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Conjugated linoleic acids (CLAs) are a group of dietary fatty acids that are widely marketed as weight loss supplements. The isomer responsible for this effect is the trans-10, cis-12 CLA (10E12Z-CLA) isomer. 10E12Z-CLA treatment during differentiation of 3T3-L1 adipocytes induces expression of prostaglandin-endoperoxide synthase-2 (Cyclooxygenase-2; COX-2). This work demonstrates that COX-2 is also induced in fully differentiated 3T3-L1 adipocytes after a single treatment of 10E12Z-CLA at both the mRNA (20-40 fold) and protein level (7 fold). Furthermore, prostaglandin (PG)F(2α), but not PGE(2), is significantly increased 10 fold. In female BALB/c mice fed 0.5% 10E12Z-CLA for 10 days, COX-2 was induced in uterine adipose (2 fold). In vitro, pharmacological COX-2 inhibition did not block the effect of 10E12Z-CLA on adipocyte-specific gene expression although PGF(2α) was dose-dependently decreased. These studies demonstrate that PGF(2α) was not by itself responsible for the reduction in adipocyte character due to 10E12Z-CLA treatment. However, PGF(2α), either exogenously or endogenously in response to 10E12Z-CLA, increased the expression of the potent mitogen and epidermal growth factor (EGF) receptor (EGFR) ligand epiregulin in 3T3-L1 adipocytes. Blocking PGF(2α) signaling with the PGF(2α) receptor (FP) antagonist AL-8810 returned epiregulin mRNA levels back to baseline. Although this pathway is not directly responsible for adipocyte dependent gene expression, these results suggest that this signaling pathway may still have broad effect on the adipocyte and surrounding cells., (Copyright © 2012. Published by Elsevier Inc.)

The trans-10, cis-12 (10e12z) conjugated linoleic acid (CLA) isomer of CLA is responsible for loss of lipid storage or adipose tissue in vitro or in vivo. This isomer also induces inflammatory signaling in both mouse and human adipocytes in vitro. However, when these events occur and whether they are significant enough to affect other cell types are unclear. In these experiments, the 3T3-L1 cell line has been used to examine the interaction between inflammatory signaling and decreased differentiation or lipid storage induced by 10e12z CLA. In assays measuring both lipid accumulation and gene expression, differentiating 3T3-L1 cells exhibit concurrent induction of inflammatory signaling, as measured by cyclooxygenase-2 expression, and a decrease in adipocyte marker gene expression. Furthermore, in fully differentiated adipocytes, as identified in microarray assays and confirmed with real-time polymerase chain reaction, 10e12z CLA also significantly affected expression of both matrix metalloprotein-3 (MMP-3), collagen VI α 3 ColVI alpha 3 (VIα3) and the cytokine epiregulin, demonstrating that the effects of 10e12z broadly impact adipocyte function. In agreement with other experimental systems, 10e12z CLA inhibited RAW 264.7 cell proliferation; however, in response to adipocyte-conditioned media, 10e12z-CLA-treated adipocytes induced proliferation of this cell line, suggesting that the effect of 10e12z CLA is context dependent. These results are largely consistent with the known activation of the inflammatory mediator nuclear factor-κB in adipocytes in vitro and in vivo by 10e12z CLA treatment and demonstrate that adipose is an important target tissue of this isomer that impacts other cell types., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Increased cholesterol efflux from macrophage-derived foam cells (MDFCs) is an important protective mechanism to decrease lipid load in the atherosclerotic plaque. Dietary alpha-linolenic acid (ALA), an omega-3 polyunsaturated fatty acid (PUFA), decreases circulating cholesterol, but its role in cholesterol efflux has not been extensively studied. Stearoyl CoA desaturase 1 (SCD1) is the rate-limiting enzyme in the synthesis of monounsaturated fatty acids (MUFAs). Endogenous MUFAs are preferentially incorporated into triglycerides, phospholipids and cholesteryl ester, which are abundant in atherosclerotic plaque. This study investigated the mechanisms by which ALA regulated SCD1 and subsequent effect on cholesterol storage and transport in MDFCs. Small interfering RNA (siRNA) also was applied to modify SCD1 expression in foam cells. Alpha-linolenic acid treatment and SCD1 siRNA significantly decreased SCD1 expression in MDFCs. The reduction of SCD1 was accompanied with increased cholesterol efflux and decreased intracellular cholesterol storage within these cells. Alpha-linolenic acid activated the nuclear receptor farnesoid-X-receptor, which in turn increased its target gene small heterodimer partner (SHP) expression, and decreased liver-X-receptor dependent sterol regulatory element binding protein 1c transcription, ultimately resulting in repressed SCD1 expression. In conclusion, repression of SCD1 by ALA favorably increased cholesterol efflux and decreased cholesterol accumulation in foam cells. This may be one mechanism by which dietary omega-3 PUFAs promote atherosclerosis regression., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Small gauge vitrectomy utilizing 23- and 25-gauge instrumentation has definite advantages, but also limitations, due to the physics of smaller instruments and sutureless surgery. Higher infusion and aspiration pressures are needed to remove the vitreous using 23- and 25-gauge probes. The advantages include decreased surgical times, less tissue manipulation, reduced inflammation and pain postoperatively with more rapid visual recovery. A disadvantage is greater instrument flexion than 20-gauge probes, making small gauge vitrectomy more appropriate for indications such as vitreous opacities, epiretinal membranes, macular holes, and simple retinal detachments. There are also some increased complications related to small gauge vitrectomy, including dislocation of cannulas intraoperatively, early postoperative hypotony, choroidal detachment, and possibly an increased risk of infectious endophthalmitis., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Conjugated linoleic acid (CLA) is a mixture of dietary fatty acids that has various beneficial effects including decreasing cancer, atherosclerosis, diabetes and inflammation in animal models. Some controversy exists on the specific isomers of CLA that are responsible for the benefits observed. This study was conducted to examine how different CLA isomers regulate gene expression in RAW 264.7. A mouse macrophage cell line, RAW 264.7, was treated with five different CLA isomers (9E,11E-, 9Z,11E-, 9Z,11Z-, 10E,12Z- and 11Z,13E-CLA). Gene expression microarrays were performed, and several significantly regulated genes of interest were verified by a real-time polymerase chain reaction (PCR). Examination of the biological functions of various significantly regulated genes by the five CLA isomers showed distinct properties. Isomers 9E,11E-, 9Z,11Z-, 10E,12Z- and 11Z,13E-CLA decreased production of proinflammatory cytokines such as interleukin (IL)-1alpha, IL-1beta and IL-6. Many of CLA's effects are believed to be mediated by the fatty acid receptors such as the peroxisome proliferator-activated receptors (PPAR) and retinoid-X-receptors (RXR). Using PPAR and RXR specific antagonists and coactivator recruitment assays, it was evident that multiple mechanisms were responsible for gene regulation by CLA isomers. Coactivator recruitment by CLA isomers showed their distinct properties as selective receptor modulators for PPARgamma and RXRalpha. These studies demonstrate distinct isomer differences in gene expression by CLA and will have important ramifications for determining the potential therapeutic benefit of these dietary fatty acids in prevention of inflammation-related diseases.

Indocyanine green (ICG) is one of several vital dyes that are used in vitreoretinal surgery to aid visualization of diaphanous collagenous tissues in what has been called chromovitrectomy. As shown herein, much has been written about the use and rather narrow safety profile of ICG. The discussion surrounding its applications would have ended long ago were it not for the occasional patient who keeps returning to the office with permanent central scotomas after ICG-assisted macular hole surgery. The purpose of this Viewpoint is to reemphasize potential methods of proper use and clarify safety issues of this particular vital dye that enhances surgical technique but not necessarily visual outcome.

Liver insufficiency and damage are major causes of death and disease worldwide and may result from exposure to environmental toxicants, specific combinations or dosages of pharmaceuticals, and microbial metabolites. The generation of reactive intermediates, in particular 4-hydroxynonenal (4-HNE), is a common event in liver damage caused by a variety of hepatotoxic drugs and solvents. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are involved in the transcriptional regulation of lipid metabolism as well as other biological functions. Importantly, we have observed that the PPARbeta/delta-/- mouse is more susceptible to chemically induced hepatotoxicity than its wild-type counterpart, and our objective in this study was to elucidate the mechanism(s) by which PPARbeta/delta confers protection to hepatocytes. We hypothesized that PPARbeta/delta plays a protective role by responding to toxic lipids and altering gene expression accordingly. In support, oxidized-VLDL and constituents including 13-S-hydroxyoctadecadienoic acid (13-S-HODE) and 4-HNE are PPARbeta/delta ligands. A structure-activity relationship was established where 4-HNE and 4-hydroperoxynonenal (4-HpNE) enhanced the activity of the PPARbeta/delta subtype while 4-hyroxyhexenal (4-HHE), 4-oxo-2-Nonenal (4-ONE), and trans-4,5-epoxy-2(E)-decenal did not activate this receptor. Increasing PPARbeta/delta activity with a synthetic agonist decreased sensitivity of hepatocytes to 4-HNE and other toxic agents, whereas inhibition of this receptor had the opposite result. Gene expression microarray analysis identified several important PPARbeta/delta-regulated detoxification enzymes involved in 4-HNE metabolism that are regulated at the transcript level. This research established 4-HNE as an endogenous modulator of PPARbeta/delta activity and raises the possibility that agonists of this nuclear receptor may be utilized to prevent or treat liver disease associated with oxidative damage.

Purpose: To evaluate complications and results of intravitreal triamcinolone acetonide for treatment of macular edema., Design: Interventional, consecutive, retrospective case series., Methods: Ninety-three eyes with macular edema arising from retinovascular etiologies were treated with 4 mg intravitreal triamcinolone. Eyes were monitored after injection for visual acuity changes and complications, including cataract formation and increase in intraocular pressure (IOP). Cataract progression was analyzed by linear regression analysis of lens scores from lens opacity standards., Results: The mean visual acuity improved from 20/125 to -1 to 20/100 + 2 by one to two months after injection (P < .001) and was 20/100 at the final examination (P = .006) at a mean of 1.2 years after injection. Complications included a severe, culture-negative inflammatory reaction in one eye (1.1%). IOP increased to 30 mm Hg or more in nine (9.7%) of 93 eyes between 1 and 140 days after injection and was more frequent in eyes receiving one or more preinjection glaucoma drops (two of 13 eyes, 15.4%, vs seven of 80 eyes, 8.75%, without preinjection glaucoma drops). Nuclear sclerosis increased at a rate of 0.175 U per year, posterior subcapsular cataracts at 0.423 U per year, and cortical cataracts at 0.045 U per year. Posterior subcapsular cataract increased by > or = 1 U or required cataract surgery in 45.2% of eyes followed at least one year., Conclusions: Intravitreal triamcinolone improves visual acuity in most eyes but eyes must be monitored carefully for increase in IOP. Posterior subcapsular cataract formation becomes visually significant in almost half of eyes by one year after injection.

Purpose: To evaluate the rate of increase in nuclear sclerosis and posterior subcapsular cataracts in eyes as a function of patient age and use of intravitreal gas at the time of vitrectomy., Design: Observational case series., Methods: Nuclear sclerosis and posterior subcapsular cataracts were evaluated as a function of patient age and use of intravitreal gas at vitrectomy., Setting: A clinical practice., Study Population: The study population consisted of 301 consecutive eyes., Observational Procedure: Nuclear sclerotic cataracts and posterior subcapsular cataracts were graded on a scale from 0 to 4.0 before and after vitrectomy., Main Outcome Measure: Linear regression analysis was performed to measure and compare the rate of change in cataract score over time based on patient age and use of intraocular gas., Results: Nuclear sclerotic cataracts showed minimal increase in patients younger than 50 years of age after vitrectomy (0.13 grades/year). Nuclear sclerotic cataracts increased at a rate of 0.7 to 0.9 grades/year (mean, 0.812) in patients aged 50 to 60 years, 60 to 70 years, 70 to 80 years, and 80+ years, even though the baseline nuclear sclerosis scores were progressively greater for each decade. The increase in nuclear sclerotic cataracts in patients younger than 50 years of age was significantly less (P <.001) than in patients aged 50 years or older. Eyes with intraocular gas use had a higher rate of nuclear sclerosis progression (0.8 grades/year) compared with eyes without intraocular gas bubbles (0.5 grades/year; P <.001). Posterior subcapsular cataract scores showed minimal or no increases in all groups., Conclusions: Patients older than 50 years of age have a similar rate of increase in nuclear sclerotic cataracts, independent of age. The rate is approximately sixfold greater than in patients younger than 50 years of age. Intravitreal gas bubbles are associated with a nuclear sclerosis increase of approximately 60% compared with eyes without use of a gas bubble.

Selenium (Se) is an essential micronutrient for all mammalian species and is associated with a variety of physiological functions, notably immune system, in the form of selenoproteins. Inadequate Se nutrition has been linked to various diseases, including rheumatoid arthritis, cardiomyopathy, and cancer. Important to this discussion is that cyclooxygenase-2 (COX-2) is over-expressed in all the aforesaid pathologies; however, a casual relationship between Se status and COX-2 expression remains to be established. The present study is based on the hypothesis that oxidant stress, a consequence of Se deficiency, lowers the activation potential of the redox-sensitive transcription factor, NF-kappaB, and that the activated NF-kappaB is required for the altered expression of COX-2. To test this hypothesis, we have investigated the relationship between Se status and COX-2 expression in response to LPS stimulation in RAW 264.7, a macrophage-like cell line. In Se-deficient cells, the Se-dependent glutathione peroxidase activity (Se-GPx), a measure of Se status, was markedly reduced and the overall oxidative stress was significantly higher than Se-supplemented cells. Upon lipopolysaccharide (LPS) stimulation, we found 2-3-folds higher COX-2 protein expression as well as higher PGE2 levels in Se-deficient cells than Se-supplemented cells. In comparison, COX-1 protein expression was not affected by either LPS stimulation or Se status. Following LPS stimulation, the nuclear localization of NF-kappaB was significantly increased in Se-deficient macrophages, thereby leading to increased expression of COX-2. This is the first report demonstrating an inverse relationship between Se status and the expression of COX-2.

Purpose: To present a dramatic case of simultaneous bilateral central retinal vein occlusion associated with leukemia and anticardiolipin autoantibodies., Methods: Interventional case report. Clinical examination, fluorescein angiography, B-mode ultrasonography, and laboratory serologies were performed on a 65-year-old man with chronic myelogenous leukemia who presented with sudden onset of decreased vision in his right eye., Results: Fundus examination disclosed a nonischemic central retinal vein occlusion. Over the next 3 weeks, a nonperfused central retinal vein occlusion developed in both eyes and subsequent neovascular glaucoma developed in his left eye. Throughout this time, his white blood cell and platelet counts remained normal and his serum viscosity remained low, but anticardiolipin antibodies were increased., Conclusion: This case reveals the occurrence of simultaneous bilateral central retinal vein occlusion associated with anticardiolipin antibodies in leukemia and suggests an additional mechanism other than hyperviscosity for bilateral central retinal vein occlusions in leukemic patients.

Purpose: To describe two patients who developed a retinal pigment epithelial tear after transpupillary thermotherapy for choroidal neovascularization., Method: Case reports., Results: Retinal pigment epithelial (retinal pigment epithelium) tear developed in 2 (8%) of 25 eyes after transpupillary thermotherapy for occult choroidal neovascularization associated with age-related macular degeneration. In both eyes, the retinal pigment epithelium tear developed between the treatment session and first post-treatment examination. In both eyes, the visual acuity was unchanged, but the complication of retinal pigment epithelium tear may result in decreased visual acuity when transpupillary thermotherapy is performed in an eye with good initial visual acuity., Conclusion: Retinal pigment epithelium tear appears to occur more frequently after transpupillary thermotherapy for poorly defined choroidal neovascularization than after conventional laser photocoagulation for poorly defined choroidal neovascularization.

Purpose: To determine the incidence and timing of increased intraocular pressure in eyes with an idiopathic macular hole treated with bovine transforming growth factor-beta 2 (TGF-beta 2) with different intraocular gas concentrations, recombinant TGF-beta 2, or placebo., Methods: Intraocular pressure was measured preoperatively and two days, two weeks, six weeks, and three months postoperatively in two prospective studies of the treatment of idiopathic macular hole with vitrectomy. Group 1 consisted of 95 eyes treated with bovine TGF-beta 2. Eyes in this group were treated with different concentrations of air and perfluoropropane (C3F8) intraocular gas bubbles. Fifteen eyes were treated with air, 15 eyes with 5% perfluoropropane, 15 eyes with 10% perfluoropropane, and 50 eyes with 16% perfluoropropane. Group 2 consisted of 29 eyes treated with recombinant TGF-beta 2. Twenty-six eyes were treated with placebo in a double-masked, randomized, placebo-controlled study evaluating recombinant TGF-beta 2 with a 16% perfluoropropane intraocular gas bubble., Results: At the two-week examination, the intraocular pressure in Group 1 eyes was > 30 mm Hg in four (26.7%) of 15 eyes treated with air, two (13.3%) of 15 eyes treated with 5% perfluoropropane, one (8.3%) of 12 eyes treated with 10% perfluoropropane, and nine (19.1%) of 47 eyes treated with 16% perfluoropropane. There was no statistically significant difference in the risk of increased intraocular pressure in eyes treated with short-, intermediate-, or long-duration gas tamponade using bovine TGF-beta 2. The intraocular pressure in Group 2 was > 30 mm Hg at the two-week examination in 11 (39.3%) of 28 eyes receiving recombinant TGF-beta 2 compared with one (4.3%) of 23 eyes receiving a placebo (P = .006)., Conclusions: Some eyes develop increased intraocular pressure after vitreous surgery for macular hole, and the increase occurs most frequently between two days and two weeks postoperatively. The risk of increased intraocular pressure is somewhat increased in eyes treated with bovine TGF-beta 2 but is markedly increased in eyes in which recombinant TGF-beta 2 is used as an adjunctive agent for macular hole surgery. Intraocular injection of growth factors produced by similar recombinant DNA techniques may result in potentially dangerous increased intraocular pressure several weeks after surgery. Impurities in the recombinant TGF-beta 2 may explain the relatively high risk of increased intraocular pressure.

Purpose: We studied the progression of cataracts and visual acuity up to 36 months after vitrectomy and instillation of transforming growth factor beta-2 for treatment of full-thickness macular holes., Methods: Sixty-four eyes with idiopathic and two with traumatic macular holes in this prospective consecutive series were divided into the following two groups: 56 phakic eyes were treated with 70, 330, or 1,330 ng of transforming growth factor beta-2 to study the progression of cataracts, and 31 phakic or pseudophakic eyes were treated with 1,330 ng of transforming growth factor beta-2 to study the long-term visual acuity after macular hole surgery., Results: Eyes in the cataract progression study had a mean preoperative nuclear sclerosis grade of 0.4, which increased to 2.4 on final lens examination at a mean of 12.4 months postoperatively. The amount of nuclear sclerosis increased progressively with duration of follow-up, and 16 (76%) of 21 eyes followed up for 24 months or more required cataract extraction. The mean preoperative posterior subcapsular cataract grade was 0.0 and increased only slightly to 0.25 on final lens examination. All eyes had initial successful closure of the macular hole, but the macular hole reopened in two eyes (between six and 12 months and at 19 months) for an overall success rate of 29 (93.5%) of 31 eyes at a mean of 19.5 months. The visual acuity increased two or more Snellen lines in 29 (93.5%) of 31 eyes. The final visual acuity was 20/40 or better in 23 (74%) of 31 eyes and the visual improvement was stable in eyes followed up for three years., Conclusions: Nuclear sclerotic cataracts progress substantially after macular hole surgery with a long-acting intraocular gas tamponade. The visual acuity often decreases 12 or more months after vitrectomy because of cataract progression, but the visual results of vitrectomy and transforming growth factor beta-2 for macular holes are excellent when the cataracts are removed.

We evaluated the fluorescein angiographic features of full-thickness macular holes before and after vitrectomy, fluid-gas exchange, and instillation of transforming growth factor beta-2 in 43 eyes in a masked fashion to evaluate the angiographic characteristics of macular holes preoperatively and the changes that occur with successful and unsuccessful closure of the macular hole. Hyperfluorescence was present in the base of the macular hole preoperatively in 34 of 43 eyes (79.1%), was questionable in eight of 43 eyes (18.6%), and was definitely absent in only one of 43 eyes (2.3%). The hyperfluorescence in the base of the macular hole disappeared in 19 of 20 eyes (95%) with successful closure of the macular hole (P < .00001) and appeared to be caused by blocked fluorescence at the site of the macular hole. The photographic features of eyes with unsuccessful closure of the macular hole changed little, except that the size of the cuff of neurosensory detachment around the hole increased and was associated with decreased postoperative visual acuity. These angiographic changes support the presence of a glial tissue plug bridging a small defect in the fovea of eyes with successful closure of a macular hole.

Using indocyanine green angiography we examined two patients with multiple evanescent white-dot syndrome. Both patients had unilateral loss of vision and a fundus appearance typical of multiple evanescent white-dot syndrome. Fluorescein angiography in both patients disclosed a patchy hyperfluorescent pattern at the level of the retinal pigment epithelium. Using indocyanine green angiography, we observed multiple deep, small, round hypofluorescent lesions that appeared early and persisted into the late phases. The spots appeared to block the underlying choroidal pattern. These hypofluorescent spots were clearly visible and present throughout the posterior pole. Many more spots were seen on indocyanine green angiography than were visible by clinical examination or angiography. After follow-up examinations, there was a rapid resolution of the spots over four to six weeks with return of vision. Our findings show that indocyanine green angiography can be a valuable tool in the recognition and further understanding of multiple evanescent white-dot syndrome.

Visual loss in eyes with full-thickness macular holes is thought to be caused by the absence of retinal function in the area of the neurosensory defect as well as reduction in retinal function in the surrounding area of neurosensory retinal detachment. To improve characterization of the visual function of eyes after successful macular hole surgery, we studied six eyes preoperatively and postoperatively with macular microperimetry using the scanning laser ophthalmoscope. Best-corrected visual acuity was improved postoperatively in all eyes. Microperimetry performed preoperatively demonstrated an absolute scotoma that corresponded to the neurosensory defect in all eyes, with surrounding concentric isopters of relative scotomata. No detectable absolute scotoma was found in any eye postoperatively. All eyes showed partial or complete resolution of the surrounding relative scotomata. Improvements in visual acuity after successful macular hole surgery may be related to disappearance of a detectable absolute scotoma as well as improvement in the surrounding retinal function.

We performed a retrospective analysis of lens changes occurring after vitrectomy for idiopathic epiretinal membranes causing macular pucker on 75 consecutive phakic eyes. Thirty-five eyes (47%) had appearance or progression of nuclear sclerosis. There were no changes in anterior subcapsular cataracts and three eyes (4%) had minimal changes in posterior subcapsular cataracts. Based on univariate analysis, presence of preoperative nuclear sclerosis, length of follow-up period, and surgeon were found to be associated with the occurrence or progression of nuclear sclerosis. Differences between surgeons were largely accounted for by the difference in proportions with preoperative nuclear sclerosis, and differing lengths of follow-up. Kaplan-Meier life table analysis performed on 53 eyes with examination of fellow eyes and longer follow-up showed significantly more nuclear sclerosis in the operated on eye when compared to the fellow eye (log-rank test, P less than .0001).

Epiretinal membranes exert a perpendicular force on the retina that is directed toward the center of the vitreous cavity and tends to elevate the retina from the retinal pigment epithelium. A scleral buckle changes the eye wall from concave to convex and reverses the direction of the vector force oriented perpendicular to the eye wall. Therefore, when a scleral buckle is used, the force from an epiretinal membrane pulls the retina toward the retinal pigment epithelium instead of causing retinal detachment.

We investigated the effect of diffuse hemorrhage on Snellen visual acuity in a model of vitreous hemorrhage in phakic and aphakic eyes. Two cylindrical test chambers with optical paths of 17 mm and 23 mm were constructed to simulate the effect of vitreous hemorrhage in phakic and aphakic eyes. The visual acuity was measured in two subjects in a double-masked fashion for 17 dilutions of whole blood between 1/100 and 1/12,800. The visual acuity decreased approximately linearly between the 1/800 and 1/4,800 dilutions of blood. The visual acuity was 20/20 in all dilutions of blood higher than 1/4,800. The visual acuity was reduced to hand motions or worse with 12.5 microliter of blood in the 5-ml test chamber under all test conditions. The visual acuity was 20/20 in all tests with 1.04 microliter of blood in the test chamber. The visual acuity decreased from 20/20 to hand motions with only a twelve-fold change in concentration of blood in the test chamber.