Local delivery of corticosteroids in clinical ophthalmology: A review.

Locally administered steroids have a long history in ophthalmology for the treatment of inflammatory conditions. Anterior segment conditions tend to be treated with topical steroids whilst posterior segment conditions generally require periocular, intravitreal or systemic administration for penetration. Over recent decades, the clinical applications of periocular steroid delivery have expanded to a wide range of conditions including macular oedema from retino-vascular conditions. Formulations have been developed with the aim to provide practical, targeted, longer-term and more efficacious therapy whilst minimizing side effects. Herein, we provide a comprehensive overview of the types of periocular steroid delivery, their clinical applications in ophthalmology and their side effects.

Integrin activation by Fam38A uses a novel mechanism of R-Ras targeting to the endoplasmic reticulum.

The integrin family of heterodimeric cell-surface receptors are fundamental in cell-cell and cell-matrix adhesion. Changes to either integrin-ligand affinity or integrin gene expression are central to a variety of disease processes, including inflammation, cardiovascular disease and cancer. In screening for novel activators of integrin-ligand affinity we identified the previously uncharacterised multi-transmembrane domain protein Fam38A, located at the endoplasmic reticulum (ER). siRNA knockdown of Fam38A in epithelial cells inactivates endogenous beta1 integrin, reducing cell adhesion. Fam38A mediates integrin activation by recruiting the small GTPase R-Ras to the ER, which activates the calcium-activated protease calpain by increasing Ca(2+) release from cytoplasmic stores. Fam38A-induced integrin activation is blocked by inhibition of either R-Ras or calpain activity, or by siRNA knockdown of talin, a well-described calpain substrate. This highlights a novel mechanism for integrin activation by Fam38A, utilising calpain and R-Ras signalling from the ER. These data represent the first description of a novel spatial regulator of R-Ras, of an alternative integrin activation-suppression pathway based on direct relocalisation of R-Ras to the ER, and of a mechanism linking R-Ras and calpain signalling from the ER with modulation of integrin-ligand affinity.

Familial retinal detachment associated with COL2A1 exon 2 and FZD4 mutations.

BACKGROUND: To characterize the clinical and genetic abnormalities within two Australian pedigrees with high incidences of retinal detachment and visual disability. DESIGN: Prospective review of two extended Australian pedigrees with high rates of retinal detachment. PARTICIPANTS: Twenty-two family members from two extended Australian pedigrees with high rates of retinal detachment were examined. METHODS: A full ophthalmic history and examination were performed, and DNA was analysed by linkage analysis and mutation screening. MAIN OUTCOME MEASURES: Characterization of a causative hereditary gene mutation in each family. RESULTS: All affected family members of one pedigree carried a C192A COL2A1 exon 2 mutation. None of the affected family members had early-onset arthritis, hearing abnormalities, abnormal clefting or facial features characteristic of classical Stickler syndrome. All affected members of the familial exudative vitreoretinopathy pedigree carried a 957delG FZD4 mutation. CONCLUSIONS: Patients with retinal detachment and a positive family history should be investigated for heritable conditions associated with retinal detachment such as Stickler syndrome and familial exudative vitreoretinopathy. The absence of non-ocular features of Stickler syndrome should raise the possibility of mutations in exon 2 of COL2A1. Similarly, late-onset familial exudative vitreoretinopathy may appear more like a rhegmatogenous detachment and not be correctly diagnosed. When a causative gene mutation is identified, cascade genetic screening of the family will facilitate genetic counselling and screening of high-risk relatives, allowing targeted management of the pre-detachment changes in affected patients.

Haemophilus parainfluenzae endocarditis presenting with symptoms of COVID-19.

A young man presented early in the UK's second COVID-19 pandemic surge with a twelve-day history of fever, dry cough, breathlessness, myalgia and loss of smell and taste. His chest X-ray showed bilateral ground-glass opacities. He was treated for COVID-19 pneumonitis but covered for bacterial infection with antibiotics. He developed shock and respiratory failure, requiring vasopressors and continuous positive airway pressure. He improved but experienced transient visual disturbances and headache. Nasopharyngeal swabs and antibody tests for COVID-19 were negative. Blood cultures grew Haemophilus parainfluenzae A new murmur prompted an echocardiogram. This confirmed a large, mobile mitral valve vegetation. An MRI of the brain showed bilateral embolic infarcts. He underwent urgent mitral valve repair and made an excellent recovery. Whether COVID-19 caused his presenting symptoms or facilitated the bacteraemia remains unclear. It seems more likely that infective endocarditis masqueraded as COVID-19. Clinicians should be aware of how context of the pandemic can bias diagnostic reasoning.

Endogenous endophthalmitis associated with intravenous drug abuse: seven-year experience at a tertiary referral center.

PURPOSE: Intravenous drug use (IVDU) is a known risk factor for endogenous endophthalmitis. Endogenous fungal endophthalmitis (EFE) is emerging as a common problem among this community. We describe the management and visual outcomes of acute IVDU-associated EFE. METHODS: A prospective consecutive case series of 19 patients presenting with presumed acute IVDU-associated EFE from 2001 to 2007 to the Royal Victorian Eye and Ear Hospital was included. All data were collected in a standardized manner. Outcome measures included visual acuity, microbial profiles, and vitrectomy rate. RESULTS: Nineteen cases of IVDU-associated EFE were identified. Eight of these (42%) were men, and the mean age was 32.7 years (SD ± 8.0 years). Presenting visual acuity ranged from 6/6 to perception of light, with 58% having a visual acuity of 6/48 or less at presentation. Thirteen (68.4%) were culture positive with all cultures identifying Candida species, and 52.7% underwent vitrectomy. Fifty percent of subjects overall achieved a final visual acuity of 6/18 or better. Men demonstrated improved visual acuity when compared with women (P = 0.04). Age had no effect on final acuity. CONCLUSION: Intravenous drug use is a significant risk factor for developing EFE. Good visual outcomes can be achieved with early treatment, often with intravitreal therapy alone.

EBUS-TBNA for the diagnosis of central parenchymal lung lesions not visible at routine bronchoscopy.

BACKGROUND: Obtaining a tissue diagnosis of malignancy is challenging in patients with suspected lung cancer presenting with centrally located intrapulmonary masses. OBJECTIVE: (1) To evaluate the yield of endobronchial ultrasound with real-time guided transbronchial needle aspiration (EBUS-TBNA) for diagnosing centrally located lesions after a non-diagnostic conventional bronchoscopy. (2) To assess the impact of EBUS-TBNA on patient management for this indication. STUDY DESIGN AND PATIENTS: A retrospective analysis of a series of patients with a central parenchymal lung lesion suspected to be lung cancer who had been referred to three university hospitals for EBUS-TBNA to obtain a tissue diagnosis was undertaken. If EBUS-TBNA did not result in a formal pathological diagnosis of malignancy, patients were subsequently referred for a transthoracic needle aspiration biopsy or a surgical diagnostic procedure. RESULTS: Sixty patients were investigated with EBUS-TBNA. The majority (82%) had a prior (non-diagnostic) flexible bronchoscopy. EBUS-TBNA was performed in an out-patient setting in 97%. With ultrasound, the primary lung lesion was observed in all cases. EBUS-TBNA confirmed lung cancer in 46 (77%). A final reference pathology diagnosis was available in 59 (98%) cases. The sensitivity of EBUS-TBNA for diagnosing lung cancer was 82% (95% confidence intervals (CI) 69-91%) with a negative predictive value of 23% (95%CI 5-53%). Based on the EBUS-TBNA findings, transthoracic needle aspiration biopsy or a surgical diagnostic procedure was cancelled in 47% and 30% of patients, respectively. No serious procedure-related complications were reported. CONCLUSION: EBUS-TBNA is a sensitive tool for the diagnosis of centrally located primary lung cancer not visible at conventional bronchoscopy. Therefore, EBUS-TBNA can impact on patient management in this setting. However, the low negative predictive value indicates that a negative EBUS-TBNA result should be confirmed by other methods. IMPLICATION: EBUS-TBNA can be considered as a diagnostic test in patients with a centrally located lung lesion after a previous non-diagnostic conventional bronchoscopy.

Avastin as an adjunct to vitrectomy in the management of severe proliferative diabetic retinopathy: a prospective case series.

PURPOSE: Bevacizumab (Avastin) is a monoclonal antibody which targets all isoforms of vascular endothelial growth factor A. Its potent anti-angiogenic effects have been shown to cause regression of neovascularization in proliferative diabetic retinopathy. The aim of this study is to investigate the role of Avastin as an adjunct to vitrectomy in the management of severe diabetic eye disease. METHODS: Sixteen patients (18 eyes) with severe proliferative diabetic retinopathy were recruited into the study. All eyes underwent a single intravitreal injection of bevacizumab 1.25 mg in 0.05 mL prior to vitrectomy surgery for the management of tractional retinal detachment or vitreous haemorrhage due to severe proliferative diabetic retinopathy. RESULTS: At 3 months, seven eyes had visual acuities which were better than baseline, four were unchanged and seven were worse. At 6 months, 14 eyes had visual acuities better than baseline, one was unchanged and three were worse. Seven of the 18 eyes (38.8%) had postoperative rebleeds, six of which required surgical washout. CONCLUSION: Avastin improved the ease of the surgery in these complex eyes and the early results are encouraging. We have found it to be particularly useful in diabetic eyes with traction detachments of short duration in which there is still active neovascularization.

Cross-linking CD98 promotes integrin-like signaling and anchorage-independent growth.

CD98, an early marker of T-cell activation, is an important regulator of integrin-mediated adhesion events. Previous studies suggest that CD98 is coupled to both cellular activation and transformation and is involved in the pathogenesis of viral infection, inflammatory disease, and cancer. Understanding of the molecular mechanisms underlying CD98 activity may have far-reaching practical applications in the development of novel therapeutic strategies in these disease states. Using small cell lung cancer cell lines, which are nonadherent, nonpolarized, and highly express CD98, we show that, in vitro, under physiological conditions, CD98 is constitutively associated with beta1 integrins regardless of activation status. Cross-linking CD98 with the monoclonal antibody 4F2 stimulated phosphatidylinositol (PI) 3-kinase, PI(3,4,5)P(3), and protein kinase B in the absence of integrin ligation or extracellular matrix engagement. Furthermore, cross-linking CD98 promoted anchorage-independent growth. Using fibroblasts derived from beta1 integrin null stem cells (GD25), wild-type GD25beta1, or GD25 cells expressing a mutation preventing beta1 integrin-dependent FAK phosphorylation, we demonstrate that a functional beta1 integrin is required for CD98 signaling. We propose that by cross-linking CD98, it acts as a "molecular facilitator" in the plasma membrane, clustering beta1 integrins to form high-density complexes. This results in integrin activation, integrin-like signaling, and anchorage-independent growth. Activation of PI 3-kinase may, in part, explain cellular transformation seen on overexpressing CD98. These results may provide a paradigm for events involved in such diverse processes as inflammation and viral-induced cell fusion.

Resectable Clinical N2 Non-Small Cell Lung Cancer; What Is the Optimal Treatment Strategy? An Update by the British Thoracic Society Lung Cancer Specialist Advisory Group.

Patients and clinicians are faced with uncertainty as to the optimal treatment strategy for potentially resectable NSCLC in which there is clinical evidence of involvement of the ipsilateral mediastinum. Randomized controlled trials and meta-analyses have failed to demonstrate superiority of one bimodality strategy over another (chemotherapy plus surgery versus chemotherapy plus radiotherapy). One trial of trimodality treatment with chemotherapy, radiotherapy, and surgery demonstrated an improvement in progression-free, but not overall, survival versus chemotherapy and radiotherapy. There are a number of limitations to the data in this complex and heterogenous patient group. No randomized controlled trial has specifically studied patients with single-station N2 disease versus multistation N2 disease. When discussing treatment for fit patients with potentially resectable cN2 NSCLC, lung cancer teams should consider trimodality treatment with chemotherapy, radiotherapy, and surgery or bimodality treatment with chemotherapy and either surgery or radiotherapy. We advocate that all patients see both a thoracic surgeon and the oncology team to discuss these different approaches.

Small cell lung cancer: the importance of the extracellular matrix.

Lung cancer is the leading cause of cancer deaths in the UK and the small cell lung cancer (SCLC) phenotype is the most aggressive form of this disease, with a high metastatic potential and the development of resistance to chemotherapy. Evidence now suggests that these features may be due to important links between the cancer cells and proteins in their local extracellular matrix (ECM). This article reviews the evidence for a chemoprotective effect of extracellular matrix in small cell lung cancer and discusses the importance of integrin-mediated signalling pathways in this setting.

EBUS-TBNA for the clarification of PET positive intra-thoracic lymph nodes-an international multi-centre experience.

INTRODUCTION: To determine the sensitivity and accuracy of endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) for clarification of the nature of fluorodeoxyglucose-positron emission tomography (FDG) positive hilar and/or mediastinal lymph nodes in patients with (suspected) lung cancer. METHODS: All consecutive patients who had undergone EBUS-TBNA alone for assessment of abnormal FDG-uptake in hilar and/or mediastinal lymph nodes between January 2005 and August 2007 were reviewed. RESULTS: One-hundred-nine patients underwent EBUS-TBNA of 127 positron emission tomography positive lymph nodes. Hilar (station 10 or 11) nodes (N1 or N3) were aspirated in 26 patients and mediastinal (stations 2, 4, 7) nodes (N2 or N3) in 90 patients. In 7 patients both hilar and mediastinal nodes were sampled. There were no procedure-related complications. Malignancy was detected in 77 (71%) cases. Thirty-two patients were tumor negative by EBUS-TBNA; subsequent surgical biopsy in 19 showed malignancy in 7. In four cases the false negative result was due to sampling error and in three cases due to detection error. In 13 cases surgical staging was not performed although long term follow-up in 3 showed no evidence of malignancy. The sensitivity and accuracy of EBUS-TBNA for malignancy in patients with reference pathology was 91% and 92%, respectively. The negative predictive value was 60%. If the 10 cases for which confirmatory surgical staging was not performed are assumed to be false negative results, overall sensitivity and accuracy were 82% and 84%, respectively. CONCLUSIONS: EBUS-TBNA offers an effective accurate, minimally invasive strategy for evaluating FDG avid hilar and mediastinal lymph nodes. However, negative findings should be confirmed by surgical staging.

Changing trends in sympathetic ophthalmia.

Sympathetic ophthalmia is a rare and potentially visually devastating bilateral panuveitis, typically following non-surgical penetrating injury to one eye. Three patients are presented where sympathetic ophthalmia developed after repeated vitreoretinal surgery. Prompt and effective management with systemic immunosuppressive agents permitted control of their disease and retention of good visual acuity in their remaining eye. Vitreoretinal surgery is an important risk factor in sympathetic ophthalmia. Informed consent for vitreoretinal surgery (especially in the re-operation setting) should now include the risk of sympathetic ophthalmia (approximately 1 in 800). Diverse clinical presentations are possible in sympathetic ophthalmia and any bilateral uveitis following vitreoretinal surgery should alert the surgeon to the possibility of sympathetic ophthalmia. Modern immunosuppressive therapy with systemic steroids and steroid-sparing agents such as cyclosporin A and azathioprine have improved the prognosis. This is particularly so in cases where early diagnosis is made and prompt and suitable immunotherapy is commenced.

Visual field assessment and the Austroads driving standard.

PURPOSE: To compare the conventional (Humphrey 24-2) automated visual field testing with the Goldmann standard visual field test for driving, and to predict how many patients with glaucoma may not meet the Australian driving standard with respect to visual fields. METHODS: Four patients (retinitis pigmentosa, glaucoma or vigabatrin treatment) with marked visual field defects as determined by uniocular static computerized perimetry (conventional testing) were re-evaluated with binocular kinetic Goldmann IV4e target field test (Australian driving standard). A series of 48 consecutive patients seen by the Glaucoma Inheritance Study in Tasmania were assessed with both static computerized perimetry and the Goldmann IV4e target test. RESULTS: The four patients with severe visual field defects (on computerized perimetry) were found to meet the driving standard on the binocular Goldmann IV4e target test. On computerized perimetry, 15 of 48 patients from the Glaucoma Inheritance Study in Tasmania were found to have visual field defects of sufficient severity that they may not meet the driving standard. However, only five of these patients failed the driving standard for visual fields, two of whom were still driving. CONCLUSIONS: Patients with severe field defects on conventional uniocular automated perimetry may still meet the Goldmann standard visual field test for driving. Approximately 30% of glaucoma patients would have visual field loss shown on Humphrey 24-2 test of a severity that requires further testing to determine if they meet the driving standard. Ten per cent of glaucoma patients tested did not meet the driving standard for visual fields.

Serum from patients with fulminant hepatic failure causes hepatocyte detachment and apoptosis by a beta(1)-integrin pathway.

Hepatocyte transplantation is restricted by the impaired ability of hepatocytes to engraft and survive in the damaged liver. Understanding the mechanisms that control this process will permit the development of strategies to improve engraftment. We studied changes in liver matrix during acute injury and delineated the mechanisms that perturb the successful adhesion and engraftment of hepatocytes. Collagen IV expression was increased in sinusoidal endothelium and portal tracts of fulminant hepatic failure explants, whereas there were minimal changes in the expression of fibronectin, tenascin, and laminin. Using an in vitro model of cellular adhesion, hepatocytes were cultured on collagen-coated plates and exposed to serum from patients with liver injury to ascertain their subsequent adhesion and survival. There was a rapid, temporally progressive decrease in the adhesive properties of hepatocytes exposed to such serum that occurred within 4 hours of exposure. Loss of activity of the beta1-integrin receptor, which controls adhesion to collagen, was seen to precede this loss of adhesive ability. Addition of the beta1-integrin activating antibody (TS2/16) to cells cultured with liver injury serum significantly increased their adhesion to collagen, and prevented significant apoptosis. In conclusion, we have identified an important mechanism that underpins the failure of infused hepatocytes to engraft and survive in liver injury. Pretreating cells with an activating antibody can improve their engraftment and survival, indicating that serum from patients with liver injury exerts a defined nontoxic biological effect. This finding has important implications in the future of cellular transplantation for liver and other organ diseases.