Evaluation of Optic Disc Edema in Long-Duration Spaceflight Crewmembers Using Retinal Photography.

BACKGROUND: Long-duration spaceflight crewmembers are at risk for spaceflight-associated neuro-ocular syndrome (SANS). One of the earliest manifestations of SANS is optic disc edema (ODE), which could be missed using the subjective Frisén scale. The primary objective of this study is to determine the inter-rater and intrarater reliability of Frisén grade for SANS-induced ODE among a trained observer cohort. The secondary objective is to propose a standardized evaluation process for SANS-induced ODE across International Space Station Partner Agencies. METHODS: Retrospective, double-blinded diagnostic study. Preflight and postflight fundus photographs were presented to subject matter experts who identified and graded ODE. Pairs of images were also compared side-by-side for disc ranking. Grader concordance was assessed for Frisén grading and disc ranking. RESULTS: Expert graders identified Grade 1 ODE in 17.35% of images from 62 crewmembers (9 female, mean [SD] age, 47.81 [5.19] years). Grades 2 and 3 were identified less than 2% of the time. Concordance in Frisén grades among pairs of graders was 70.99%. Graders identified a difference in preflight and postflight fundus photographs 17.21% of the time when using disc ranking. Pairs of graders had complete concordance in disc ranking 79.79% of the time. Perfect intrarater agreement between Frisén grade and disc ranking occurred 77.7% of the time. CONCLUSIONS: These findings demonstrate intergrader and intragrader variability when using the Frisén scale to identify SANS-induced ODE, which is typically milder in presentation than terrestrial cases of idiopathic intracranial hypertension. It is possible to miss early ODE on fundoscopy alone, making it insufficient as a sole criterion for the diagnosis of SANS. A more sensitive and objective method of surveillance is necessary to monitor international crewmembers for ODE, perhaps using a multimodal approach that includes technology such as optical coherence tomography.

Rehabilitation of cortically induced visual field loss.

PURPOSE OF REVIEW: Homonymous visual field defects are a common sequela of stroke, and are assumed to be permanent within a few weeks of the event. Because consensus about the efficacy of rehabilitation is lacking, visual therapy is rarely prescribed. Here, we review current rehabilitation options and strategies in the translational pipeline that could change these perspectives. RECENT FINDINGS: The mainstays of available therapy for homonymous visual defects are compensation training and substitution, which allow patients to better use their spared vision. However, early clinical studies suggest that vision can partially recover following intensive training inside the blind field. Research into the relative efficacy of different restorative approaches continues, providing insights into neurophysiologic substrates of recovery and its limitations. This, in turn, has led to new work examining the possible benefits of earlier intervention, advanced training procedures, noninvasive brain stimulation, and pharmacological adjuvants, all of which remain to be vetted through properly powered, randomized, clinical trials. SUMMARY: Research has uncovered substantial visual plasticity after occipital strokes, suggesting that rehabilitative strategies for this condition should be more aggressive. For maximal benefit, poststroke vision-restorative interventions should begin early, and in parallel with strategies that optimize everyday use of an expanding field of view.

Efficacy of Visual Retraining in the Hemianopic Field after Stroke: Results of a Randomized Clinical Trial.

PURPOSE: To evaluate the efficacy of motion discrimination training as a potential therapy for stroke-induced hemianopic visual field defects. DESIGN: Clinical trial. PARTICIPANTS: Forty-eight patients with stroke-induced homonymous hemianopia (HH) were randomized into 2 training arms: intervention and control. Patients were between 21 and 75 years of age and showed no ocular issues at presentation. METHODS: Patients were trained on a motion discrimination task previously evidenced to reduce visual field deficits, but not in a randomized clinical trial. Patients were randomized with equal allocation to receive training in either their sighted or deficit visual fields. Training was performed at home for 6 months, consisting of repeated visual discriminations at a single location for 20 to 30 minutes daily. Study staff and patients were masked to training type. Testing before and after training was identical, consisting of Humphrey visual fields (Carl Zeiss Meditech), macular integrity assessment perimetry, OCT, motion discrimination performance, and visual quality-of-life questionnaires. MAIN OUTCOME MEASURES: Primary outcome measures were changes in perimetric mean deviation (PMD) on Humphrey Visual Field Analyzer in both eyes. RESULTS: Mean PMDs improved over 6 months in deficit-trained patients (mean change in the right eye, 0.58 dB; 95% confidence interval, 0.07-1.08 dB; mean change in the left eye 0.84 dB; 95% confidence interval, 0.22-1.47 dB). No improvement was observed in sighted-trained patients (mean change in the right eye, 0.12 dB; 95% confidence interval, -0.38 to 0.62 dB; mean change in the left eye, 0.10 dB; 95% confidence interval, -0.52 to 0.72 dB). However, no significant differences were found between the alternative training methods (right eye, P = 0.19; left eye, P = 0.10). CONCLUSIONS: To date, no widely accepted therapy is available to treat HH. This study evaluated the efficacy of a promising potential treatment, visual perceptual training. We failed to find a difference between treatment training within the deficit field and control training within the sighted field when performed in a home environment.

The Aryl Hydrocarbon Receptor and Its Ligands Inhibit Myofibroblast Formation and Activation: Implications for Thyroid Eye Disease.

Thyroid eye disease (TED) is a degenerative disease that manifests with detrimental tissue remodeling, myofibroblast accumulation, and scarring in the orbit of affected individuals. Currently, there are no effective therapies for TED that target or prevent the excessive tissue remodeling caused by myofibroblast formation and activation. The canonical cytokine that induces myofibroblast formation is transforming growth factor (TGF)-ß. The TGF-ß signaling pathway is influenced by aryl hydrocarbon receptor (AHR) signaling pathways. We hypothesized that AHR agonists can prevent myofibroblast formation in fibroblasts from patients with TED, and thus AHR ligands are potential therapeutics for the disease. Orbital fibroblasts explanted from patients with TED were treated with TGF-ß to induce myofibroblast formation, contraction, and proliferation. We found that AHR ligands prevent TGF-ß-dependent myofibroblast formation, and this ability is dependent on AHR expression. The AHR and AHR ligands block profibrotic Wnt signaling by inhibiting the phosphorylation of GSK3ß to prevent myofibroblast formation. These results provide new insight into the molecular pathways underlying orbital scarring in TED. These novel studies highlight the potential of the AHR and AHR ligands as future therapeutic options for eye diseases and possibly also for other scarring conditions.

Salinomycin and other polyether ionophores are a new class of antiscarring agent.

Although scarring is a component of wound healing, excessive scar formation is a debilitating condition that results in pain, loss of tissue function, and even death. Many tissues, including the lungs, heart, skin, and eyes, can develop excessive scar tissue as a result of tissue injury, chronic inflammation, or autoimmune disease. Unfortunately, there are few, if any, effective treatments to prevent excess scarring, and new treatment strategies are needed. Using HEK293FT cells stably transfected with a TGFß-dependent luciferase reporter, we performed a small molecule screen to identify novel compounds with antiscarring activity. We discovered that the polyether ionophore salinomycin potently inhibited the formation of scar-forming myofibroblasts. Salinomycin (250 nm) blocked TGFß-dependent expression of the cardinal myofibroblast products α smooth muscle actin, calponin, and collagen in primary human fibroblasts without causing cell death. Salinomycin blocked phosphorylation and activation of TAK1 and p38, two proteins fundamentally involved in signaling myofibroblast and scar formation. Expression of constitutively active mitogen activated kinase kinase 6, which activates p38 MAPK, attenuated the ability of salinomycin to block myofibroblast formation, demonstrating that salinomycin targets the p38 kinase pathway to disrupt TGFß signaling. These data identify salinomycin and other polyether ionophores as novel potential antiscarring therapeutics.

Integrating the Internship into Ophthalmology Residency Programs: Association of University Professors of Ophthalmology American Academy of Ophthalmology White Paper.

Future ophthalmologists will need to have broad skills to thrive in complex health care organizations. However, training for ophthalmologists does not take advantage of all of the postgraduate years (PGYs). Although the traditional residency years seem to have little excess capacity, enhancing the internship year does offer an opportunity to expand the time for ophthalmology training in the same 4 PGYs. Integrating the internship year into residency would allow control of all of the PGYs, allowing our profession to optimize training for ophthalmology. In this white paper, we propose that we could capture an additional 6 months of training time by integrating basic ophthalmology training into the intern year. This would allow 6 additional months to expand training in areas such as quality improvement or time for "mini-fellowships" to allow graduates to develop a deeper set of skills.

Thy1 (CD90) controls adipogenesis by regulating activity of the Src family kinase, Fyn.

Worldwide obesity rates are at epidemic levels, and new insight into the regulation of obesity and adipogenesis are required. Thy1 (CD90), a cell surface protein with an enigmatic function, is expressed on subsets of fibroblasts and stem cells. We used a diet-induced obesity model to show that Thy1-null mice gain weight at a faster rate and gain 30% more weight than control C57BL/6 mice. During adipogenesis, Thy1 expression is lost in mouse 3T3-L1 cells. Overexpression of Thy1 blocked adipocyte formation and reduced mRNA and protein expression of an adipocyte marker, fatty acid-binding protein 4, by 5-fold. Although preadipocyte fibroblasts expressed Thy1 mRNA and protein, adipocytes from mouse and human fat tissue had almost undetectable Thy1 levels. Thy1 decreases the activity of the adipogenic transcription factor PPARγ by more than 60% as shown by PPARγ-dependent reporter assays. Using both genetic and pharmacologic approaches, we show Thy1 expression dampens PPARγ by inhibiting the activity of the Src-family kinase, Fyn. Thus, these studies reveal Thy1 blocks adipogenesis and PPARγ by inhibiting Fyn and support the idea that Thy1 is a novel therapeutic target in obesity.

Mapracorat, a selective glucocorticoid receptor agonist, upregulates RelB, an anti-inflammatory nuclear factor-kappaB protein, in human ocular cells.

Selective glucocorticoid receptor agonists (SEGRAs) are a new class of compounds under clinical evaluation for treatment of ocular inflammation. Widely prescribed therapeutics, such as glucocorticoids, are effective at reducing ocular inflammation, but their long term use predisposes to undesirable side effects. The purpose of this study was to investigate a novel SEGRA, mapracorat (BOL-303242-X), and the differences in mapracorat's mechanism of action compared with traditional steroids (i.e. dexamethasone). Keratocytes from three different humans were cultured and treated with mapracorat or dexamethasone, with and without a strong provoking agent, interleukin (IL)-1ß. The effects of mapracorat compared to dexamethasone were determined by measuring protein levels (Western blotting) and DNA binding (ELISA) for two nuclear factor-kappaB (NF-κB) family members, RelA and RelB. Cytokine production (i.e. IL-6, IL-8, prostaglandin E2 (PGE2)) was characterized by immunoassay. Our findings reveal mechanistic differences between mapracorat and traditional steroid therapies. Mapracorat showed partial attenuation of the classical NF-κB pathway, consistent with traditional steroids. However, mapracorat uniquely potentiated a novel anti-inflammatory mechanism through rapid upregulation of RelB, an anti-inflammatory member of the NF-κB alternative pathway. Mapracorat potently inhibits ocular inflammation in vitro and is a promising new treatment for ocular inflammatory disease. Mapracorat acts, in part, by a novel mechanism via upregulation of RelB in the NF-κB alternative pathway.

The idiopathic intracranial hypertension treatment trial: design considerations and methods.

BACKGROUND: The objectives of this study were to present the rationale for the main aspects of the study design and describe the trial methodology for the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). METHODS: Eligible candidates with mild visual field loss (automated perimetric mean deviation [PMD] -2 to -7 dB) were randomized to receive either acetazolamide or matching placebo tablets. Randomized participants were offered participation in a supervised dietary program. The primary outcome variable, PMD, was measured at 6 months. Additionally, cerebrospinal fluid from subjects and serum from study participants and matched controls were collected for genetic analysis and vitamin A studies. An ancillary optical coherence substudy was added to investigate the changes of papilledema in the optic nerve head and retina that correlate with Frisén grading, visual field deficits, and low-contrast visual acuity. RESULTS: The randomized trial entered 165 participants from March 17, 2010, through November 27, 2012, from the United States and Canada. The primary outcome (month 6) visits were successfully completed by June 15, 2013. Blood specimens were obtained from 165 controls without IIH to investigate vitamin A metabolism and genetic markers of potential risk factors for IIH. CONCLUSIONS: The IIHTT is the first randomized, double-masked placebo-controlled trial to study the effectiveness of medical treatment for patients with IIH.

Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial.

IMPORTANCE: Acetazolamide is commonly used to treat idiopathic intracranial hypertension (IIH), but there is insufficient information to establish an evidence base for its use. OBJECTIVE: To determine whether acetazolamide is beneficial in improving vision when added to a low-sodium weight reduction diet in patients with IIH and mild visual loss. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, double-masked, placebo-controlled study of acetazolamide in 165 participants with IIH and mild visual loss who received a low-sodium weight-reduction diet. Participants were enrolled at 38 academic and private practice sites in North America from March 2010 to November 2012 and followed up for 6 months (last visit in June 2013). All participants met the modified Dandy criteria for IIH and had a perimetric mean deviation (PMD) between -2 dB and -7 dB. The mean age was 29 years and all but 4 participants were women. INTERVENTIONS: Low-sodium weight-reduction diet plus the maximally tolerated dosage of acetazolamide (up to 4 g/d) or matching placebo for 6 months. MAIN OUTCOMES AND MEASURES: The planned primary outcome variable was the change in PMD from baseline to month 6 in the most affected eye, as measured by Humphrey Field Analyzer. Perimetric mean deviation is a measure of global visual field loss (mean deviation from age-corrected normal values), with a range of 2 to -32 dB; larger negative values indicate greater vision loss. Secondary outcome variables included changes in papilledema grade, quality of life (Visual Function Questionnaire 25 [VFQ-25] and 36-Item Short Form Health Survey), headache disability, and weight at month 6. RESULTS: The mean improvement in PMD was greater with acetazolamide (1.43 dB, from -3.53 dB at baseline to -2.10 dB at month 6; n = 86) than with placebo (0.71 dB, from -3.53 dB to -2.82 dB; n = 79); the difference was 0.71 dB (95% CI, 0 to 1.43 dB; P = .050). Mean improvements in papilledema grade (acetazolamide: -1.31, from 2.76 to 1.45; placebo: -0.61, from 2.76 to 2.15; treatment effect, -0.70; 95% CI, -0.99 to -0.41; P < .001) and vision-related quality of life as measured by the National Eye Institute VFQ-25 (acetazolamide: 8.33, from 82.97 to 91.30; placebo: 1.98, from 82.97 to 84.95; treatment effect, 6.35; 95% CI, 2.22 to 10.47; P = .003) and its 10-item neuro-ophthalmic supplement (acetazolamide: 9.82, from 75.45 to 85.27; placebo: 1.59, from 75.45 to 77.04; treatment effect, 8.23; 95% CI, 3.89 to 12.56; P < .001) were also observed with acetazolamide. Participants assigned to acetazolamide also experienced a reduction in weight (acetazolamide: -7.50 kg, from 107.72 kg to 100.22 kg; placebo: -3.45 kg, from 107.72 kg to 104.27 kg; treatment effect, -4.05 kg, 95% CI, -6.27 to -1.83 kg; P < .001). CONCLUSIONS AND RELEVANCE: In patients with IIH and mild visual loss, the use of acetazolamide with a low-sodium weight-reduction diet compared with diet alone resulted in modest improvement in visual field function. The clinical importance of this improvement remains to be determined. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01003639.

Training in Cortically Blinded Fields Appears to Confer Patient-Specific Benefit Against Retinal Thinning.

Purpose: Damage to the adult primary visual cortex (V1) causes vision loss in the contralateral hemifield, initiating a process of transsynaptic retrograde degeneration (TRD). Here, we examined retinal correlates of TRD using a new metric to account for global changes in inner retinal thickness and asked if perceptual training in the intact or blind field impacts its progression. Methods: We performed a meta-analysis of optical coherence tomography data in 48 participants with unilateral V1 stroke and homonymous visual defects who completed clinical trial NCT03350919. After measuring the thickness of the macular ganglion cell and inner plexiform layer (GCL-IPL) and the peripapillary retinal nerve fiber layer (RNFL), we computed individual laterality indices (LI) at baseline and after ∼6 months of daily motion discrimination training in the intact or blind field. Increasingly positive LI denoted greater layer thinning in retinal regions affected versus unaffected by the cortical damage. Results: Pretraining, the affected GCL-IPL and RNFL were thinner than their unaffected counterparts, generating LI values positively correlated with time since stroke. Participants trained in their intact field exhibited increased LIGCL-IPL. Those trained in their blind field had no significant change in LIGCL-IPL. LIRNFL did not change in either group. Conclusions: Relative shrinkage of the affected versus unaffected macular GCL-IPL can be reliably measured at an individual level and increases with time post-V1 stroke. Relative thinning progressed during intact-field training but appeared to be halted by training within the blind field, suggesting a potentially neuroprotective effect of this simple behavioral intervention.

Vision-related quality of life after unilateral occipital stroke.

BACKGROUND/OBJECTIVES: Stroke damage to the primary visual cortex induces large, homonymous visual field defects that impair daily living. Here, we asked if vision-related quality of life (VR-QoL) is impacted by time since stroke. SUBJECTS/METHODS: We conducted a retrospective meta-analysis of 95 occipital stroke patients (female/male = 26/69, 27-78 years old, 0.5-373.5 months poststroke) in whom VR-QoL was estimated using the National Eye Institute Visual Functioning Questionnaire (NEI-VFQ) and its 10-item neuro-ophthalmic supplement (Neuro10). Visual deficit severity was represented by the perimetric mean deviation (PMD) calculated from 24-2 Humphrey visual fields. Data were compared with published cohorts of visually intact controls. The relationship between VR-QoL and time poststroke was assessed across participants, adjusting for deficit severity and age with a multiple linear regression analysis. RESULTS: Occipital stroke patients had significantly lower NEI-VFQ and Neuro10 composite scores than controls. All subscale scores describing specific aspects of visual ability and functioning were impaired except for ocular pain and general health, which did not differ significantly from controls. Surprisingly, visual deficit severity was not correlated with either composite score, both of which increased with time poststroke, even when adjusting for PMD and age. CONCLUSIONS: VR-QoL appears to improve with time postoccipital stroke, irrespective of visual deficit size or patient age at insult. This may reflect the natural development of compensatory strategies and lifestyle adjustments. Thus, future studies examining the impact of rehabilitation on daily living in this patient population should consider the possibility that their VR-QoL may change gradually over time, even without therapeutic intervention.

Training in cortically-blind fields confers patient-specific benefit against retinal thinning after occipital stroke.

Purpose: Damage to the adult primary visual cortex (V1) causes vision loss in the contralateral hemifield, initiating a process of trans-synaptic retrograde degeneration (TRD). Here, we examined retinal correlates of TRD using a new metric to account for global changes in inner retinal thickness, and asked if perceptual training in the intact or blind field impacts its progression. Methods: We performed a meta-analysis of optical coherence tomography (OCT) data in 48 participants with unilateral V1 stroke and homonymous visual defects, who completed clinical trial NCT03350919. After measuring the thickness of the macular ganglion cell and inner plexiform layers (GCL-IPL), and the peripapillary retinal nerve fiber layer (RNFL), we computed individual laterality indices (LI) at baseline and after ~6 months of daily motion discrimination training in the intact- or blind-field. Increasingly positive LI denoted greater layer thinning in retinal regions affected versus unaffected by the cortical damage. Results: Pre-training, the affected GCL-IPL and RNFL were thinner than their unaffected counterparts, generating LI values positively correlated with time since stroke. Participants trained in their intact-field exhibited increased LIGCL-IPL. Those trained in their blind-field had no significant change in LIGCL-IPL. LIRNFL did not change in either group. Conclusions: Relative shrinkage of the affected versus unaffected macular GCL-IPL can be reliably measured at an individual level and increases with time post-V1 stroke. Relative thinning progressed during intact-field training, but appeared to be halted by training within the blind field, suggesting a potentially neuroprotective effect of this simple behavioral intervention.

Proof-of-concept and Randomized, Placebo-controlled Trials of an FcRn Inhibitor, Batoclimab, for Thyroid Eye Disease.

CONTEXT: Inhibition of the neonatal fragment crystallizable receptor (FcRn) reduces pathogenic thyrotropin receptor antibodies (TSH-R-Ab) that drive pathology in thyroid eye disease (TED). OBJECTIVE: We report the first clinical studies of an FcRn inhibitor, batoclimab, in TED. DESIGN: Proof-of-concept (POC) and randomized, double-blind placebo-controlled trials. SETTING: Multicenter. PARTICIPANTS: Patients with moderate-to-severe, active TED. INTERVENTION: In the POC trial, patients received weekly subcutaneous injections of batoclimab 680 mg for 2 weeks, followed by 340 mg for 4 weeks. In the double-blind trial, patients were randomized 2:2:1:2 to weekly batoclimab (680 mg, 340 mg, 255 mg) or placebo for 12 weeks. MAIN OUTCOME: Change from baseline in serum anti-TSH-R-Ab and total IgG (POC); 12-week proptosis response (randomized trial). RESULTS: The randomized trial was terminated because of an unanticipated increase in serum cholesterol; therefore, data from 65 of the planned 77 patients were analyzed. Both trials showed marked decreases in pathogenic anti-TSH-R-Ab and total IgG serum levels (P < .001) with batoclimab. In the randomized trial, there was no statistically significant difference with batoclimab vs placebo in proptosis response at 12 weeks, although significant differences were observed at several earlier timepoints. In addition, orbital muscle volume decreased (P < .03) at 12 weeks, whereas quality of life (appearance subscale) improved (P < .03) at 19 weeks in the 680-mg group. Batoclimab was generally well tolerated, with albumin reductions and increases in lipids that reversed upon discontinuation. CONCLUSIONS: These results provide insight into the efficacy and safety of batoclimab and support its further investigation as a potential therapy for TED.

Peroxisome proliferator-activated receptor gamma ligands inhibit transforming growth factor-beta-induced, hyaluronan-dependent, T cell adhesion to orbital fibroblasts.

Thyroid eye disease is characterized by the infiltration of leukocytes and accumulation of hyaluronan (HA) in orbital tissue. Inflamed orbital tissue expands in size due to excessive HA and to the formation of scar tissue (fibrosis) and/or adipose accumulation. Transforming growth factor ß (TGF-ß) acts as a key inducer of fibrosis by enhancing extracellular matrix production. Treatment of primary human orbital fibroblasts with TGF-ß led to significant increases in both HA synthesis and secretion. TGF-ß also strongly induced hyaluronan synthase 1 (HAS1) and HAS2 mRNA levels, which increased 50- and 6-fold, respectively. Remarkably, the addition of the peroxisome proliferator-activated receptor (PPARγ) ligands pioglitazone (Pio) or rosiglitazone (Rosi) to TGF-ß-treated orbital fibroblasts attenuated HA synthesis and reduced HAS1 and HAS2 mRNA levels. The attenuation of TGF-ß function by Pio and Rosi was independent of PPARγ activity. Furthermore, Pio and Rosi treatment inhibited TGF-ß-induced T cell adhesion to orbital fibroblasts. Our findings demonstrate that TGF-ß plays an important role in HA synthesis and in the inflammatory response by enhancing or facilitating inflammatory cell infiltration and adhesion to orbital tissue. Pio and Rosi exhibit anti-fibrotic and anti-inflammatory activity and may be useful in treating thyroid eye disease.

The aryl hydrocarbon receptor ligand ITE inhibits TGFß1-induced human myofibroblast differentiation.

Fibrosis can occur in any human tissue when the normal wound healing response is amplified. Such amplification results in fibroblast proliferation, myofibroblast differentiation, and excessive extracellular matrix deposition. Occurrence of these sequelae in organs such as the eye or lung can result in severe consequences to health. Unfortunately, medical treatment of fibrosis is limited by a lack of safe and effective therapies. These therapies may be developed by identifying agents that inhibit critical steps in fibrotic progression; one such step is myofibroblast differentiation triggered by transforming growth factor-ß1 (TGFß1). In this study, we demonstrate that TGFß1-induced myofibroblast differentiation is blocked in human fibroblasts by a candidate endogenous aryl hydrocarbon receptor (AhR) ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). Our data show that ITE disrupts TGFß1 signaling by inhibiting the nuclear translocation of Smad2/3/4. Although ITE functions as an AhR agonist, and biologically persistent AhR agonists, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, cause severe toxic effects, ITE exhibits no toxicity. Interestingly, ITE effectively inhibits TGFß1-driven myofibroblast differentiation in AhR(-/-) fibroblasts: Its ability to inhibit TGFß1 signaling is AhR independent. As supported by the results of this study, the small molecule ITE inhibits myofibroblast differentiation and may be useful clinically as an antiscarring agent.

Reliability of estimating ductions in thyroid eye disease: an International Thyroid Eye Disease Society multicenter study.

PURPOSE: To determine intraobserver and interobserver reliability of 3 clinical techniques for measuring ocular ductions in patients with thyroid eye disease and to compare these with an established method using a Goldmann perimeter. Our secondary goals were to compare the clinical methods for test duration, ease of learning and performance, and whether these differed between novices and experts. DESIGN: Multicenter, prospective, comparative trial. PARTICIPANTS: We recruited 38 patients with thyroid orbitopathy and reduced ocular motility from 7 academic centers. METHODS: At each center, 2 novices and 2 experts measured the ocular ductions of each eye of each patient in 4 directions (0°, 90°, 180°, and 270°) using 3 techniques (best guess [BG], light reflex [LR], and a ruler measuring [RU] technique). Test duration and clinicians' feedback were recorded. A subjective and objective measurement for ocular ductions using a Goldmann perimeter was performed for each subject by a trained technician. The 3 clinical measurements and the perimetry measurements were performed twice, separated by ≥1 hour. MAIN OUTCOME MEASURES: We measured the intraobserver and interobserver reliability of the 3 clinical techniques and intraobserver reliability of Goldmann perimeter. Clinical testing reliability was compared between experts and novices. We also examined test duration and clinician feedback. RESULTS: The LR technique had significantly better intraobserver and interobserver repeatability compared with the BG or RU clinical measurements and statistically was equivalent to the gold-standard perimetric technique. Reliability was constant regardless of the amount of restriction in ocular movement. There was no difference between reliability values for experts and novices. The LR and BG techniques were significantly faster than the RU or perimetry techniques and were considered easiest to learn and perform, but clinicians had most confidence in the LR technique results. CONCLUSIONS: The LR technique for measuring ocular ductions in thyroid orbitopathy is more reliable than other clinical techniques and as reliable as the established technique using the perimeter. However, unlike the latter method, it is easier to learn and perform by both novices and experts, is significantly faster, and can be performed by the clinician without machinery or a trained technician.

Lemierre syndrome causing bilateral cavernous sinus thrombosis.

Lemierre syndrome is an uncommon septic thrombophlebitis of the veins of the head and the neck usually occurring after a severe oropharyngeal infection. Although subsequent septic emboli most commonly affect distant sites, such as the lungs and joints, the authors present a case of Lemierre syndrome causing bilateral cavernous sinus syndrome.