HMGB1 in the pathogenesis of ultraviolet-induced ocular surface inflammation.

High-mobility group box 1 (HMGB1) functions as a transcription-enhancing nuclear protein as well as a crucial cytokine that regulates inflammation. This study demonstrated that secretion of HMGB1 due to ultraviolet (UV) radiation inducing ocular surface inflammation-mediated reactive oxygen species (ROS) production. After treating conjunctival epithelial cells with UV radiation, HMGB1 was translocated from the nucleus to the cytoplasm and then eventually to the extracellular space. HMGB1 played a crucial role in UV-induced conjunctival neutrophil infiltration, which subsided when mice were pretreated with the HMGB1 inhibitors soluble receptor for advanced glycation endproducts (sRAGEs) and HMGB1 A box protein. In case of using ROS quencher, there was decrease in UV-induced HMGB1 secretion in conjunctival epithelial cells and mice. Considering that UV-induced chronic inflammation causes ocular surface change as pterygium, we have confirmed high HMGB1 translocation and ROS expression in human pterygium. Our findings therefore revealed a previously unknown mechanism of UV-induced ocular inflammation related to ROS and HMGB1 suggesting a new medical therapeutic target.

Internal spherical aberration by ray tracing-type aberrometry in multifocal pseudophakic eyes.

PURPOSE: To demonstrate the results of the ray tracing-type aberrometer in measuring spherical aberration (SA) in pseudophakic eyes with monofocal intraocular lens (IOL), aspheric monofocal IOL, or aspheric diffractive multifocal IOL. METHODS: Total, corneal, and internal SA were measured using iTrace at a 6-mm pupil size in 27 eyes of 27 patients implanted with a monofocal spherical IOL (group 1: Natural, SN60AT), 30 eyes of 30 patients implanted with a monofocal aspheric IOL (group 2: IQ, SN60WF), and 30 eyes of 30 patients implanted with a multifocal aspheric IOL (group 3: ReSTOR, SN6AD1) at 3 months after cataract surgery. We compared the internal SAs of these IOLs in pupil sizes of 3, 4, 5, and 6 mm. RESULTS: There were no demographic statistically significant differences among the groups. The internal SA of group 1 had a positive value. The internal SA of group 2 was -0.175 ± 0.135 µm in 5-mm pupils and -0.227 ± 0.253 µm in 6-mm pupils. The internal SA of group 3 was -0.072 ± 0.128 µm in 5-mm pupils and -0.173 ± 0.231 µm in 6-mm pupils. CONCLUSION: Measuring internal SA with iTrace yields relatively accurate results in all types of IOLs with adequate pupil sizes.

Comparison of patient outcomes after implantation of Visian toric implantable collamer lens and iris-fixated toric phakic intraocular lens.

PURPOSE: We compared visual and refractive outcomes after implantation of Visian toric implantable collamer lenses (toric ICLs) and iris-fixated toric pIOLs (toric Artisans). PATIENTS AND METHODS: A comparative retrospective analysis was performed. Toric ICLs were implanted into 30 eyes of 18 patients, and toric Artisans into 31 eyes of 22 recipients. We measured the logarithms of the minimum angle of resolution of uncorrected visual acuity (logMAR UCVA), logMAR of best spectacle-corrected corrected VA (logMAR BSCVA), MR, SE, and astigmatism (by the power vector method) before surgery and 1, 3, and 6 months thereafter. Differences between patients receiving each type of lens were compared by using a mixed model of repeated measures. RESULTS: Visual improvements were evident after operation in both groups. By comparing the attempted to the achieved SE values, we were able to confirm that correction of refractive error was similar in both groups. However, the logMAR UCVA was significantly higher in the toric ICL group at all postoperative time points. Although manifest cylinder power and astigmatism (calculated by using the power vector method) gradually decreased in the toric ICL group, cylinder power 1 month postoperatively increased from -2.62 to -2.75 D; astigmatism was also increased at this time in the toric Artisan group. CONCLUSION: The two tested toric pIOLs were similar in terms of the ability to correct refractive error, as assessed 3 months postoperatively. However toric ICLs corrected astigmatism more rapidly and safely. Notably, the large difference in astigmatism level between the two groups 1 month postoperatively indicates that toric ICLs are more effective when used to correct astigmatism.

Comparison of laser epithelial keratomileusis and photorefractive keratectomy for low to moderate myopia.

PURPOSE: To compare the effectiveness, safety, and stability of laser epithelial keratomileusis (LASEK), a modified photorefractive keratectomy (PRK) technique, with those of conventional PRK for low to moderate myopia. SETTING: Department of Ophthalmology, Yonsei University School of Medicine, Seoul, Korea. METHODS: In this prospective study, 27 patients with a manifest refraction of -3.00 to -6.50 diopters were treated and followed for 3 months. In each case, PRK was performed in 1 eye and LASEK in the other eye. The first eye treated and the surgical method used in the first eye were randomized. Postoperative pain, epithelial healing time, uncorrected visual acuity (UCVA), manifest refraction, corneal haze, and surgical preference were examined in PRK- and LASEK-treated eyes. RESULTS: During the 3 month follow-up, there were no significant between-eye differences in epithelial healing time, UCVA, or refractive error. However, LASEK-treated eyes had lower postoperative pain scores (P =.047) and corneal haze scores (1 month; P =.02) than PRK-treated eyes. Seventeen patients (63%) preferred the LASEK procedure. CONCLUSIONS: Laser epithelial keratomileusis safely and effectively treated eyes with low to moderate myopia. It reduced the incidence of significant postoperative pain and corneal haze and may prevent the flap- and interface-related problems of laser in situ keratomileusis.

Factors that influence the mutagenic patterns of DNA adducts from chemical carcinogens.

Carcinogens are generally mutagens, which is understandable given that tumor cells grow uncontrollably because they have mutations in critical genes involved in growth control. Carcinogens often induce a complex pattern of mutations (e.g., GC-->TA, GC-->AT, etc.). These mutations are thought to be initiated when a DNA polymerase encounters a carcinogen-DNA adduct during replication. In principle, mutational complexity could be due to either a collection of different adducts each inducing a single kind of mutation (Hypothesis 1a), or a single adduct inducing different kinds of mutations (Hypothesis 1b). Examples of each are discussed. Regarding Hypothesis 1b, structural factors (e.g., DNA sequence context) and biological factors (e.g., differing DNA polymerases) that can affect the pattern of adduct mutagenesis are discussed. This raises the question: how do structural and biological factors influence the pattern of adduct mutagenesis. For structural factors, three possibilities are considered: (Hypothesis 2a) a single conformation of an adduct giving rise to multiple mutations -- dNTP insertion by DNA polymerase being influenced by (e.g.) the surrounding DNA sequence context; (Hypothesis 2b) a variation on this ("dislocation mutagenesis"); or (Hypothesis 2c) a single adduct adopting multiple conformations, each capable of giving a different pattern of mutations. Hypotheses 2a, 2b and 2c can each in principle rationalize many mutational results, including how the pattern of adduct mutagenesis might be influenced by factors, such as DNA sequence context. Five lines of evidence are discussed suggesting that Hypothesis 2c can be correct for base substitution mutagenesis. For example, previous work from our laboratory was interpreted to indicate that [+ta]-B[a]P-N(2)-dG in a 5'-CGG sequence context (G115) could be trapped in a conformation giving predominantly G-->T mutations, but heating caused the adduct to equilibrate to its thermodynamic mixture of conformations, leading to a decrease in the fraction of G-->T mutations. New work is described suggesting that [+ta]-B[a]P-N(2)-dG at G115 can also be trapped predominantly in the G-->A mutational conformation, from which equilibration can also occur, leading to an increase in the fraction of G-->T mutations. Evidence is also presented that the fraction of G-->T mutations is higher when [+ta]-B[a]P-N(2)-dG at G115 is in ss-DNA ( approximately 89%) vs. ds-DNA ( approximately 66%), a finding that can be rationalized if the mixture of adduct conformations is different in ss- and ds-DNA. In summary, the factors affecting adduct mutagenesis are reviewed and five lines of evidence that support one hypothesis (2c: adduct conformational complexity can cause adduct mutational complexity) are discussed.

Toward an understanding of the role of DNA adduct conformation in defining mutagenic mechanism based on studies of the major adduct (formed at N(2)-dG) of the potent environmental carcinogen, benzo[a]pyrene.

The process of carcinogenesis is initiated by mutagenesis, which often involves replication past damaged DNA. One question - what exactly is a DNA polymerase seeing when it incorrectly copies a damaged DNA base (e.g., inserting dATP opposite a dG adduct)? - has not been answered in any case. Herein, we reflect on this question, principally by considering the mutagenicity of one activated form of benzo[a]pyrene, (+)-anti-B[a]PDE, and its major adduct [+ta]-B[a]P-N(2)-dG. In previous work, [+ta]-B[a]P-N(2)-dG was shown to be capable of inducing>95% G-->T mutations in one sequence context (5'-TGC), and approximately 95% G-->A mutations in another (5'-AGA). This raises the question - how can a single chemical entity induce different mutations depending upon DNA sequence context? Our current working hypothesis is that adduct conformational complexity causes adduct mutational complexity, where DNA sequence context can affect the former, thereby influencing the latter. Evidence supporting this hypothesis was discussed recently (Seo et al., Mutation Res. [in press]). Assuming this hypothesis is correct (at least in some cases), one goal is to consider what these mutagenic conformations might be. Based on molecular modeling studies, 16 possible conformations for [+ta]-B[a]P-N(2)-dG are proposed. A correlation between molecular modeling and mutagenesis work suggests a hypothesis (Hypothesis 3): a base displaced conformation with the dG moiety of the adduct in the major vs. minor groove gives G-->T vs. G-->A mutations, respectively. (Hypothesis 4, which is a generalized version of Hypothesis 3, is also proposed, and can potentially rationalize aspects of both [+ta]-B[a]P-N(2)-dG and AP-site mutagenesis, as well as the so-called "A-rule".) Finally, there is a discussion of how conformational complexity might explain some unusual mutagenesis results that suggest [+ta]-B[a]P-N(2)-dG can become trapped in different conformations, and why we think it makes sense to interpret adduct mutagenesis results by modeling ds-DNA (at least in some cases), even though the mutagenic event must occur at a ss/ds-DNA junction in the presence of a DNA polymerase.

New fixation device for photorefractive surgery and its effect on corneal epithelial wound healing.

PURPOSE: A new eyeball fixation device during photorefractive surgery was designed and tested. The device fixates the eyeball by means of a suction ring, and is then fixated to the headrest of the patient's chair via clipper and metal frames. METHODS: Photorefractive keratectomy (PRK) was performed on PMMA contact lenses placed over the patient's cornea (n=6) to evaluate smoothness of the ablated surface and on rabbit (n=24) and patient (n=30) corneas for evaluation of wound healing time. Decentration with fixation was examined using videokeratography after PRK. RESULTS: After fixation, only small amounts of corneal movement from the patient's pulsating heart were noted. The mean smoothness (root mean square) of the PMMA contact lens ablated surface was 0.43 +/- 0.16 microm in non-fixated eyes and 0.26 +/-0.05 microm in fixated eyes. Mean epithelial healing rate was 47.93 +/- 21.80 microm/hr in non-fixated rabbit eyes and 66.49 +/- 20 microm/hr in fixated rabbit eyes. Mean epithelial healing time was 3.47 +/- 1.11 days in non-fixated human eyes and 2.53 +/- 0.51 days in fixated human eyes. Mean decentration after PRK was 0.30 +/- 0.28 mm in fixated human eyes. CONCLUSION: Fixating the eyeball allows less movement of the eye and achieves a smoother ablation surface for more rapid epithelial healing after PRK.

Characterization of stable high molecular weight mutagenic product(s) of plant-activated m-phenylenediamine.

Monocyclic aromatic amines are environmental contaminants and many are promutagens and procarcinogens. Cultured tobacco cells, strain TX1, activated m-phenylenediamine into a frameshift mutagen that reverted the hisD3052 allele in Salmonella typhimurium strains TA98 and YG1024. However, the plant-activated products were refractory in strain TA98/1,8-DNP6. This indicated that these plant-activated products were substrates for bacterial acetyl-CoA: N-hydroxyarylamine O-acetyltransferase. A stable, high molecular weight (> 300 kDa) proximal mutagen was isolated by molecular ultrafiltration membranes. No parent compound was associated with the isolated mutagenic fraction. The high molecular weight fraction induced mutation in S. typhimurium strains TA98, YG1021 and YG1024. From these data we propose a model for the plant-activation of aromatic amine promutagens.