vital issue for oculoplastic surgeons. We present the case of a patient with nontraumatic eyeball rupture receiving dermis-fat graft after early implant exposure. The present case with multiple penetrating keratoplasty history underwent emergent evisceration and silicon sphere implantation due to nontraumatic eyeball rupture with severe uvea prolapse. The surrounding corneal tissue of the rupture aperture was almost unidentified before the operation. Deep superior sulcus syndrome and orbital implant exposure developed 2 months after the operation; hence, orbital reconstruction and dermis-fat graft transplantation were performed. Orbital reconstruction and orbital implant exposure management are discussed in the content.

Risk of skin cancer in patients with pterygium: a nationwide population-based cohort study in Taiwan.

This study investigated the association between pterygium and skin cancer linking to ultraviolet (UV) radiation using claims data from 1997-2010, obtained from the Taiwan National Health Insurance Research Database. The study included 19,701 patients with pterygium and 78,804 sex- and age-frequency-matched comparison subjects. Multivariate Cox regression analyses were performed to assess the relationship between pterygium and risk of skin cancer by the end of 2010. The incidence rates of malignant melanoma (MM) and nonmelanoma skin cancer (NMSC) in two cohorts and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of the diseases were measured. Results showed that the incidences of MM and NMSC were both higher in the pterygium cohort than in the comparison cohort (5.5 vs 3.2 and 32.3 vs 15.0 per 100,000 person years, respectively). After adjusting for age, sex, UV index, occupation, and the other comorbidities, pterygium remained a significant predictor of NMSC (hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.11-2.42), but not MM (HR, 1.46; 95% CI, 0.59-3.65). These results suggest that pterygium patients are associated with an increased risk of NMSC, but not significant for MM.

Atypical Rosai-Dorfman disease with lacrimal gland involvement.

PURPOSE: Rosai-Dorfman disease is a rare, benign, idiopathic histocytic proliferative disorder that typically presents in young adults with painless cervical lymphadenopathy. Here we report an atypical case of Rosai-Dorfman disease involving orbit tissue and lacrimal gland, unilaterally. CASE: A 69-year-old Asian women developed a painless palpable mass with local edema over the left upper eyelid over several months. Computed tomography (CT) showed an orbital mass with homogenous soft tissue density over the left lacrimal gland and superior orbital area. The patient underwent complete excision of the orbital tumor. OBSERVATIONS: The histopathology revealed diffuse and nodular infiltrations of S-100 positive histiocytes, plasma cells and lymphocytes. Emperipolesis (lymphocytophagocytosis) was also noted. These findings were consistent with Rosai-Dorfman disease. Chest CT revealed hilar lymphadenopathy. Three months after excision of the orbital mass, the patient developed lymphadenopathy in the extremities that resolved spontaneously over a few weeks. There were no complications or recurrence without systemic treatment after the complete excision. CONCLUSIONS: Orbital Rosai-Dorfman disease is a rare disorder, especially in Asia. Though there is no consensus on therapeutic choices, including corticosteroids, chemotherapy, radiation therapy, and surgical excision, the complete surgical excision performed in this case was without complication and had a favorable outcome.

Normal myofibrillar development followed by progressive sarcomeric disruption with actin accumulations in a mouse Cfl2 knockout demonstrates requirement of cofilin-2 for muscle maintenance.

Cofilin-2, a small actin-binding protein and member of the AC protein family that includes cofilin-1 and destrin, is predominantly expressed at sarcomeres in skeletal and cardiac muscles. The role of cofilin-2 in muscle development and function is unclear. In humans, recessive cofilin-2 mutations have been associated with nemaline myopathy with minicores. To investigate the functional role of cofilin-2 in vivo, we generated constitutive and muscle-specific cofilin-2-deficient mice using a cre-loxP strategy. Cofilin-2-deficient mice were similar to their wild-type (WT) littermates at birth, but died by day 8. They were significantly smaller, severely weak and had very little milk in their stomachs. The sarcomeric structure was intact at birth, but by Day 7, skeletal muscles showed severe sarcomeric disruptions starting at the Z-line, along with filamentous actin accumulations consistent with a lack of actin depolymerization activity. Cofilin-2-deficient muscles contained elevated numbers of slow fibers and exhibited upregulation of slow fiber-specific genes. Increased amounts of other sarcomeric proteins including α-actinin-2, α-sarcomeric actin and tropomyosin were also present. While destrin was not expressed in either WT or cofilin-2-deficient muscles, cofilin-1 was similarly expressed in developing myofibers of both genotypes. There was no evidence for compensatory changes in expression of either family member in cofilin-2-deficient tissues. The onset of pathology and weakness in cofilin-2-deficient muscles correlated with normal developmental loss of cofilin-1 expression within myofibers, suggesting that cofilin-1 serves as an early developmental sarcomeric isoform. Overall, cofilin-2, although not critical for muscle development, is essential for muscle maintenance.

Polymorphisms in steroidogenesis genes, sex steroid levels, and high myopia in the Taiwanese population.

PURPOSE: To evaluate the relationship among single nucleotide polymorphisms (SNPs) in steroidogenesis enzyme genes, serum levels of sex steroids, and high myopia in Taiwanese male and female populations. METHODS: A campus-based sample of 283 cases (145 males and 138 females) with high myopia and 280 controls (144 males and 136 females) with low myopia or emmetropia was studied. Estradiol, progesterone, and testosterone levels were determined using enzyme-linked immunosorbent assay kits. We genotyped six SNPs within five steroidogenesis enzyme genes (17 alpha-hydroxylase/17,20 lyase [CYP17A1], 3 beta-hydroxysteroid dehydrogenase [HSD3B1], 17 beta-hydroxysteroid dehydrogenase 1 [HSD17B1], steroid-5-alpha-reductase, alpha polypeptide 2 [SRD5A2], and aromatase [CYP19A1]) using polymerase chain reaction-restriction fragment length polymorphism methods. Student's t-tests, χ(2) tests, logistic regression, multifactor dimensionality reduction (MDR) methods, and ANOVA were used to determine significance. RESULTS: An MDR analysis corroborated the synergistic genotype association and demonstrated that synergistic interaction between rs6203 (HSD3B1), rs10046 (CYP19A1), and sex might confer susceptibility to high myopia (p=0.019). In both male and female subjects, levels of testosterone were significantly higher in cases than in controls; in male subjects, the levels of estradiol were significantly higher and those of progesterone were significantly lower in cases (all p-values <0.001). The rs605059 (HSD17B1), with sex-gene interaction, showed association with estradiol levels in males (p=0.035) and testosterone levels in females (p=0.027). CONCLUSIONS: Testosterone levels correlate with high myopia, and interaction of steroidogenesis enzyme genes and sex may be a modulating factor in sex hormone metabolism and high-myopia risk.

The association of haplotype at the lumican gene with high myopia susceptibility in Taiwanese patients.

OBJECTIVE: To investigate the association of genetic polymorphisms in the dermatan sulfate proteoglycan 3 (DSPG3), lumican (LUM), and decorin (DCN) genes (component genes of the sclera) with high myopia susceptibility in Taiwanese people. DESIGN: Prospective case-control study. PARTICIPANTS: Hospital clinic-based samples of 120 unrelated patients with extremely high myopia were studied. One hundred thirty-seven unrelated emmetropic individuals served as controls. METHODS: Four, 8, and 4 single nucleotide polymorphism (SNPs) were genotyped within the DSPG3, lumican, and decorin genes, respectively, using direct DNA sequencing. Pairwise linkage disequilibrium, haplotype analysis, adjusted logistic regression, and multifactor dimensionality reduction (MDR) methods were used to determine significant associations. MAIN OUTCOME MEASURES: The association of haplotypes at the lumican gene with high myopia development. RESULTS: The lumican gene SNP rs3759223:T-->C demonstrated a significant association with high myopia (P = 2.83 x 10(-4)). Four lumican SNPs showed significant linkage disequilibrium and formed a haplotype block. Sliding window haplotype analyses revealed that the block consisting of rs3759223 and rs3741834 showed significant goodness of fit (global P = 1.0725 x 10(-6)). Haplotype-specific tests showed that the C-C and T-C haplotypes were associated significantly with high myopia, with odds ratios (95% confidence intervals) of 19.32 (2.55-146.54) and 0.69 (0.46-1.04), respectively. rs3759223 and rs3741834 are in a putative regulatory element of the lumican gene, which influences fibrillogenesis of scleral collagen fibers and the development of myopia. The results of an MDR analysis corroborated the single-locus association and suggested a significant 2-locus interaction model composed of SNPs rs2300588 and rs3741834 in the lumican gene. CONCLUSIONS: Genetic variation in the regulatory domains of the lumican gene, where both rs3759223 and rs3741834 are located, are associated with high myopia susceptibility among the Han Chinese, making this region worthy of further investigation.

The association of membrane frizzled-related protein (MFRP) gene with acute angle-closure glaucoma--a pilot study.

PURPOSE: The membrane frizzled-related protein (MFRP) has been proposed as a probable candidate gene for extreme hyperopia and nanophthalmos, which are factors for angle-closure glaucoma. The purpose of our study was to investigate whether there are significant associations between angle-closure glaucoma and sequence variants in the MFRP gene reported previously in Taiwanese subjects. METHODS: Genomic DNA was collected from 63 subjects with angle-closure glaucoma and 66 age-matched and gender-matched controls without angle-closure glaucoma. Three sequence variants were detected by polymerase chain reaction (PCR) and direct sequencing in all of the cases and controls. RESULTS: None of the three sequence variants showed a significant result in terms of association with disease. The pairwise linkage disequilibrium (LD) mapping confirmed that these alleles have a comparatively strong LD index greater than 0.7 for D' and greater than 0.4 for r(2) at these polymorphisms. However, we found there were no statistical associations between any of the three sequence variants located on MFRP and angle-closure glaucoma. CONCLUSIONS: In our pilot study, variations that we tested in MFRP were not associated with the development of acute angle-closure glaucoma in Taiwanese subjects.

Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category.

Experimental autoimmune uveitis (EAU) represents autoimmune uveitis in humans. We examined the role of the interleukin (IL)-23-IL-17 and IL-12-T helper cell (Th)1 pathways in the pathogenesis of EAU. IL-23 but not IL-12 was necessary to elicit disease by immunization with the retinal antigen (Ag) interphotoreceptor retinoid-binding protein (IRBP) in complete Freund's adjuvant. IL-17 played a dominant role in this model; its neutralization prevented or reversed disease, and Th17 effector cells induced EAU in the absence of interferon (IFN)-gamma. In a transfer model, however, a polarized Th1 line could induce severe EAU independently of host IL-17. Furthermore, induction of EAU with IRBP-pulsed mature dendritic cells required generation of an IFN-gamma-producing effector response, and an IL-17 response by itself was insufficient to elicit pathology. Finally, genetic deficiency of IL-17 did not abrogate EAU susceptibility. Thus, autoimmune pathology can develop in the context of either a Th17 or a Th1 effector response depending on the model. The data suggest that the dominant effector phenotype may be determined at least in part by conditions present during initial exposure to Ag, including the quality/quantity of Toll-like receptor stimulation and/or type of Ag-presenting cells. These data also raise the possibility that the nonredundant requirement for IL-23 in EAU may extend beyond its role in promoting the Th17 effector response and help provide a balance in the current Th1 versus Th17 paradigm.

Topical administration of a multi-targeted kinase inhibitor suppresses choroidal neovascularization and retinal edema.

Age-related macular degeneration, diabetic retinopathy, and retinal vein occlusions are complicated by neovascularization and macular edema. Multi-targeted kinase inhibitors that inhibit select growth factor receptor tyrosine kinases and/or components of their down-stream signaling cascades (such as Src kinases) are rationale treatment strategies for these disease processes. We describe the discovery and characterization of two such agents. TG100572, which inhibits Src kinases and selected receptor tyrosine kinases, induced apoptosis of proliferating endothelial cells in vitro. Systemic delivery of TG100572 in a murine model of laser-induced choroidal neovascularization (CNV) caused significant suppression of CNV, but with an associated weight loss suggestive of systemic toxicity. To minimize systemic exposure, topical delivery of TG100572 to the cornea was explored, and while substantial levels of TG100572 were achieved in the retina and choroid, superior exposure levels were achieved using TG100801, an inactive prodrug that generates TG100572 by de-esterification. Neither TG100801 nor TG100572 were detectable in plasma following topical delivery of TG100801, and adverse safety signals (such as weight loss) were not observed even with prolonged dosing schedules. Topical TG100801 significantly suppressed laser-induced CNV in mice, and reduced fluorescein leakage from the vasculature and retinal thickening measured by optical coherence tomography in a rat model of retinal vein occlusion. These data suggest that TG100801 may provide a new topically applied treatment approach for ocular neovascularization and retinal edema.

SCH 412499: biodistribution and safety of an adenovirus containing P21(WAF-1/CIP-1) following subconjunctival injection in Cynomolgus monkeys.

Monkey studies were conducted for the preclinical safety assessment of SCH 412499, an adenovirus encoding p21, administered by subconjunctival injection prior to trabeculectomy for postoperative maintenance of the surgical opening. Biodistribution of SCH 412499 was minimal and there was no systemic toxicity. Findings included swollen, partially closed or shut eye(s) and transient congestion in the conjunctiva. A mononuclear cell infiltrate was present in the conjunctiva, choroid and other ocular tissues, but completely or partially resolved over time. Electroretinograms and visual evoked potentials revealed no adverse findings. Thus, the findings are not expected to preclude the clinical investigation of SCH 412499.

p21WAF-1/Cip-1 gene therapy as an adjunct to glaucoma filtration surgery.

Glaucoma is a blinding eye disease characterized by elevated intraocular pressure (IOP). Glaucoma filtration surgery (GFS) is designed to reduce IOP, but wound healing responses to the procedure can result in surgical failure. Anti-metabolites used in conjunction with GFS are commonly employed to control the wound healing response, but have unwanted side effects. This review describes the therapeutic potential of ocular gene therapy using an adenovirus vector containing the human p21WAF-1/Cip-1 gene (rAd-p21) to control unwanted wound healing post-GFS. Here, we summarize encouraging preclinical data in relevant models, and propose rAd-p21 gene therapy as an alternative to the currently used methods of wound healing modulation.