Chris Or

Acute lung injury induces cardiovascular dysfunction: Effects of IL-6 and budesonide/formoterol

Acute lung injury (ALI) is associated with systemic inflammation and cardiovascular dysfunction. IL-6 is a biomarker of this systemic response and a predictor of cardiovascular events, but its possible causal role is uncertain. Inhaled corticosteroids and long-acting β2 agonists (ICS/LABA) down-regulate the systemic expression of IL-6, but whether they can ameliorate the cardiovascular dysfunction related to ALI is uncertain. We sought to determine whether IL-6 contributes to the cardiovascular dysfunction related to ALI, and whether budesonide/formoterol ameliorates this process. Wild-type mice were pretreated for 3 hours with intratracheal budesonide, formoterol, or both, before LPS was sprayed into their tracheas. IL-6-deficient mice were similarly exposed to LPS. Four hours later, bronchoalveolar lavage fluid (BALF) and serum were collected, and endothelial and cardiac functions were measured, using wire myography of the aortic tissue and echocardiography, respectively. LPS significantly impaired vasodilatory responses to acetylcholine (P < 0.001) and cardiac output (P = 0.002) in wild-type but not IL-6-deficient mice. Intratracheal instillations of exogenous IL-6 into IL-6-deficient mice restored these impairments (vasodilatory responses to acetylcholine, P = 0.005; cardiac output, P = 0.025). Pretreatment with the combination of budesonide and formoterol, but not either alone, ameliorated the vasodilatory responses to acetylcholine (P = 0.018) and cardiac output (P < 0.001). These drugs also attenuated the rise in the systemic expression of IL-6 (P < 0.05) related to LPS. IL-6 contributes to the cardiovascular dysfunction related to LPS, and pretreatment with budesonide/formoterol reduces the systemic expression of IL-6 and improves cardiovascular dysfunction. ICS/LABA may reduce acute cardiovascular events related to ALI.

Exacerbation of choroidal and retinal pigment epithelial atrophy after anti-vascular endothelial growth factor treatment in neovascular age-related macular degeneration.

Purpose: To study the progression of retinal pigment epithelium (RPE) and choroidal atrophy in patients with neovascular age-related macular degeneration (AMD) and to assess for a possible association with the number and type of anti–vascular endothelial growth factor treatments. Methods: Patients with neovascular AMD and a minimum of 1-year follow-up were reviewed. Fellow eyes with nonneovascular AMD were used as control eyes. Retinal pigment epithelial atrophy area and choroidal thickness were determined using spectral-domain optical coherence tomography. Multivariable regression models were used for statistical analyses. Results: A total of 415 eyes were included in the study, with a mean follow-up of 2.2 years. Eyes with neovascular AMD had greater progression of RPE atrophy and choroidal atrophy compared with those with nonneovascular AMD (P < 0.001). Progression of RPE atrophy and choroidal atrophy was independently associated with the total number of injections of bevacizumab and ranibizumab (all P values ⩽ 0.001). In the subgroup of 84 eyes with neovascular AMD and without RPE atrophy at baseline, only bevacizumab was associated with the progression of RPE atrophy (P = 0.003). This study likely lacked statistical power to detect an association with ranibizumab in this subgroup. Conclusion: Retinal pigment epithelial atrophy and choroidal atrophy in neovascular AMD seem to be exacerbated by anti–vascular endothelial growth factor treatment. Possible differences between bevacizumab and ranibizumab require further investigation.

Optical coherence tomography-based measurement of drusen load predicts development of advanced age-related macular degeneration.

PURPOSE To determine whether baseline drusen load, as measured using spectral-domain optical coherence tomography (SD OCT), is a useful predictor of development of advanced age-related macular degeneration (AMD). DESIGN Retrospective cohort study. METHODS setting: Academic clinical practice. study population: All patients with non-neovascular AMD and no retinal pigment epithelial (RPE) atrophy at baseline who were seen between 2007 and 2012 in a single academic retina practice. A minimum of 1 year of follow-up was required. observation: Drusen load (area and volume) was assessed using automated SD OCT software algorithms. main outcome measure: RPE atrophy area, assessed using an automated SD OCT software algorithm, and the development of neovascular AMD. RESULTS Eighty-three patients met the inclusion criteria with a mean age of 80 years and a mean follow-up time of 2.8 years. Repeated-measures analysis of variance showed an association between drusen area (P = .005) and drusen volume (P = .001) and the development of RPE atrophy. We also found an association between drusen area (P = .001) and drusen volume (P = .001) and the development of neovascular AMD. CONCLUSIONS Drusen load, as measured using SD OCT, is associated with the development of RPE atrophy and neovascular AMD. SD OCT assessments of drusen load are simple and practical measurements that may be useful in stratifying the risk of developing advanced AMD. These measurements have potential applications in both routine clinical care and clinical trials.

Endotoxin-induced cardiovascular dysfunction in mice: effect of simvastatin

Lung infections are associated with acute lung injury (ALI), systemic inflammation, and vascular events. Clinical studies suggest that statins improve health outcomes of patients with pneumonia and ALI. The mechanisms by which this occurs are unknown. The aim of this study was to determine whether statins attenuate systemic inflammation and cardiovascular dysfunction related to ALI in mice. Simvastatin (SS; 20 mg/kg) or vehicle solution was instilled intraperitoneally into mice 24 h before and again just prior to intratracheal LPS instillation (1 μg/g). These mice were then anesthetized with 2.0% isoflurane and underwent a short surgical procedure to instill LPS. Four hours later, IL-6 levels in bronchoalveolar lavage fluid and in arterial and venous serum were measured. Cardiac function was evaluated using 2-D echocardiography, and endothelial function was determined using wire myography on aortic sections. LPS induced a significant increase in serum IL-6 levels. SS reduced venous (P = 0.040) but not arterial concentrations of IL-6 (P = 0.112). SS improved the maximal vasodilatory response of the aorta to ACh (P = 0.004) but not to sodium nitroprusside (P = 1.000). SS also improved cardiac output (P = 0.023). Vasodilatory response to ACh was impaired when aorta from untreated mice was incubated with ex vivo IL-6 (P = 0.004), whereas in the aorta from mice pretreated with SS, the vasodilatory response did not change with IL-6 incubation (P = 0.387). SS significantly improved LPS-induced cardiovascular dysfunction possibly by reducing systemic expression of IL-6 and its downstream signaling pathways. These findings may explain how statins improve health outcomes in patients with ALI.

Optical coherence tomography in the diagnosis and management of uveitis

Optical coherence tomography (OCT) has become an integral tool in the imaging of numerous diseases of the posterior segment. The diagnostic investigation of infectious and noninfectious uveitic conditions often requires multiple imaging modalities in the appropriate clinical context. Modern OCT technology has proved useful not only in the diagnostic investigation of these conditions, but also in monitoring of their clinical course and therapeutic response. Inflammation-induced changes at the level of the retina, retinal pigment epithelium, and choroid can now easily be identified in these conditions using OCT. Prognostic information on visual acuity outcome can also be estimated based on OCT findings. Numerous OCT findings have been described in the setting of the various uveitides. Although none of these findings appear to be pathognomonic for diagnosis of specific uveitic syndromes, in the appropriate clinical context they can add a great deal of information in the diagnosis and management of uveitis.

Pro-inflammatory and anti-angiogenic effects of bisphosphonates on human cultured retinal pigment epithelial cells.

Aim Bisphosphonates have been shown to induce ocular inflammatory diseases such as uveitis and scleritis, while being protective against angiogenic diseases like neovascular age-related macular degeneration (AMD). Therefore, we studied the effects of bisphosphonates on primary culture of human fetal retinal pigment epithelium (hRPE), a cell type known to secrete both inflammatory and angiogenic factors. Alendronate and etidronate were selected for this experiment as they are members of the two structurally different classes of bisphosphonates. Methods Primary cultures of hRPE were serum-starved for 24 h and then treated for 24 h with alendronate (0.0001, 0.1, 100 µM) or etidronate (0.01, 1 µM). Cell viability was measured using the MTT assay. Investigation of secreted cytokines induced by bisphosphonates was performed using a human cytokine 29-Plex Panel (Bio-Plex) array and the results were analysed with an analysis of variance (ANOVA). Results Etidronate, at the lower concentration, significantly increased the expression of interleukin (IL)-6 (p=0.03) and IL-8 (p=0.04). At the higher concentration, etidronate significantly decreased the expression of granulocyte macrophage colony-stimulating factor (p=0.02) and basic fibroblast growth factor (bFGF) (p=0.02). Alendronate, at the highest concentration, significantly increased the expression of IL-8 (p=0.02) and decreased the expression of eotaxin (p=0.02). Alendronate also significantly decreased the expression of bFGF at all concentrations (p<0.05) and demonstrated a trend towards decreasing vascular endothelial growth factor expression at low concentration. Conclusions Alendronate and etidronate display dose dependent effects in hRPE cells. Alendronate and etidronate administration resulted in concentration dependent elevations in inflammatory cytokines. Furthermore, alendronate and etidronate administration resulted in reduced expression of a number of angiogenic factors. These findings may explain the increased incidence of ocular inflammation as well as the therapeutic effect on neovascular AMD which have been described with bisphosphonates.

Alterations in intraocular cytokine levels following intravitreal ranibizumab

OBJECTIVE Our previous work has shown that, after intravitreal bevacizumab (IVB) administration, decreases in the levels of vascular endothelial growth factor (VEGF)-A and placental growth factor (PlGF), along with increases in the levels of interleukin (IL)-8 and transforming growth factor (TGF)-β2, can be observed. It is not yet known if similar changes occur after intravitreal ranibizumab (IVR). The purpose of this study was to examine intraocular cytokine changes after IVR. DESIGN Prospective clinical study. PARTICIPANTS Subjects with proliferative diabetic retinopathy requiring pars plana vitrectomy (PPV) were recruited. METHODS Participants received IVR as pre-treatment before PPV. Aqueous humour levels of IL-8, VEGF-A, PlGF, and TGF-β2 were measured at time of pre-treatment and PPV. Results were analyzed using univariate statistical models. RESULTS A total of 14 participants were recruited. After IVR administration, we observed a decrease in the levels of VEGF-A and PlGF, and an increase in the levels of IL-8 and TGF-β2. These results were statistically significant only for VEGF-A (p = 0.0001) and IL-8 (p = 0.0002). CONCLUSIONS The changes in cytokine levels after IVR mirror the changes seen after IVB. Further studies are warranted in order to determine if there are any differences between IVB and IVR in this regard.

Vitelliform focal choroidal excavation.

Focal choroidal excavations (FCE) are characterized by foveal or perifoveal choroid excavations seen on optical coherence tomography (OCT). The authors report a case of FCE associated with a vitelliform lesion within the excavation. A case of FCE associated with a small vitelliform lesion has been described previously, but the larger extent of the vitelliform lesion observed in the current case has not been previously reported. This may represent a novel category of FCE, vitelliform focal choroidal excavation, in which deposition of vitelliform material is associated with its development.

Uveitic crystalline maculopathy.

BackgroundThe purpose of this case report is to present a novel cause of crystalline maculopathy.FindingsA 52-year-old Japanese female presented with a 4-month history of decreased vision in the left eye. Best corrected visual acuity in the left eye was 20/40. Dilated fundus examination of the right eye was unremarkable, but that of the left eye demonstrated foveal yellow-green intraretinal crystals and mild vitritis. Optical coherence tomography of the left eye revealed small intraretinal fluid cysts and intraretinal crystals. Ultra-widefield fluorescein angiography was normal in the right eye, but that of the left eye demonstrated features of intermediate uveitis. There was no history or findings to suggest any cause for the crystals other than the uveitis.ConclusionsWe propose that this may represent a novel category of crystalline retinopathy, termed uveitic crystalline maculopathy. We hypothesize that breakdown of the blood-retinal barrier as seen in uveitis may contribute to the deposition of crystals in the macula, although the precise composition of the crystals is unknown.

Acute retinal necrosis secondary to cytomegalovirus following successful treatment of cytomegalovirus anterior uveitis in an immunocompetent adult.

radiation to the tumour bed and concurrent chemotherapy, which was completed in May 2009. In September 2009, the patient self-palpated a mass in her right cheek. CT showed multiple enhancing lesions along the right masseter muscle that were confirmed to be recurrent ACC. In October 2009, the patient began enrollment in Phase I trials, but unfortunately the ACC continued to progress. She experienced development of recurrent metastatic lesions in her neck, lungs, diffuse bony calvarial metastasis, dural-based metastasis, metastases in the masseter muscles, left orbital apex, liver, and spine despite treatment on multiple Phase I trials. In August 2010, the patient died secondary to respiratory failure caused by lung metastases. The 2 cases described in this report represent late relapses after IAC followed by surgery and radiation. In 1 case, because of the complication of jaw claudications, the definitive surgical treatment for the lacrimal gland ACC was delayed, and the patient initially refused an orbital exenteration, although later had to have an exenteration because of extensive recurrence of mass and intracranial extension of tumour. In the second case, despite the fact that the full prescribed course of treatment was given, including neoadjuvant IAC, orbital exenteration, and postoperative high-dose radiation therapy and intravenous chemotherapy, the patient still experienced development of massive diffuse metastasis and died. Our observations in the 2 cases reported in this article suggest that the potential toxicities of IAC and late recurrences may be underappreciated based on the published literature to date. Tse et al., in the Discussion of their report of their protocol prescribing IAC followed by orbital exenteration followed by radiation therapy and adjuvant chemotherapy, state that ‘‘toxicity from IAC is substantial,’’ but in the Results of the article, they do not report any specific side effects associated with IAC in the 9 patients treated with this regimen, making it difficult to know what the actual toxicity profile associated with IAC for ACC of lacrimal gland might be. To our knowledge, the patient described in case 1 of this report who experienced development of jaw claudication and possibly a stroke requiring hospitalization may be the only documented case in the literature with significant toxicity associated with IAC for lacrimal gland ACC.