Electrophilic PPARγ ligands inhibit corneal fibroblast to myofibroblast differentiation in vitro: a potentially novel therapy for corneal scarring.

A critical component of corneal scarring is the TGFß-induced differentiation of corneal keratocytes into myofibroblasts. Inhibitors of this differentiation are potentially therapeutic for corneal scarring. In this study, we tested the relative effectiveness and mechanisms of action of two electrophilic peroxisome proliferator-activated receptor gamma (PPARγ) ligands: cyano-3,12-dioxolean-1,9-dien-28-oic acid-methyl ester (CDDO-Me) and 15-deoxy-Δ(-12,14)-prostaglandin J(2) (15d-PGJ(2)) for inhibiting TGFß-induced myofibroblast differentiation in vitro. TGFß was used to induce myofibroblast differentiation in cultured, primary human corneal fibroblasts. CDDO-Me and 15d-PGJ(2) were added to cultures to test their ability to inhibit this process. Myofibroblast differentiation was assessed by measuring the expression of myofibroblast-specific proteins (αSMA, collagen I, and fibronectin) and mRNA (αSMA and collagen III). The role of PPARγ in the inhibition of myofibroblast differentiation by these agents was tested in genetically and pharmacologically manipulated cells. Finally, we assayed the importance of electrophilicity in the actions of these agents on TGFß-induced αSMA expression via Western blotting and immunofluorescence. Both electrophilic PPARγ ligands (CDDO-Me and 15d-PGJ(2)) potently inhibited TGFß-induced myofibroblast differentiation, but PPARγ was only partially required for inhibition of myofibroblast differentiation by either agent. Electrophilic PPARγ ligands were able to inhibit myofibroblast differentiation more potently than non-electrophilic PPARγ ligands, suggesting an important role of electrophilicity in this process. CDDO-Me and 15d-PGJ(2) are strong inhibitors of TGFß-induced corneal fibroblast to myofibroblast differentiation in vitro, suggesting this class of agents as potential novel therapies for corneal scarring warranting further study in pre-clinical animal models.

Anticancer Role of PPARgamma Agonists in Hematological Malignancies Found in the Vasculature, Marrow, and Eyes.

The use of targeted cancer therapies in combination with conventional chemotherapeutic agents and/or radiation treatment has increased overall survival of cancer patients. However, longer survival is accompanied by increased incidence of comorbidities due, in part, to drug side effects and toxicities. It is well accepted that inflammation and tumorigenesis are linked. Because peroxisome proliferator-activated receptor (PPAR)-gamma agonists are potent mediators of anti-inflammatory responses, it was a logical extension to examine the role of PPARgamma agonists in the treatment and prevention of cancer. This paper has two objectives: first to highlight the potential uses for PPARgamma agonists in anticancer therapy with special emphasis on their role when used as adjuvant or combined therapy in the treatment of hematological malignancies found in the vasculature, marrow, and eyes, and second, to review the potential role PPARgamma and/or its ligands may have in modulating cancer-associated angiogenesis and tumor-stromal microenvironment crosstalk in bone marrow.

Regulation of Lymphocyte Function by PPARgamma: Relevance to Thyroid Eye Disease-Related Inflammation.

Thyroid eye disease (TED) is an autoimmune condition in which intense inflammation leads to orbital tissue remodeling, including the accumulation of extracellular macromolecules and fat. Disease progression depends upon interactions between lymphocytes and orbital fibroblasts. These cells engage in a cycle of reciprocal activation which produces the tissue characteristics of TED. Peroxisome proliferator-activated receptor-gamma (PPARgamma) may play divergent roles in this process, both attenuating and promoting disease progression. PPARgamma has anti-inflammatory activity, suggesting that it could interrupt intercellular communication. However, PPARgamma activation is also critical to adipogenesis, making it a potential culprit in the pathological fat accumulation associated with TED. This review explores the role of PPARgamma in TED, as it pertains to crosstalk between lymphocytes and fibroblasts and the development of therapeutics targeting cell-cell interactions mediated through this signaling pathway.

The relation of Graves' ophthalmopathy to circulating thyroid hormone status.

AIM: The risk factors and epidemiological data for Graves' ophthalmopathy with and without abnormal circulating thyroid levels were examined to determine the relation of thyroid dysfunction to ophthalmopathy. METHODS: The authors retrospectively evaluated 482 patients seen with Graves' ophthalmopathy. Of these, 413 were classified as having abnormal levels of circulating thyroid hormone (ALTH) and 69 as having normal levels of circulating thyroid hormone (NLTH). RESULTS: Patients in the NLTH group, compared to the ALTH group, were older on average (56 (SD 13.5) v 52 (15.4)) and had a higher age adjusted body mass index (26.1 (0.8) v 23.4 (0.3)). In addition, a higher percentage of NLTH patients had hypercholesterolaemia. Those in the ALTH group were more likely to be female (76% v 51%), to have a family history of thyroid problems, and to have had eye surgery. CONCLUSION: NLTH and ALTH appear to differ from each other in terms of risk factors and epidemiological characteristics. Additionally, thyroid dysfunction seems to be associated with a more severe ophthalmopathy compared to the euthyroid state.

Orbital presentations of giant cell arteritis.

BACKGROUND: giant cell arteritis (GCA) is a systemic vasculitis that may affect the optic nerve and cause blindness (e.g. ischemic optic neuropathy). Orbital inflammatory disease, however, is an uncommon presentation of GCA. PURPOSE: to alert clinicians to the orbital presentations of GCA. PATIENTS AND METHODS: a retrospective case series from tertiary care academic ophthalmic referral centers of four patients with orbital manifestations of giant cell arteritis. RESULTS: presentation of cases and review of the literature. In three cases, a temporal artery biopsy was diagnostic of GCA, but in one case, an orbital biopsy was needed to confirm the diagnosis. CONCLUSION: GCA can have orbital manifestations and clinicians should be aware of this unusual presentation of GCA in cases of presumed orbital inflammatory pseudotumor in the elderly.

The epidemiology of giant cell arteritis : a 12-year retrospective study.

OBJECTIVE: To study the incidence of biopsy-proven giant cell arteritis (GCA) in a Hispanic population with clinical features suggestive of GCA. DESIGN: Retrospective review. PARTICIPANTS: Records of 121 consecutive patients who underwent temporal artery biopsy at the Doheny Eye Institute and the Los Angeles County/University of Southern California Hospital from January 1986 through April 1998 were reviewed. MAIN OUTCOME MEASURES: The incidence of biopsy-proven GCA was determined, and the biopsy-positive group was compared with the biopsy-negative group. Study variables included age at diagnosis, gender, erythrocyte sedimentation rate (ESR), and ethnic background. RESULTS: Among these 121 patients who underwent temporal artery biopsy, the mean age of those in the biopsy-positive group (75.2 +/- 5.0 years) was higher than that of those in the biopsy-negative group (69.1 +/- 9.2 years; P < 0.0001). There was no statistical correlation between biopsy-positive and biopsy-negative groups for gender or ESR level, but ESR was statistically significant for whites when we controlled for race. Nineteen of 66 white patients (29%) had positive biopsy results, whereas only 1 of the 9 Asian patients (11%) none of the 40 Hispanic patients (0%; P < 0.0001) and none of the 6 African American patients (0%) had positive biopsy results. CONCLUSIONS: Giant cell arteritis occurs primarily in the white population. None of the Hispanic patients in our study was found to have positive biopsy results. Hispanic persons may have unknown factors that protect them from this disease. Further study is necessary to examine the genetic predisposition.

Exudative retinal detachment in relapsing polychondritis : case report and literature review.

OBJECTIVE: To report the atypical ocular symptoms (arterialized conjunctival vessels, exudative retinal detachment) that can be the presenting manifestations of relapsing polychondritis. DESIGN: Observational case report and literature review. METHODS: A complete ocular and systemic evaluation was performed on a patient with relapsing polychondritis and exudative retinal detachment. MAIN OUTCOME MEASURES: Retinal, choroidal, and scleral findings. RESULTS: A 73-year-old man with relapsing polychondritis presented with a unilateral large bullous exudative retinal detachment and marked choroidal and scleral thickening bilaterally. CONCLUSIONS: Ophthalmologists should consider relapsing polychondritis in the differential diagnosis of exudative retinal detachment. A combination of echographic and laboratory findings can assist in the accurate diagnosis of this rare condition.

The role of restricted motility in determining outcomes for vertical strabismus surgery in Graves' ophthalmology.

OBJECTIVE: To identify factors predictive of operative success or failure for vertical muscle surgery performed in patients with Graves' ophthalmopathy. DESIGN: Prospective noncomparative case series. PARTICIPANTS: Thirty-one consecutive patients with Graves' ophthalmopathy who demonstrated vertical ocular motor imbalance, with or without simultaneous horizontal muscle imbalance. INTERVENTION: Vertical extraocular muscle surgery performed either in isolation or in association with horizontal muscle surgery. MAIN OUTCOME MEASUREMENTS: Vertical limitations of extraocular muscles were correlated with preoperative hypertropia. Stepwise linear regression was used to determine the significant predictors of postoperative hypertropia in primary gaze. Logistic analysis was used to estimate the probability of surgical failure (>5 diopters) on the basis of preoperative parameters. RESULTS: The amount of preoperative hypertropia was negatively correlated with total restriction of vertical ductions (r = -0.52, P < 0.01). Preoperative hypertropia was positively correlated with asymmetry in muscle restriction between the two eyes (r = 0.67, P < 0.0001). The best predictor of preoperative hypertropia was the difference between restriction of the contralateral opposing recti, namely the right superior rectus, and the left inferior rectus, as well as the right inferior rectus and the left superior rectus (r = 0.74, P < 0.0001). Restriction of the contralateral opposing recti was also the most significant predictor of surgical success (postoperative hypertropia < 5 prism diopters). CONCLUSIONS: Surgery tailored to address restriction of ductions, specifically the difference between contralateral opposing recti, is likely to improve the success of initial surgery beyond that based primarily on the magnitude of the vertical deviation.

Occurrence of familial nonarteritic anterior ischemic optic neuropathy in a case series.

OBJECTIVE: To report on the occurrence of familial nonarteritic anterior ischemic optic neuropathy (NAION) in our NAION series. METHODS: One hundred forty-eight consecutive retrievable cases of NAION were surveyed regarding the occurrence of NAION in other family members. Medical records of affected family members were reviewed, and clinical characteristics of documented familial NAION cases were described. RESULTS: Of 79 patients who returned the survey, four reported one or more relatives with previously diagnosed NAION. There were nine cases of documented NAION in these four families. All cases occurred in siblings, with a mean age at onset of 55 years. Six patients had second eye involvement and in five, involvement became bilateral within 4 years after initial onset. None of the patients had diabetes; two had hypertension. CONCLUSION: A small number of patients with NAION may belong to a familial subclass. Three previous reports of familial NAION further support this hypothesis.

Age-related deterioration of motion perception and detection.

PURPOSE: The purpose of this study was to evaluate the effect of aging on motion detection and perception. METHODS: Forty-six subjects, ages 19-92 years, were asked to view a motion stimulus. Infrared oculography was used to objectively evaluate motion detection by documenting the presence of optokinetic nystagmus as the subjects viewed the stimulus. Subjective responses to motion perception were recorded using a computer joystick. RESULTS: Optokinetic nystagmus was clearly detectable in all 46 subjects. Motion detection and perception thresholds showed age-related deterioration. No relationship was found to gender or age-gender interaction. CONCLUSION: The results indicate motion detection and perception thresholds deteriorate with age. This may reflect a susceptibility to age-related degeneration in specific cortical areas responsible for motion perception as well as neurodegeneration in the retinogeniculate pathway.

Comparison of visual function in fellow eyes after bilateral nonarteritic anterior ischemic optic neuropathy.

PURPOSE: Although previous studies have examined the risk of bilaterality of nonarteritic ischemic optic neuropathy (NAION), none have compared extensively the extent of visual loss between fellow eyes. The authors examined cases of bilateral NAION to determine the extent of vision loss in the second eye compared with that in the first eye. METHODS: Thirty-one cases of bilateral NAION were reviewed. Variables included age, gender, and the presence of comorbid disease. Visual function was assessed by Snellen visual acuity, color vision, and pattern and mean deviation of the visual fields. RESULTS: No correlation was detected between the extent or pattern of visual loss in fellow eyes. No significant difference in visual function existed between first and second eyes for the patients overall. Patients who retained better visual function in the second eye were significantly older than those who retained better visual function in the first eye (visual acuity, P = 0.0005; color vision, P = 0.07; mean deviation, P = 0.02). In patients older than 50 years of age (25 of 31 cases), the second eye had significantly better visual acuity (P = 0.04) and less Humphrey visual field mean deviation (P = 0.04) than the first eye. CONCLUSION: Visual function in the second eye correlated poorly with that of the first eye. Older patients with bilateral NAION retained better visual function in the second eye than in the first eye. For younger patients, the extent of visual loss in the second eye could not be predicted based on the visual loss in the first eye.

Septic cavernous sinus thrombosis following transsphenoidal craniotomy. Case report.

The authors present a case of late-onset cavernous sinus thrombosis in a 74-year-old man who had undergone transsphenoidal craniotomy for a pituitary macroadenoma 9 weeks previously. The patient developed headache, rapidly progressive ophthalmoplegia, and signs of orbital congestion. After 2 days of ineffective broad spectrum antibiotic therapy he underwent a second transsphenoidal craniotomy for abscess drainage. Intraoperative cultures grew 4+ non-hemolytic Streptococcus, 4+ Staphylococcus coagulase negative, and 4+ Haemophilus influenzae. The patient was maintained on intravenous antibiotic therapy for the following 6 weeks, resulting in a complete clinical recovery. To the authors' knowledge, this is the first report of a septic cavernous sinus thrombosis following a transsphenoidal craniotomy.

Pseudotumor associated with CNS lymphoma.

A 42-year-old immune-competent woman with orbital pseudotumor and presumed intracranial extension into the temporal lobe responded well clinically and radiologically to high-doses of corticosteroids. Five months later, she developed worsening headaches and recurrence of the temporal lobe lesion. Biopsy revealed a central nervous system (CNS) lymphoma with severe reactive gliosis abutting an area of subarachnoid lymphocytic infiltrate.

Extraocular muscle changes in experimental orbital venous stasis: some similarities to Graves' orbitopathy.

BACKGROUND: Graves' orbitopathy (GO) is generally considered to have an autoimmune etiology. Recently, however, it has been hypothesized that orbital venous obstruction may contribute significantly to the clinical manifestations. To determine whether such obstruction could induce histologic and clinical findings consistent with GO, we developed an animal model of orbital venous obstruction by ligating the draining ophthalmic veins of the right eyes of four cats. METHODS: The branches of the ophthalmic veins were isolated and ligated following a lateral orbitotomy. Weekly photographs and echographs were taken of the cats; one cat was killed at each of four time points, namely 1, 2, 3, and 4 weeks after surgery. Histologic stains were applied to isolated orbital tissues to characterize pathologic changes. RESULTS: Clinically, there was onset of marked proptosis, chemosis, and exotropia. Histological findings within the extraocular muscles included activation and the presence of acid mucopolysaccharides 1 week after ligation, increased collagen and the presence of lymphoid cells at 2 weeks after ligation, and persistent interstitial lymphocytic infiltrates the 3rd and 4th weeks after ligation. CONCLUSION: Without evoking a primary orbital inflammation or inducing a systemic autoimmune disease, an animal model has been developed that closely mimics many of the advanced clinical and histologic changes that occur in GO.

Choroidal effusion as a mechanism for transient myopia induced by hydrochlorothiazide and triamterene.

PURPOSE: We treated a case of transient myopia in a patient being treated with hydrochlorothiazide and triamterene for tinnitus. METHODS: The patient underwent gonioscopic, ophthalmoscopic, and echographic examinations. RESULTS: Examination showed anterior chamber flattening and echography disclosed bilateral 360-degree shallow choroidal detachments. CONCLUSION: All of the patient's symptoms and signs resolved after the cessation of drug therapy.

Dissociation between the detection and perception of motion in Alzheimer's disease.

To better understand the damage to the motion pathway that occurs in senile dementia of the Alzheimer type (SDAT), we developed a system to assess separately the conscious perception and unconscious detection of motion in patients with SDAT. Motion perception thresholds were significantly elevated in SDAT (n = 9) compared with controls (n = 12), but motion detection thresholds were normal. This dissociation between the perception and detection of motion in early SDAT parallels histologic evidence of a disconnection between primary and association visual cortices. This disconnection may underlie the severe visual perception deficits seen in SDAT.