RETINAL AND CHOROIDAL VASCULAR OCCLUSION FOLLOWING AQUEOUS MISDIRECTION SYNDROME IN A PATIENT WITH SICKLE CELL TRAIT.

PURPOSE: To report a patient with retinal and choroidal vascular occlusion as a presenting sign of sickle cell trait following the development of aqueous misdirection syndrome. METHODS: Retrospective chart review. RESULTS: A patient treated for bilateral chronic angle-closure glaucoma with sequential EX-PRESS glaucoma filtration device surgery developed sequential bilateral aqueous misdirection syndrome. The left eye developed retinal arterial and localized choroidal vascular occlusions subsequent to an acute elevation in intraocular pressure and possibly the use of oral acetazolamide. The patient was subsequently found to have sickle cell trait. The right eye developed aqueous misdirection with acute elevation of intraocular pressure as well, but the patient was not treated with oral acetazolamide and did not develop vascular occlusion. CONCLUSION: Retinal and choroidal vascular occlusions can be the presenting sign of a patient with sickle cell trait. Sickle cell screening may be beneficial in African American or Middle Eastern patients after an acute rise in intraocular pressure, particularly before initiation of treatment with oral carbonic anhydrase inhibitors.

Is Estrogen a Therapeutic Target for Glaucoma?

This article's objective is to provide an overview of the association between estrogen and glaucoma. A literature synthesis was conducted of articles published in peer-reviewed journals screened through May 5, 2015, using the PubMed database. Keywords used were "estrogen and glaucoma," "reproductive factors and glaucoma," and "estrogen, nitric oxide and eye." Forty-three journal articles were included. Results indicated that markers for lifetime estrogen exposure have been measured by several studies and show that the age of menarche onset, oral contraceptive (OC) use, bilateral oophorectomy, age of menopause onset and duration between menarche to menopause are associated with primary open-angle glaucoma (POAG) risk. The Blue Mountain Eye Study found a significantly increased POAG risk with later (>13 years) compared with earlier (≤12 years) age of menarche. Nurses' Health Study (NHS) investigators found that OC use of greater than 5 years was associated with a 25% increased risk of POAG. The Mayo Clinic Cohort Study of Oophorectomy and Aging found that women who underwent bilateral oophorectomy before age 43 years had an increased risk of glaucoma. The Rotterdam Study found that women who went through menopause before reaching the age of 45 years had a higher risk of open-angle glaucoma (2.6-fold increased risk), while the NHS showed a reduced risk of POAG among women older than 65 who entered menopause after age ≥ 54 years. Increased estrogen states may confer a reduced risk of glaucoma or glaucoma-related traits such as reduced intraocular pressure (IOP). Pregnancy, a hyperestrogenemic state, is associated with decreased IOP during the third trimester. Though the role of postmenopausal hormone (PMH) use in the reduction of IOP is not fully conclusive, PMH use may reduce the risk of POAG. From a genetic epidemiologic perspective, estrogen metabolic pathway single nucleotide polymorphisms (SNPs) were associated with POAG in women and polymorphisms in endothelial nitric oxide synthase, a gene receptive to estrogen regulation, are associated with glaucoma. The study concluded that increasing evidence suggests that lifetime exposure to estrogen may alter the pathogenesis of glaucoma. Estrogen exposure may have a neuroprotective effect on the progression of POAG but further studies need to confirm this finding. The role of sex-specific preventive and therapeutic treatment may be on the horizon.

Exfoliation syndrome: a disease with an environmental component.

PURPOSE OF REVIEW: Exfoliation syndrome (XFS), the most common cause of secondary open angle glaucoma, is associated with significant ocular morbidity. Recent studies have pointed toward environmental components that may alter the risk of XFS development. This review focuses on the recent studies elucidating the role of environmental factors that play a role in the development of exfoliation syndrome. RECENT FINDINGS: In XFS, aberrant microfibril formation emanating from the cell-extracellular matrix interface admixes with other macromolecules and is cross-linked by lysyl oxidase like 1 (LOXL1) activity. A common gene variant in the LOXL1 enzyme, an enzyme critical for enhancing the tensile strength of collagen and elastin in extracellular matrices, has been found in approximately 90% of XFS cases. However, approximately 80% of controls also have disease-associated LOXL1 gene variants. These findings point toward other nongenetic factors influencing the development of XFS. Increasing latitude, solar radiation, climatic variables and dietary factors such as high coffee consumption and low dietary folate intake are among the nongenetic factors associated with increased risk of XFS. SUMMARY: A greater understanding of the environmental components associated with XFS may lead to lifestyle preventive strategies to ameliorate disease burden.

Nuclear import of serum response factor in airway smooth muscle.

We have previously shown that the transcription-promoting activity of serum response factor (SRF) is partially regulated by its extranuclear redistribution. In this study, we examined the cellular mechanisms that facilitate SRF nuclear entry in canine tracheal smooth muscle cells. We used in vitro pull-down assays to determine which karyopherin proteins bound SRF and found that SRF binds KPNA1 and KPNB1 through its nuclear localization sequence. Immunoprecipitation studies also demonstrated direct SRF-KPNA1 interaction in HEK293 cells. Import assays demonstrated that KPNA1 and KPNB1 together were sufficient to mediate rapid nuclear import of SRF-GFP. Our studies also suggest that SRF is able to gain nuclear entry through an auxiliary, nuclear localization sequence-independent mechanism.

Transcriptional profiling of the age-related response to genotoxic stress points to differential DNA damage response with age.

The p53 DNA damage response attenuated with age and we have evaluated downstream factors in the DNA damage response. In old animals p21 protein accumulates in the whole cell fraction but significantly declines in the nucleus, which may alter cell cycle and apoptotic programs in response to DNA damage. We evaluated the transcriptional response to DNA damage in young and old and find 2692 genes are differentially regulated in old compared to young in response to oxidative stress (p<0.005). As anticipated, the transcriptional profile of young mice is consistent with DNA damage induced cell cycle arrest while the profile of old mice is consistent with cell cycle progression in the presence of DNA damage, suggesting the potential for catastrophic accumulation of DNA damage at the replication fork. Unique sets of DNA repair genes are induced in response to damage in old and young, suggesting the types of damage accumulating differs between young and old. The DNA repair genes upregulated in old animals point to accumulation of replication-dependent DNA double strand breaks (DSB). Expression data is consistent with loss of apoptosis following DNA damage in old animals. These data suggest DNA damage responses differ greatly in young and old animals.

Inhibition of transforming growth factor beta-enhanced serum response factor-dependent transcription by SMAD7.

Transforming growth factor (TGF)-beta is present in large amounts in the airways of patients with asthma and with other diseases of the lung. We show here that TGFbeta treatment increased transcriptional activation of SM22alpha, a smooth muscle-specific promoter, in airway smooth muscle cells, and we demonstrate that this effect stems in part from TGFbeta-induced enhancement of serum response factor (SRF) DNA binding and transcription promoting activity. Overexpression of Smad7 inhibited TGFbeta-induced stimulation of SRF-dependent promoter function, and chromatin immunoprecipitation as well as co-immunoprecipitation assays established that endogenous or recombinant SRF interacts with Smad7 within the nucleus. The SRF binding domain of Smad7 mapped to the C-terminal half of the Smad7 molecule. TGFbeta treatment weakened Smad7 association with SRF, and conversely the Smad7-SRF interaction was increased by inhibition of the TGFbeta pathway through overexpression of a dominant negative mutant of TGFbeta receptor I or of Smad3 phosphorylation-deficient mutant. Our findings thus reveal that SRF-Smad7 interactions in part mediate TGFbeta regulation of gene transcription in airway smooth muscle. This offers potential targets for interventions in treating lung inflammation and asthma.