The Role of Mitochondria-Linked Fatty-Acid Uptake-Driven Adipogenesis in Graves Orbitopathy.

CONTEXT: Depot-specific expansion of orbital adipose tissue (OAT) in Graves orbitopathy (GO; an autoimmune condition producing proptosis, visual impairment and reduced quality of life) is associated with fatty acid (FA)-uptake-driven adipogenesis in preadipocytes/fibroblasts (PFs). OBJECTIVE: This work sought a role for mitochondria in OAT adipogenesis in GO. METHODS: Confluent PFs from healthy OAT (OAT-H), OAT from GO (OAT-GO) and white adipose tissue in culture medium compared with culture medium containing a mixed hormonal cocktail as adipogenic medium (ADM), or culture-medium containing FA-supplementation, oleate:palmitate:linoleate (45:30:25%) with/without different concentration of mitochondrial biosubstrate adenosine 5'-diphosphate/guanosine 5'-diphosphate (ADP/GDP), AICAR (adenosine analogue), or inhibitor oligomycin-A for 17 days. Main outcome measures included oil-red-O staining and foci count of differentiated adipocytes for in vitro adipogenesis, flow cytometry, relative quantitative polymerase chain reaction, MTS-assay/106 cells, total cellular-ATP detection kit, and Seahorse-XFe96-Analyzer for mitochondria and oxidative-phosphorylation (OXPHOS)/glycolysis-ATP production analysis. RESULTS: During early adipogenesis before adipocyte formation (days 0, 4, and7), we observed OAT-specific cellular ATP production via mitochondrial OXPHOS in PFs both from OAT-H and OAT-GO, and substantially disrupted OXPHOS-ATP/glycolysis-ATP production in PFs from OAT-GO, for example, a 40% reduction in OXPHOS-ATP and trend-increased glycolysis-ATP production on days 4 and 7 compared with day 0, which contrasted with the stable levels in OAT-H. FA supplementation in culture-medium triggered adipogenesis in PFs both from OAT-H and OAT-GO, which was substantially enhanced by 1-mM GDP reaching 7% to 18% of ADM adipogenesis. The FA-uptake-driven adipogenesis was diminished by oligomycin-A but unaffected by treatment with ADP or AICAR. Furthermore, we observed a significant positive correlation between FA-uptake-driven adipogenesis by GDP and the ratios of OXPHOS-ATP/glycolysis-ATP through adipogenesis of PFs from OAT-GO. CONCLUSION: Our study confirmed that FA uptake can drive OAT adipogenesis and revealed a fundamental role for mitochondria-OXPHOS in GO development, which provides potential for therapeutic interventions.

Distinctive Features of Orbital Adipose Tissue (OAT) in Graves' Orbitopathy.

Depot specific expansion of orbital-adipose-tissue (OAT) in Graves' Orbitopathy (GO) is associated with lipid metabolism signaling defects. We hypothesize that the unique adipocyte biology of OAT facilitates its expansion in GO. A comprehensive comparison of OAT and white-adipose-tissue (WAT) was performed by light/electron-microscopy, lipidomic and transcriptional analysis using ex vivo WAT, healthy OAT (OAT-H) and OAT from GO (OAT-GO). OAT-H/OAT-GO have a single lipid-vacuole and low mitochondrial number. Lower lipolytic activity and smaller adipocytes of OAT-H/OAT-GO, accompanied by similar essential linoleic fatty acid (FA) and (low) FA synthesis to WAT, revealed a hyperplastic OAT expansion through external FA-uptake via abundant SLC27A6 (FA-transporter) expression. Mitochondrial dysfunction of OAT in GO was apparent, as evidenced by the increased mRNA expression of uncoupling protein 1 (UCP1) and mitofusin-2 (MFN2) in OAT-GO compared to OAT-H. Transcriptional profiles of OAT-H revealed high expression of Iroquois homeobox-family (IRX-3&5), and low expression in HOX-family/TBX5 (essential for WAT/BAT (brown-adipose-tissue)/BRITE (BRown-in-whITE) development). We demonstrated unique features of OAT not presented in either WAT or BAT/BRITE. This study reveals that the pathologically enhanced FA-uptake driven hyperplastic expansion of OAT in GO is associated with a depot specific mechanism (the SLC27A6 FA-transporter) and mitochondrial dysfunction. We uncovered that OAT functions as a distinctive fat depot, providing novel insights into adipocyte biology and the pathological development of OAT expansion in GO.

Management of acute retrobulbar haemorrhage: a survey of non-ophthalmic emergency department physicians.

INTRODUCTION: Acute retrobulbar haemorrhage (RBH) with orbital compartment syndrome is a sight-threatening ophthalmic emergency requiring treatment with lateral canthotomy and cantholysis (LC/C). However, such cases may present to non-ophthalmic emergency departments (ED) out-of-hours, when specialist intervention is not readily available. We completed a survey of ED physicians to explore experiences of RBH and confidence in undertaking LC/C. METHODS: From February to April 2018, an online survey was sent to ED physicians of all training grades in seven UK locations. The survey comprised a case vignette of a patient presenting with clinical features of RBH with orbital compartment syndrome, with multiple choice questions on the diagnosis, management and onward referral of such cases. Additional questions explored the experience of RBH, LC/C and perspectives on current and future training of ED physicians in this area. RESULTS: 190 ED doctors completed the survey (response rate 70%). While 82.8% correctly diagnosed RBH and 95.7% recognised irreversible visual loss as a consequence of untreated RBH with orbital compartment syndrome, 78.7% indicated that they would initially undertake CT imaging rather than performing LC/C. Only 38.9% had previously encountered a case of RBH and only 37.1% would perform LC/C themselves, with 91.4% indicating that this was due to lack of training. 92.2% felt that more training was required for ED physicians in RBH management and performing LC/C. CONCLUSION: While cases of RBH with orbital compartment syndrome are infrequent, it is important that RBH management with the vital, sight-saving skill of LC/C is added to the United Kingdom Royal College of Emergency Medicine training curriculum. At present, though the majority of ED physicians can identify RBH, the minority are willing or able to undertake LC/C, potentially risking irreversible but avoidable visual loss.

Periocular necrotising fasciitis: a multicentre case series.

INTRODUCTION: Necrotising fasciitis (NF) is a severe infection of deep subcutaneous soft tissues with high morbidity and mortality. Periocular necrotising fasciitis (PONF) is a very rare condition with many unanswered questions about the presentation and management. We present a retrospective case series of patients with PONF from three centres in Australia and two in the UK to investigate the clinical and microbiological characteristics and outcomes and report on patients treated with antibiotics alone. RESULTS: Twenty-nine patients (20 men; 69%) with PONF were identified and followed up for between 2 months and 10 years (median 57, mean 52.6 months) between 1990 and 2013. Conditions associated with chronic immunocompromise were present in 16/29 (55%). Twenty-one (75%) recalled minor periocular trauma or an infected lesion, two having been assaulted by the same assailant. Systemic shock occurred in 6/29 (21%) patients and 1 died. Group A, ß-haemolytic Streptococcus was the most common bacterium identified (25/29, 86%). Intravenous antibiotics were used in all patients, and up to five tissue debridements were required to control the disease in 23/29 (74%); reconstructive surgery was required in 12/29 (41%) patients. One patient died from the disease and visual loss occurred in four eyes of four patients (14%). CONCLUSIONS: PONF has a better prognosis than disease elsewhere in the body, but is still associated with significant risk of visual loss and a small risk of death. Intravenous antibiotic treatment with cautious observation may be reasonable in selected patients with a low threshold for debridement.

Ocular Findings in Alemtuzumab (Campath-1H)-induced Thyroid Eye Disease.

Alemtuzumab (Campath-1H) is a humanized anti-CD52 monoclonal antibody used in the treatment of multiple sclerosis (MS). Studies demonstrate significant reduction in relapse risk and the risk of accumulating sustained disability. Adverse events include infusion-associated reactions, infections, and secondary autoimmunity. Systemic thyroid disease is the most common secondary autoimmune event and affects up to approximately 30% of treated patients. This is the first description of the ocular findings and management in a case of thyroid eye disease (Graves' Ophthalmopathy [GO]) following alemtuzumab therapy. The ocular disease was managed conservatively while the systemic Graves' was managed with thyroidectomy.

Surgical Management of Cicatricial Ectropion in Pityriasis Rubra Pilaris.

Pityriasis rubra pilaris is an idiopathic, papulosquamous dermatological disease. It is clinically and histologically distinct from, but may resemble, psoriasis. Pityriasis rubra pilaris can be self-limiting but may also run a protracted, relapsing course. Medical treatment may involve topical emollients, systemic retinoids, methotrexate, and/or tumor necrosis factor antagonists. Ocular complications include cicatricial ectropion. The authors describe the surgical management of 3 patients with cicatricial ectropion secondary to pityriasis rubra pilaris. All patients had procedures involving skin grafts; 1 patient required multiple operations. The management principles are discussed, including the role and timing of surgery, within the context of emerging treatments for pityriasis rubra pilaris. Patients with pityriasis rubra pilaris and cicatricial ectropion should be closely managed by both ophthalmologist and dermatologist. The eyelid position may improve with conservative or surgical measures. If surgery is required, the limitations of skin grafting under these circumstances should be anticipated and patients counseled appropriately.

Prolonged mydriasis after inadvertent topical administration of the calcium channel antagonist amlodipine: implications for glaucoma drug development.

CONTEXT: Calcium channel inhibitors are being investigated as potential therapeutic adjuncts to reduce painful ciliary muscle spasm and control intraocular pressure in glaucoma. Relatively little is known about the effect of topical administration of calcium channel blockers in humans. OBJECTIVE: (1) To describe prolonged fixed pupil dilation resulting from exposure to topical amlodipine (2) to review the evidence that links calcium channel blockers with mydriasis and (3) to discuss the implications for glaucoma pharmacotherapy. DESIGN: Single interventional case report, literature review (including human and animal studies) and analysis of reported adverse drug reactions (ADRs) records in the USA and UK. CASE: A 35-year-old female doctor presented to eye casualty with blurred vision and bilateral, fixed, dilated pupils. A history of exposure to liquid amlodipine while preparing a paediatric chemotherapy regimen for a neuroblastoma patient was elicited. The patient was reassured and observed. RESULTS: Pupil function returned to normal within 48 h. A multi-national review of adverse drug reactions reports was conducted, as well as an extensive literature search for case reports and experimental studies. To the authors' knowledge this is the first report of amlodipine causing mydriasis and we discuss the potential molecular mechanism. CONCLUSIONS: This case is the first to suggest that calcium channel blockers can cause prolonged mydriasis. These agents have been investigated as potential adjuncts in glaucoma therapy. As accidental topical exposure to amlodipine can cause prolonged pupil dilation, it could precipitate angle closure in predisposed patients.

The versatility of the temporoparietal fascial graft (TPFG) in orbital implant exposure.

BACKGROUND: The use of TPFGs for hydroxyapatite, porous polyethylene and silicone implant exposure has been described previously. To the authors' knowledge, this is the first description of this technique for acrylic implant exposure and paediatric patients. PURPOSE: To demonstrate the versatility of the TPFG in orbital implant exposures of varying duration, implant types and patient age as well as for recurrent exposure. METHODS: Retrospective, interventional, non-comparative case series. RESULTS: Twelve patients (13 grafts) are presented with a mean follow-up of 9.5 months. The duration of exposure prior to grafting ranged from 1-11 months occurring in bioceramic, hydroxyapatite, porous polyethylene and acrylic implant types. There were 2 graft failures (success rate 84.6%), one of which was treated with a 2nd TPFG. Two of the cases were from the paediatric age group. CONCLUSION: This study provides further supporting evidence for the safety and efficacy of the TPFG and demonstrates the use of this graft in a variety of different clinical situations.