Person: Sullivan, David
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Sullivan
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Sullivan, David
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Publication Influence of Aging on the Polar and Neutral Lipid Profiles in Human Meibomian Gland Secretions(American Medical Association (AMA), 2006) Sullivan, Benjamin D.; Evans, James E.; Dana, Reza; Sullivan, DavidObjective To determine whether aging is associated with significant alterations in the polar and neutral lipid profiles in human meibomian gland secretions. Methods Meibomian gland secretions were collected from both eyes of younger and older men and women. Samples were processed for high-performance liquid chromatography or mass spectrometry and for the analysis of associated spectra of fragment ions. Subjects also underwent slitlamp evaluations of the eyelid. Results Aging is associated with numerous significant alterations in the lipid profiles of human meibomian gland secretions. Analysis of polar and neutral lipid patterns identified ions that were significantly different in secretions of younger vs older men and women, as well as ions that varied significantly only between men and women. Correlation coefficients within, but not between, groups were high. Aging was accompanied by increased opacity of meibomian gland secretions and by eyelid and eyelid margin changes. Conclusion Aging is associated with significant sex-related alterations in the polar and neutral lipid profiles of human meibomian gland secretions. Clinical Relevance The observed changes may contribute to the age-related increase in the prevalence of dry eye syndromes.Publication Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets(The Association for Research in Vision and Ophthalmology, 2018) Cooke Bailey, Jessica N.; Gharahkhani, Puya; Kang, Jae Hee; Butkiewicz, Mariusz; Sullivan, David; Weinreb, Robert N.; Aschard, Hugues; Allingham, R. Rand; Ashley-Koch, Allison; Lee, Richard K.; Moroi, Sayoko E.; Brilliant, Murray H.; Wollstein, Gadi; Schuman, Joel S.; Fingert, John H.; Budenz, Donald L.; Realini, Tony; Gaasterland, Terry; Scott, William K.; Singh, Kuldev; Sit, Arthur J.; Igo, Robert P.; Song, Yeunjoo E.; Hark, Lisa; Ritch, Robert; Rhee, Douglas J.; Vollrath, Douglas; Zack, Donald J.; Medeiros, Felipe; Vajaranant, Thasarat S.; Chasman, Daniel I.; Christen, William G.; Pericak-Vance, Margaret A.; Liu, Yutao; Kraft, Phillip; Richards, Julia E.; Rosner, Bernard; Hauser, Michael A.; Craig, Jamie E.; Burdon, Kathryn P.; Hewitt, Alex W.; Mackey, David A.; Haines, Jonathan L.; MacGregor, Stuart; Wiggs, Janey; Pasquale, LouisPurpose Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.Publication Impact of aromatase absence on murine intraocular pressure and retinal ganglion cells(Nature Publishing Group UK, 2018) Chen, Xiaomin; Liu, Yang; Zhang, Yi; Kam, Wendy; Pasquale, Louis; Sullivan, DavidWe hypothesize that aromatase, an enzyme that regulates estrogen production, plays a significant role in the control of intraocular pressure (IOP) and retinal ganglion cells (RGCs). To begin to test our hypothesis, we examined the impact of aromatase absence, which completely eliminates estrogen synthesis, in male and female mice. Studies were performed with adult, age-matched wild type (WT) and aromatase knockout (ArKO) mice. IOP was measured in a masked fashion in both eyes of conscious mice at 12 and 24 weeks of age. Retinas were obtained and processed for RGC counting with a confocal microscope. IOP levels in both 12- and 24-week old female ArKO mice were significantly higher than those of age- and sex-matched WT controls. The mean increase in IOP was 7.9% in the 12-week-, and 19.7% in the 24-week-old mice, respectively. These changes were accompanied by significant 9% and 7% decreases in RGC numbers in the ArKO female mice, relative to controls, at 12- and 24-weeks, respectively. In contrast, aromatase deficiency did not lead to an increased IOP in male mice. There was a significant reduction in RGC counts in the 12-, but not 24-, week-old male ArKO mice, as compared to their age- and sex-matched WT controls. Overall, our findings show that aromatase inhibition in females is associated with elevated IOP and reduced RGC counts.Publication Growth Hormone Influence on the Morphology and Size of the Mouse Meibomian Gland(Hindawi Publishing Corporation, 2016) Liu, Yang; Knop, Erich; Knop, Nadja; Sullivan, David; List, Edward O.; Kopchick, John J.; Kam, Wendy; Ding, JuanPurpose. We hypothesize that growth hormone (GH) plays a significant role in the regulation of the meibomian gland. To test our hypothesis, we examined the influence of GH on mouse meibomian gland structure. Methods. We studied four groups of mice, including (1) bovine (b) GH transgenic mice with excess GH; (2) GH receptor (R) antagonist (A) transgenic mice with decreased GH; (3) GHR knockout (−/−) mice with no GH activity; and (4) wild type (WT) control mice. After mouse sacrifice, eyelids were processed for morphological and image analyses. Results. Our results show striking structural changes in the GH-deficient animals. Many of the GHR−/− and GHA meibomian glands featured hyperkeratinized and thickened ducts, acini inserting into duct walls, and poorly differentiated acini. In contrast, the morphology of WT and bGH meibomian glands appeared similar. The sizes of meibomian glands of bGH mice were significantly larger and those of GHA and GHR−/− mice were significantly smaller than glands of WT mice. Conclusions. Our findings support our hypothesis that the GH/IGF-1 axis plays a significant role in the control of the meibomian gland. In addition, our data show that GH modulates the morphology and size of this tissue.Publication Does androgen insufficiency cause lacrimal gland inflammation and aqueous tear deficiency?(Association for Research in Vision and Ophthalmology, 1999) Sullivan, David; Krenzer, Kathleen; Sullivan, Benjamin; Tolls, Dorothy Bazzinotti; Toda, Ikuko; Dana, M. RezaPURPOSE: The current investigators have shown that androgen treatment suppresses inflammation and stimulates the function of lacrimal glands in mouse models of Sjögren's syndrome. Recently, others have hypothesized that androgen insufficiency induces an autoimmune process in lacrimal tissue, leading to inflammation, a Sjögren's syndrome-like pathology, and aqueous tear deficiency. The purpose of the present study was to test this hypothesis. METHODS: Lacrimal glands were obtained from adult testicular feminized (Tfm) and control mice; castrated rats, guinea pigs, and rabbits; and castrated rats without anterior or whole pituitary glands and were processed for histology and image analysis. Tear volumes were measured in mice, in patients taking antiandrogen medications, and in age-matched human control subjects. RESULTS: Tfm mice, which are completely resistant to classical androgen action, did not have increased lymphocyte infiltration in their lacrimal glands or decreased tear volumes. No inflammation was evident in lacrimal tissues of male or female rats, guinea pigs, or rabbits 12 to 31 days after castration, no inflammation existed in rat lacrimal glands 15 to 31 days after orchiectomy and pituitary removal, and no aqueous tear deficiency was apparent in patients receiving antiandrogen therapy. CONCLUSIONS: Androgen deficiency may promote the progression of Sjögren's syndrome and its associated lacrimal gland inflammation, meibomian gland dysfunction, and severe dry eye. However, androgen insufficiency alone does not cause lacrimal gland inflammation, a Sjögren's syndrome-like pathology in lacrimal tissue, or aqueous tear deficiency in nonautoimmune animals and humans.Publication Hormone Replacement Therapy and Dry Eye Syndrome(American Medical Association (AMA), 2001) Schaumberg, Debra A.; Buring, Julie; Sullivan, David; Dana, RezaContext Postmenopausal hormone replacement therapy (HRT) use is common in the United States. Some research suggests that estrogen may have detrimental effects on the tear film and could influence the development of dry eye syndrome, but few data are available on this relationship. Objective To determine the relationship of HRT and dry eye syndrome. Design, Setting, and Participants The Women's Health Study, a large cohort study in which 25 665 postmenopausal women provided information about use of HRT at baseline (1992), 12, and 36 months and dry eye syndrome at 48 months. Main Outcome Measures (1) Clinically diagnosed dry eye syndrome, as reported by participants; (2) severe symptoms (both ocular dryness and irritation either constantly or often); and (3) either clinically diagnosed dry eye syndrome or severe symptoms, compared between women who used HRT vs those who did not. Results For the combined end point of either clinically diagnosed dry eye syndrome or severe symptoms, the multivariable-adjusted odds ratios were 1.69 (95% confidence interval [CI], 1.49-1.91) for estrogen use alone and 1.29 (95% CI, 1.13-1.48) for estrogen plus progesterone/progestin use compared with no HRT use. Each 3-year increase in the duration of HRT use was associated with a significant 15% (95% CI, 11%-19%) elevation in risk of clinically diagnosed dry eye syndrome or severe symptoms. Results were similar for the combined end point of clinically diagnosed dry eye syndrome and severe symptoms. Conclusions These data suggest that women who use HRT, particularly estrogen alone, are at increased risk of dry eye syndrome. Physicians caring for women who are taking or considering HRT should be apprised of this potential complication.Publication Complete Androgen Insensitivity Syndrome(American Medical Association (AMA), 2002) Sullivan, Benjamin; Evans, James E.; Cermack, Jennifer M.; Dana, Reza; Sullivan, DavidObjective To determine whether androgen receptors affect the fatty acid profiles of neutral and polar lipids in human meibomian gland secretions. Methods Meibomian gland secretion samples were obtained from both eyes of (1) women with complete androgen insensitivity syndrome, a condition characterized by dysfunctional androgen receptors, and (2) age-matched female and male controls. Samples were processed for high-performance liquid chromatography, mass spectrometry, or both and for analysis of the mass spectra of neutral and polar lipid fatty acid fragment ions by 3 different methods. Results Androgen receptor dysfunction is associated with significant alterations in the appearance of numerous molecular species in the neutral and polar lipid fractions of meibomian gland secretions. The ability to detect these differences, and to assess their nature and extent, was facilitated by the use of several analytic approaches. Sex-related differences exist in the expression of a variety of neutral and, especially, polar fatty acid products in meibomian gland secretions. Conclusions Androgens exert a significant effect on neutral and polar lipids in human meibomian gland secretions, and these hormonal effects may be mediated through androgen receptors.Publication Impact of Dry Eye Syndrome on Vision-Related Quality of Life(Elsevier BV, 2007) Miljanovic, Biljana; Dana, Reza; Sullivan, David; Schaumberg, Debra A.Purpose To evaluate the impact of dry eye syndrome (DES) on vision-associated quality of life. Design Cross-sectional study. Methods We identified 450 participants in the Women’s Health Study (WHS) and 240 participants in the Physicians’ Health Study (PHS) and sent a supplementary questionnaire asking how much their everyday activities were limited by symptoms of dry eye and to what degree problems with their eyes limited them in reading, driving, working at the computer, their professional activity, and watching TV. By design, one-third of study subjects had clinically diagnosed DES or severe symptoms and two-thirds did not. We used logistic regression to examine relationships of DES with reported problems with everyday activities in each cohort and pooled estimates using meta-analysis methods. Results Of the participants invited, 85% completed the supplementary questionnaire, including 135 WHS and 55 PHS participants with DES, and 250 WHS and 149 PHS participants without DES. Controlling for age, diabetes, hypertension and other factors, those with DES were more likely to report problems with reading (OR=3.64, 95% CI 2.45–5.40, P< 0.0001); carrying out professional work (OR=3.49, 95% CI 1.72–7.09, P= 0.001); using a computer (OR=3.37, 95% CI 2.11–5.38, P< 0.0001); TV watching (OR=2.84, 95% CI 1.05–7.74, P=0.04); driving during the day (OR=2.80, 95% CI 1.58–4.96, P< 0.0001); and driving at night (OR=2.20, 95% CI 1.48–3.28, P<0.0001). Conclusions DES is associated with a measurable adverse impact on several common and important tasks of daily living, further implicating this condition as an important public health problem deserving increased attention and resources.Publication Prevalence of Dry Eye Disease Among US Men(American Medical Association (AMA), 2009) Schaumberg, Debra A.; Dana, Reza; Buring, Julie; Sullivan, DavidObjective To estimate the prevalence and risk factors for dry eye disease (DED) among US men. Methods Cross-sectional prevalence survey among male participants 50 years and older in the Physicians' Health Studies I (N = 18 596) and II (N = 6848). We defined DED as the presence of clinically diagnosed dry eye or severe symptoms (both dryness and irritation constantly or often). We calculated the age-standardized prevalence of DED adjusted to the age distribution of US men in 2004 and projected estimates forward to 2030. We compared DED prevalence with a similar cohort of women and examined associations with possible risk factors. Results The prevalence of DED increased with age, from 3.90% among men aged 50 to 54 years to 7.67% among men 80 years and older (Pfor trend <.001). High blood pressure (odds ratio, 1.28; 95% confidence interval, 1.12-1.45) and benign prostatic hyperplasia (odds ratio, 1.26; 95% confidence interval, 1.09-1.44) were associated with a higher risk of DED. Use of antidepressants, antihypertensives, and medications to treat benign prostatic hyperplasia were also associated with increased risk of DED. The age-standardized prevalence of DED was 4.34%, or 1.68 million men 50 years and older, and is expected to affect more than 2.79 million US men by 2030. Conclusions Dry eye disease is prevalent and increases with age, hypertension, benign prostatic hyperplasia, and antidepressant use.Publication Do Cyclosporine A, an IL-1 Receptor Antagonist, Uridine Triphosphate, Rebamipide, and/or Bimatoprost Regulate Human Meibomian Gland Epithelial Cells?(The Association for Research in Vision and Ophthalmology, 2016) Kam, Wendy; Liu, Yang; Ding, Juan; Sullivan, DavidPurpose Researchers have hypothesized that treatment with cyclosporine A (CyA), interleukin-1 receptor antagonists (IL-1RA; e.g., anakinra), P2Y2 receptor agonists (e.g., uridine triphosphate; UTP), and rebamipide may alleviate human meibomian gland dysfunction (MGD) and/or dry eye disease. Investigators have also proposed that prostaglandin analogues (e.g., bimatoprost) may induce MGD. Our goal was to determine whether these compounds directly influence human meibomian gland epithelial cell (HMGEC) function. Methods: Multiple concentrations of each compound were tested for effects on immortalized (I) HMGEC morphology and survival. Nontoxic dosages were used for our studies. Immortalized HMGEC were cultured in the presence of vehicle, CyA, IL-1RA, UTP, rebamipide, or bimatoprost for up to 6 days in various media. Experiments included positive controls for proliferation (epidermal growth factor and bovine pituitary extract), differentiation (azithromycin), and signaling pathway activation (insulin-like growth factor 1). Cells were analyzed for neutral lipid staining, lysosome accumulation, lipid composition, and phosphatidylinositol-3-kinase/Akt (AKT), phosphorylation. Results: Our findings demonstrate that CyA, IL-1RA, UTP, rebamipide, and bimatoprost had no effect on the proliferation; neutral lipid content; lysosome number; or levels of free cholesterol, triglycerides, or phospholipids in IHMGECs. Cylosporine A, IL-1RA, rebamipide, and bimatoprost significantly reduced the phosphorylation of AKT, as compared to control. Of interest, tested doses of CyA above 8 nM killed the IHMGECs. Conclusions: Our results show that CyA, IL-1RA, UTP, rebamipide, and bimatoprost do not influence the proliferation or differentiation of IHMGEC. However, with the exception of UTP, these compounds do decrease the activity of the AKT signaling pathway, which is known to promote cell survival.