Publications by authors named "Sofia Theodoropoulou"

32 Publications

Study of Xbal and Pvull polymorphisms of estrogen receptor alpha (ERα) gene in girls with precocious/early puberty.

Endocrine 2021 May 4. Epub 2021 May 4.

Pediatric Endocrinology Unit, Third Department of Pediatrics, "Attikon" University Hospital, National and Kapodistrian University of Athens, Athens, Greece.

Purpose: Studies examining association of estrogen receptor alpha (ERα) polymorphisms with early puberty are scarce and results are controversial; data in Caucasian girls are lacking. Main objective was to determine association of Xbal and Pvull polymorphisms of ERα gene in Greek girls with precocious/early puberty METHODS: We studied 107 girls with idiopathic precocious/early puberty and 81 young women with pubertal maturation within normal age (controls). Pubertal stage, height SDS (HSDS), and BMI z-score were determined in patients. In controls, height was measured and menarcheal age was self-reported. All participants in the study were genotyped for XbaI and PvuII polymorphisms of the ERα gene.

Results: There was no significant difference in XbaI and PvuII polymorphisms between patients and controls. Homozygous, xx and pp, girls had an earlier onset of puberty, although non-significant, than heterozygous or with no polymorphisms p = 0.9; in girls with pubertal onset <7 years, the association tended to become significant, p = 0.09. Girls with xxpp genotype were significantly taller, HSDS 1.63, p = 0.014. In controls, homozygosity for Xbal (xx) and PvuII (pp) was associated with significantly earlier menarche than in women with no polymorphism, p = 0.013 and p = 0.026, respectively, and xxpp genotype was associated with taller adult height, p = 0.017.

Conclusion: XbaI and PvuII polymorphisms are not related to idiopathic precocious/early puberty. Early pubertal girls homozygous for both polymorphisms presented earlier onset of puberty, although statistically non-significant, and taller height than girls heterozygous or without these polymorphisms. Homozygosity for both polymorphisms is associated with earlier menarche and taller adult height.
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http://dx.doi.org/10.1007/s12020-021-02695-0DOI Listing
May 2021

Interleukin-33 regulates metabolic reprogramming of the retinal pigment epithelium in response to immune stressors.

JCI Insight 2021 04 22;6(8). Epub 2021 Apr 22.

Academic Unit of Ophthalmology, Translational Health Sciences, Bristol Medical School.

It remains unresolved how retinal pigment epithelial cell metabolism is regulated following immune activation to maintain retinal homeostasis and retinal function. We exposed retinal pigment epithelium (RPE) to several stress signals, particularly Toll-like receptor stimulation, and uncovered an ability of RPE to adapt their metabolic preference on aerobic glycolysis or oxidative glucose metabolism in response to different immune stimuli. We have identified interleukin-33 (IL-33) as a key metabolic checkpoint that antagonizes the Warburg effect to ensure the functional stability of the RPE. The identification of IL-33 as a key regulator of mitochondrial metabolism suggests roles for the cytokine that go beyond its extracellular "alarmin" activities. IL-33 exerts control over mitochondrial respiration in RPE by facilitating oxidative pyruvate catabolism. We have also revealed that in the absence of IL-33, mitochondrial function declined and resultant bioenergetic switching was aligned with altered mitochondrial morphology. Our data not only shed new light on the molecular pathway of activation of mitochondrial respiration in RPE in response to immune stressors but also uncover a potentially novel role of nuclear intrinsic IL-33 as a metabolic checkpoint regulator.
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http://dx.doi.org/10.1172/jci.insight.129429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119202PMC
April 2021

Treatment with interleukin-33 is non-toxic and protects retinal pigment epithelium in an ageing model of outer retinal degeneration.

J Cell Mol Med 2020 11 20;24(22):13546-13550. Epub 2020 Oct 20.

Department of Ophthalmology, Cheltenham General Hospital, Cheltenham, UK.

The leading cause of central vision loss, age-related macular degeneration (AMD), is a degenerative disorder characterized by atrophy of retinal pigment epithelium (RPE) and photoreceptors. For 15% of cases, neovascularization occurs, leading to acute vision loss if left untreated. For the remaining patients, there are currently no treatment options and preventing progressive RPE atrophy remains the main therapeutic goal. Previously, we have shown treatment with interleukin-33 can reduce choroidal neovascularization and attenuate tissue remodelling. Here, we investigate IL-33 delivery in aged, high-fat diet (HFD) fed mice on a wildtype and complement factor H heterozygous knockout background. We characterize the non-toxic effect following intravitreal injection of IL-33 and further demonstrate protective effects against RPE cell death with evidence of maintaining metabolic retinal homeostasis of Cfh+/-~HFD mice. Our results further support the potential utility of IL-33 to prevent AMD progression.
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http://dx.doi.org/10.1111/jcmm.16000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701527PMC
November 2020

Treatment of diabetic retinopathy through neuropeptide Y-mediated enhancement of neurovascular microenvironment.

J Cell Mol Med 2020 04 6;24(7):3958-3970. Epub 2020 Mar 6.

Academic Unit of Ophthalmology, Bristol Medical School, University of Bristol, Bristol, UK.

Diabetic retinopathy (DR) is one of the most severe clinical manifestations of diabetes mellitus and a major cause of blindness. DR is principally a microvascular disease, although the pathogenesis also involves metabolic reactive intermediates which induce neuronal and glial activation resulting in disruption of the neurovascular unit and regulation of the microvasculature. However, the impact of neural/glial activation in DR remains controversial, notwithstanding our understanding as to when neural/glial activation occurs in the course of disease. The objective of this study was to determine a potential protective role of neuropeptide Y (NPY) using an established model of DR permissive to N-methyl-D-aspartate (NMDA)-induced excitotoxic apoptosis of retinal ganglion cells (RGC) and vascular endothelial growth factor (VEGF)-induced vascular leakage. In vitro evaluation using primary retinal endothelial cells demonstrates that NPY promotes vascular integrity, demonstrated by maintained tight junction protein expression and reduced permeability in response to VEGF treatment. Furthermore, ex vivo assessment of retinal tissue explants shows that NPY can protect RGC from excitotoxic-induced apoptosis. In vivo clinical imaging and ex vivo tissue analysis in the diabetic model permitted assessment of NPY treatment in relation to neural and endothelial changes. The neuroprotective effects of NPY were confirmed by attenuating NMDA-induced retinal neural apoptosis and able to maintain inner retinal vascular integrity. These findings could have important clinical implications and offer novel therapeutic approaches for the treatment in the early stages of DR.
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http://dx.doi.org/10.1111/jcmm.15016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171318PMC
April 2020

Dysregulated claudin-5 cycling in the inner retina causes retinal pigment epithelial cell atrophy.

JCI Insight 2019 08 8;4(15). Epub 2019 Aug 8.

Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.

Age-related macular degeneration (AMD) is the leading cause of central retinal vision loss worldwide, with an estimated 1 in 10 people over the age of 55 showing early signs of the condition. There are currently no forms of therapy available for the end stage of dry AMD, geographic atrophy (GA). Here, we show that the inner blood-retina barrier (iBRB) is highly dynamic and may play a contributory role in GA development. We have discovered that the gene CLDN5, which encodes claudin-5, a tight junction protein abundantly expressed at the iBRB, is regulated by BMAL1 and the circadian clock. Persistent suppression of claudin-5 expression in mice exposed to a cholesterol-enriched diet induced striking retinal pigment epithelium (RPE) cell atrophy, and persistent targeted suppression of claudin-5 in the macular region of nonhuman primates induced RPE cell atrophy. Moreover, fundus fluorescein angiography in human and nonhuman primate subjects showed increased retinal vascular permeability in the evening compared with the morning. These findings implicate an inner retina-derived component in the early pathophysiological changes observed in AMD, and we suggest that restoring the integrity of the iBRB may represent a novel therapeutic target for the prevention and treatment of GA secondary to dry AMD.
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http://dx.doi.org/10.1172/jci.insight.130273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693834PMC
August 2019

Corrigendum to "Restoring retinal neurovascular health via substance P" [Exp. Cell Res. (2019)].

Exp Cell Res 2019 Sep 5;382(2):111482. Epub 2019 Jul 5.

Academic Unit of Ophthalmology, Bristol Medical School, University of Bristol, Bristol, UK; National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital and University College London Institute of Ophthalmology, London, UK. Electronic address:

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http://dx.doi.org/10.1016/j.yexcr.2019.06.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876269PMC
September 2019

Restoring retinal neurovascular health via substance P.

Exp Cell Res 2019 07 14;380(2):115-123. Epub 2019 Apr 14.

Academic Unit of Ophthalmology, Bristol Medical School, University of Bristol, Bristol, UK; National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital and University College London Institute of Ophthalmology, London, UK. Electronic address:

Regulation of vascular permeability plays a major role in the pathophysiology of visually threatening conditions such as retinal vein occlusion and diabetic retinopathy. Principally, several factors such as vascular endothelial growth factor (VEGF), are up-regulated or induced in response to hypoxia thus adversely affecting the blood-retinal barrier (BRB), resulting in retinal edema and neovascularisation. Furthermore, current evidence supports a dysregulation of the inner retinal neural-vascular integrity as a critical factor driving retinal ganglion cell (RGC) death and visual loss. The principal objective of this study was to interrogate whether Substance P (SP), a constitutive neurotransmitter of amacrine and ganglion cells, may protect against N-methyl-d-aspartate (NMDA)-induced excitotoxic apoptosis of ganglion cells and VEGF-induced vessel leakage in the retina. Tight junctional protein expression and a Vascular Permeability Image Assay were used to determine vascular integrity in vitro. The protective effect of SP on RGC was established in ex vivo retinal explants and in vivo murine models. After NMDA administration, a reduction in TUNEL+ cells and a maintained number of Brn-3a+ cells were found, indicating an inhibition of RGC apoptosis mediated by SP. Additionally, SP maintained endothelial tight junctions and decreased VEGF-induced vascular permeability. In conclusion, administration of SP protects against NMDA apoptosis of RGC and VEGF-induced endothelial barrier breakdown.
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http://dx.doi.org/10.1016/j.yexcr.2019.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548993PMC
July 2019

Müller Cells Stabilize Microvasculature through Hypoxic Preconditioning.

Cell Physiol Biochem 2019 ;52(4):668-680

Academic Unit of Ophthalmology, Bristol Medical School, University of Bristol, Bristol, UK,

Background/aims: Hypoxia of the retina is a common pathogenic drive leading to vision loss as a result of tissue ischemia, increased vascular permeability and ultimately retinal neovascularisation. Here we tested the hypothesis that Müller cells stabilize the neurovascular unit, microvasculature by suppression of HIF-1α activation as a result of hypoxic preconditioning.

Methods: Tube Formation Assay and In vitro Vascular Permeability Image Assay were used to analyze angiogenesis and vascular integrity. Seahorse XF Cell Mito Stress Test was used to measure mitochondrial respiration. Gene and protein expression were examined by qRTPCR, ELISA and western blot.

Results: Hypoxic insult induces a significant induction of proangiogenic factors including vascular endothelial growth factor (VEGF) and angiopoietinlike 4 (ANGPTL-4) resulting in angiogenesis and increased vascular permeability of vascular endothelial cells. Hypoxic preconditioning of a human retinal Müller glia cell line significantly attenuates HIF-1α activation through the inhibition of mTOR and concomitant induction of aerobic glycolysis, stabilizing endothelial cells.

Conclusion: Hypoxic preconditioning of Müller cells confers a robust protection to endothelial cells, through the suppression of HIF1α activation and its downstream regulation of VEGF and ANGPTL-4.
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http://dx.doi.org/10.33594/000000047DOI Listing
April 2019

Clinical pathophysiology of thyroid eye disease: The Cone Model.

Eye (Lond) 2019 02 18;33(2):244-253. Epub 2019 Jan 18.

Trainee Ophthalmologist, Bristol Eye Hospital, Bristol, UK.

The clinical features of thyroid eye disease are dictated by the orbit's compartmentalisation; particularly, the muscle cone, which is delimited by the rectus muscles, their inter-muscular septa and the posterior sclera. The cone is anchored to the orbit apex and contains the posterior globe, the muscle bellies, a fat pad, and the blood circulation, optic nerve, and CSF sheath. It is surrounded by mobile extraconal fat, retained by the orbital septum.Thyroid eye disease is caused by expansion of muscle bellies and fat within the cone. Mechanical properties of the cone determine that the disease partitions into three phases: circumferential expansion, with forward displacement of extraconal fat; axial elongation, with increasing cone pressure; impedance of posterior venous outflow, with cone oedema and venous flow reversal.Venous flow reversal can be observed in the conjunctival circulation. It is initially transient, accompanying rises in cone pressure caused by eye movements, but later becomes permanent. It is a useful clinical sign that locates diseased muscles and anticipates venous compressive crises.Strabismus arises when inflamed rectus muscles, swollen by hydrated glycosaminoglycans, lose contractility and compliance. The incomitance is moderated by increasing stiffness affecting all the rectus muscles, as they are stretched during cone expansion.Immunomodulation, which rapidly reduces cone volume, relieving muscle elongation and stiffness, may paradoxically unmask strabismus. However, ciclosporin A suppresses late post-inflammatory fibrosis and only 4 of 71 patients so-treated required strabismus surgery.The cone model also accounts for the variety of clinical presentations of thyroid eye disease.
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http://dx.doi.org/10.1038/s41433-018-0302-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367424PMC
February 2019

Serous macular detachment due to nasally located optic disc pit-coloboma.

Int J Ophthalmol 2018 18;11(11):1879-1880. Epub 2018 Nov 18.

Department of Ophthalmology, Attikon Hospital, University of Athens, Athens 12462, Greece.

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http://dx.doi.org/10.18240/ijo.2018.11.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232316PMC
November 2018

Comment re: Comparison of the horizontal diameter to a modeled area of traction in eyes with vitreomacular traction: is the diameter close enough to the truth?

Graefes Arch Clin Exp Ophthalmol 2018 12 25;256(12):2483-2484. Epub 2018 Aug 25.

2nd Department of Ophthalmology, University of Athens, Athens, Greece.

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http://dx.doi.org/10.1007/s00417-018-4113-7DOI Listing
December 2018

A Perspective of AMD Through the Eyes of Immunology.

Invest Ophthalmol Vis Sci 2018 03;59(4):AMD83-AMD92

Translational Health Sciences (Ophthalmology), University of Bristol, Bristol, United Kingdom.

Despite strong genetic associations, compelling human histological data and numerous hypotheses generated with supportive animal data, the mechanisms of inflammation or inflammatory control of cell health during progression of age-related macular degeneration arguably remain elusive. This perspective delivers a view that maintaining tissue health requires active immune cellular and tissue pathways, but when responses are perturbed or exaggerated, chronic inflammation is destructive. There are potential pathways and processes to enable understanding and determine how potential causative factors including altered cellular metabolism, senescence, oxidative stress disrupt tissue homeostasis are engaged. Establishing differences in the immune phenotype between normal aging and AMD, and how the inter-relatedness of these triggers contribute to pathobiology is integral for future therapeutic success.
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http://dx.doi.org/10.1167/iovs.18-23893DOI Listing
March 2018

Short-term safety of dexamethasone implant for treatment of macular edema due to retinal vein occlusion, in eyes with glaucoma or treated ocular hypertension.

Graefes Arch Clin Exp Ophthalmol 2017 Apr 22;255(4):725-732. Epub 2016 Nov 22.

Gloucestershire Eye Unit, Cheltenham General Hospital, Sandford Road, Cheltenham, UK.

Purpose: To report the short-term safety of dexamethasone implants to treat macular edema due to retinal vein occlusion (RVO), in eyes with treated glaucoma or ocular hypertension at baseline using an as-needed re-treatment regimen.

Methods: Retrospective clinical database study from two centers using the same electronic medical record system. Extracted data included: intraocular pressure (IOP), visual acuity (VA), central 1 mm retinal thickness (CRT) by optical coherence tomography, phakic status, number of injections, glaucoma treatment, and peri-operative complications.

Results: Thirty-three eyes of 33 patients on IOP-lowering treatment for glaucoma or ocular hypertension (OHT) at baseline and mean IOP of 16 mmHg at baseline received one to four (mean, 1.8; median, 1) dexamethasone implants over 18 months for RVO-related macular edema. Fourteen eyes (42 %) had IOP of ≥21 mmHg, and three eyes (9 %) had IOP of ≥35 mmHg at one or more visits during the study period. Nine of 14 eyes (64 %) with raised IOP required additional topical treatment only for a mean (SE) period of 8.5 months (3.2), while the remaining five eyes (36 %) required long-term additional IOP-lowering treatment for a mean (SE) of 16 months (1.44). Surgery for IOP lowering was not required in any eye. Mean VA (SE) improved from 44 (3) ETDRS letters at baseline to 47 letters (5) at 2 months (p = 0.049), 48 (8) letters at 6 months and 46 (4) letters at 12 months. Mean CRT (SE) improved from 530 (25) μm at baseline to 323 (27) μm at 2 months (p < 0.001), 498 (76) μm at 6 months, and 359 (25) μm at 12 months (p < 0.001).

Conclusion: The short-term IOP rise after intravitreal dexamethasone implant in eyes with glaucoma or ocular hypertension at baseline was acceptable and consistent with previous reports in patients without preexisting glaucoma. Treated OHT or glaucoma may not be a strict contraindication against the use of dexamethasone implant, but close monitoring of IOP is required.
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http://dx.doi.org/10.1007/s00417-016-3553-1DOI Listing
April 2017

Optical Coherence Tomography Angiography Findings in Dengue-Related Maculopathy: A Case Report.

Ophthalmic Surg Lasers Imaging Retina 2016 11;47(11):1057-1060

The ophthalmic manifestations of dengue fever include a visually impairing maculopathy, where patients are left with a central or paracentral relative scotoma. The authors present a case of a 26-year-old female patient returning from Thailand with unilateral reduction in visual acuity and a central scotoma associated with dengue fever. The authors report the use of the optical coherence tomography angiography (OCTA) as a noninvasive imaging platform to demonstrate its value in showing the persistent changes corresponding to the functional central scotoma in dengue-related maculopathy, which often cannot be visualized clinically or by standard OCT and fundus fluorescein angiography. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1057-1060.].
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http://dx.doi.org/10.3928/23258160-20161031-12DOI Listing
November 2016

Interleukin-33 regulates tissue remodelling and inhibits angiogenesis in the eye.

J Pathol 2017 Jan 16;241(1):45-56. Epub 2016 Nov 16.

Academic Unit of Ophthalmology, School of Clinical Sciences, University of Bristol, Bristol, UK.

Age-related macular degeneration (AMD) is the leading cause of central vision loss worldwide. Loss of retinal pigment epithelium (RPE) is a major pathological hallmark in AMD with or without pathological neovascularization. Although activation of the immune system is implicated in disease progression, pathological pathways remain diverse and unclear. Here, we report an unexpected protective role of a pro-inflammatory cytokine, interleukin-33 (IL-33), in ocular angiogenesis. IL-33 and its receptor (ST2) are expressed constitutively in human and murine retina and choroid. When RPE was activated, IL-33 expression was markedly elevated in vitro. We found that IL-33 regulated tissue remodelling by attenuating wound-healing responses, including reduction in the migration of choroidal fibroblasts and retinal microvascular endothelial cells, and inhibition of collagen gel contraction. In vivo, local administration of recombinant IL-33 inhibited murine choroidal neovascularization (CNV) formation, a surrogate of human neovascular AMD, and this effect was ST2-dependent. Collectively, these data demonstrate IL-33 as a potential immunotherapy and distinguishes pathways for subverting AMD pathology. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.4816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683707PMC
January 2017

Impairing autophagy in retinal pigment epithelium leads to inflammasome activation and enhanced macrophage-mediated angiogenesis.

Sci Rep 2016 Feb 5;6:20639. Epub 2016 Feb 5.

School of Clinical Sciences, University of Bristol, Bristol, UK.

Age-related decreases in autophagy contribute to the progression of age-related macular degeneration (AMD). We have now studied the interaction between autophagy impaired in retinal pigment epithelium (RPE) and the responses of macrophages. We find that dying RPE cells can activate the macrophage inflammasome and promote angiogenesis. In vitro, inhibiting rotenone-induced autophagy in RPE cells elicits caspase-3 mediated cell death. Co-culture of damaged RPE with macrophages leads to the secretion of IL-1β, IL-6 and nitrite oxide. Exogenous IL-6 protects the dysfunctional RPE but IL-1β causes enhanced cell death. Furthermore, IL-1β toxicity is more pronounced in dysfunctional RPE cells showing reduced IRAK3 gene expression. Co-culture of macrophages with damaged RPE also elicits elevated levels of pro-angiogenic proteins that promote ex vivo choroidal vessel sprouting. In vivo, impaired autophagy in the eye promotes photoreceptor and RPE degeneration and recruitment of inflammasome-activated macrophages. The degenerative tissue environment drives an enhanced pro-angiogenic response, demonstrated by increased size of laser-induced choroidal neovascularization (CNV) lesions. The contribution of macrophages was confirmed by depletion of CCR2(+) monocytes, which attenuates CNV in the presence of RPE degeneration. Our results suggest that the interplay between perturbed RPE homeostasis and activated macrophages influences key features of AMD development.
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http://dx.doi.org/10.1038/srep20639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742917PMC
February 2016

Role of interleukin 33/ST2 axis in the immune-mediated pathogenesis of age-related macular degeneration.

Lancet 2015 Feb;385 Suppl 1:S97

Academic Unit of Ophthalmology, School of Clinical Sciences, University of Bristol, Bristol, UK.

Background: Age-related macular degeneration is a leading cause of irreversible blindness. Altered immune responses drive degeneration, in response to oxidative stress and hypoxia-induced regulation of metabolism. We tested the hypothesis that toll-like receptor activation of retinal pigment epithelium and cellular metabolic switch upregulate interleukin 33, which acts through its receptor ST2 to activate both choroidal stromal fibroblasts and mast cells. By such mechanisms, the fibrosis and insidious degeneration, which we observe clinically, is accentuated.

Methods: Retinal pigment epithelial cells (ARPE-19 and B6-RPE07) were stimulated with toll-like receptor ligands, and energetic pathways were assessed through lactate production and the expression of glycolytic enzymes. Expression profile and secretion of interleukin 33 were determined by RT-PCR and western blots. Function and expression profile of bone-marrow-derived mast cells and human choroidal fibroblasts were also assessed.

Findings: The production of lactate, determining aerobic glycolysis, increased after stimulation of retinal pigment epithelial cells with LPS or poly(I:C), indicating an increase in the glycolytic activity after toll-like receptor stimulation. Increased levels of GLUT1 transcripts, and upregulation of GAPDH expression corroborated this finding. Furthermore, increased expression of interleukin 33 was dependent on a glycolytic metabolic switch and was enhanced under hypoxic conditions. ST2 was highly expressed in retinal pigment epithelium, choroidal mast cells, and choroidal fibroblasts in mouse and man. ST2+ bone-marrow-derived mast cells generated a spectrum of inflammatory cytokines and PGS2 when cultured with interleukin-33-rich retinal pigment epithelium supernatant. Interleukin-33 treatment impaired fibroblast migration and gel contraction alongside suppression of MMP-2 and MMP-9 expression.

Interpretation: Our data highlight an unrecognised link between retinal pigment epithelium bioenergetic status and tissue remodelling of choroidal stroma. Our findings suggest that the interleukin 33/ST2 axis and changing bioenergetic sources are potential therapeutic targets to inhibit progression of age-related macular degeneration.

Funding: National Institute for Health Research, National Eye Research Centre.
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http://dx.doi.org/10.1016/S0140-6736(15)60412-3DOI Listing
February 2015

Effects of metformin on retinoblastoma growth in vitro and in vivo.

Int J Oncol 2014 Dec 11;45(6):2311-24. Epub 2014 Sep 11.

Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.

Recent studies suggest that the anti-diabetic drug metformin may reduce the risk of cancer and have anti-proliferative effects for some but not all cancers. In this study, we examined the effects of metformin on human retinoblastoma cell proliferation in vitro and in vivo. Two different human retinoblastoma cell lines (Y79, WERI) were treated with metformin in vitro and xenografts of Y79 cells were established in nu/nu immune-deficient mice and used to assess the effects of pharmacological levels of metformin in vivo. Metformin inhibited proliferation of the retinoblastoma cells in vitro. Similar to other studies, high concentrations of metformin (mM) blocked the cell cycle in G0‑G1, indicated by a strong decrease of G1 cyclins, especially cyclin D, cyclin-dependent kinases (4 and 6), and flow cytometry assessment of the cell cycle. This was associated with activation of AMPK, inhibition of the mTOR pathways and autophagy marker LC3B. However, metformin failed to suppress growth of xenografted tumors of Y79 human retinoblastoma cells in nu/nu mice, even when treated with a maximally tolerated dose level achieved in human patients. In conclusion, suprapharmacological levels (mM) of metformin, well above those tolerated in vivo, inhibited the proliferation of retinoblastoma cells in vitro. However, physiological levels of metformin, such as seen in the clinical setting, did not affect the growth of retinoblastoma cells in vitro or in vivo. This suggests that the potential beneficial effects of metformin seen in epidemiological studies may be limited to specific tumor types or be related to indirect effects/mechanisms not observed under acute laboratory conditions.
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http://dx.doi.org/10.3892/ijo.2014.2650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215581PMC
December 2014

Spontaneous resolution of vitreomacular traction demonstrated by spectral-domain optical coherence tomography.

Am J Ophthalmol 2014 Apr 18;157(4):842-851.e1. Epub 2014 Jan 18.

2nd Department of Ophthalmology, University of Athens, Athens, Greece.

Purpose: To evaluate the natural course of idiopathic vitreomacular traction (VMT) with spectral-domain optical coherence tomography (SDOCT) from the vitreomacular adhesion (VMA) stage to the spontaneous resolution of VMT.

Design: Prospective observational case series.

Methods: We studied the natural course of idiopathic VMT in 46 eyes (46 patients), divided into those that proceeded to spontaneous VMT resolution (12 cases) and those that remained at the VMT stage (34 cases). All patients were examined with SDOCT at regular 3-month intervals. We recorded the vitreomacular angle of VMA nasally and temporally, the horizontal diameter of VMA, macular thickness, visual acuity, photoreceptor layer, and external limiting membrane.

Results: In the 12 eyes that proceeded to spontaneous resolution, the vitreous adhesion angle had a mean increase of 38 degrees at VMT, compared to the angle at the VMA stage. In the 34 eyes that remained at the VMT stage, the mean angle of traction increased by only 1 degree throughout follow-up. In all 46 patients, the angle at the VMT stage was significantly associated with traction resolution (nasally P = .001, temporally P < .001). The likelihood of resolution was more than 99% lower for patients with a VMT diameter >400 μm compared with that of eyes with a VMT diameter <400 μm. Patients with broad-type VMT remained at the same stage, whereas patients with V-type VMT had 80% probability of resolution.

Conclusions: Spontaneous VMT resolution is negatively associated with the horizontal adhesion diameter. The strength of the traction exerted by the vitreous on the fovea seems to be positively related to the size of the vitreomacular angle.
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http://dx.doi.org/10.1016/j.ajo.2014.01.011DOI Listing
April 2014

Photoreceptor layer changes overlying drusen in eyes with age-related macular degeneration associated with vitreomacular traction.

Eur J Ophthalmol 2014 Jul-Aug;24(4):582-92. Epub 2013 Dec 12.

2nd Department of Ophthalmology, "Attikon" University Hospital, University of Athens, Athens - Greece.

Purpose: To investigate by spectral-domain optical coherence tomography (SD-OCT) changes of photoreceptor layers over drusen in cases of dry type age-related macular degeneration associated with vitreomacular traction (VMT).

Methods: Clinical examination, fluorescein angiography, fundus photography, and SD-OCT data were retrospectively studied for a consecutive series of 27 patients with drusen, pseudodrusen, and VMT. Control groups of 32 patients with VMT without drusen and 34 patients with drusen and pseudodrusen without VMT were also studied.

Results: The examination revealed disruption of the line corresponding to the inner segment ellipsoid (ISel), previously called inner segment/outer segment junction, of photoreceptor layer, and development of cystoid edema in significantly higher incidence in VMT associated with drusen group. 22 out of 32 eyes with VMT and drusen (68.75%) had disrupted ISel, compared to 8 out of 37 (21.6%) control eyes with drusen only and to 12 out of 37 (32.4%) control eyes with VMT only. Chi-square analysis showed significant association between drusen and pseudodrusen on fovea, VMT, and localization of ISel disruption. The changes of the ISel were mainly found in the area that corresponded to VMT. The SD-OCT revealed drusen throughout the macula and discontinuation of ISel only in the fovea in 4 of 32 (12.5%) eyes with VMT, whereas none of 37 control eyes with drusen only had similar appearance.

Conclusions: The drusen in association with the cystoid macular edema induced by vitreous traction contribute to the photoreceptor layer defect overlying drusen in the fovea. In addition, the number of drusen and pseudodrusen was increased in the area of the vitreous traction compared to the peripheral retina.
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http://dx.doi.org/10.5301/ejo.5000412DOI Listing
October 2014

Ultra-wide field imaging of retinopathy of prematurity (ROP) using Optomap-200TX.

BMJ Case Rep 2013 Oct 8;2013. Epub 2013 Oct 8.

Department of Ophthalmology, Victoria Hospital, Kirkcaldy, UK.

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http://dx.doi.org/10.1136/bcr-2013-200734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822072PMC
October 2013

Diet and cataract: a case-control study.

Int Ophthalmol 2014 Feb 29;34(1):59-68. Epub 2013 May 29.

Department of Hygiene, Epidemiology & Medical Statistics, Medical School, University of Athens, 75 Mikras Asias Street, 11527, Athens, Greece.

We conducted a case-control study to assess the association between diet and risk of cataract in Athens, Greece. Totals of 314 cases and 314 frequency-matched controls of both sexes, aged 45-85 years and attending the ophthalmology department of a major teaching hospital in Athens, Greece, were included in the study. All participants were interviewed using a semi-quantitative food-frequency questionnaire, covering the average frequency of consumption of about 120 food items. Analyses were conducted through multiple logistic regression. The analysis was carried out taking cataract as a general outcome (all types of cataract combined) and repeated by the specific type of cataract. We found significant inverse associations of cataract with dietary consumption of fish (OR = 0.69, p < 0.001), vegetables (OR = 0.47, p < 0.001), fruits (OR = 0.53, p < 0.001), and potatoes (OR = 0.76, p = 0.004), while consumption of meat was positively associated with cataract (OR = 1.46, p = 0.001). High intake of total fat (OR = 2.00, p < 0.001) and cholesterol (OR = 1.65, p < 0.001) increased the risk of cataract. There was a protective association between cataract risk and intake of carbohydrates (OR = 0.39, p < 0.001), carotene (OR = 0.56, p < 0.001), vitamins C and E (OR = 0.50, p < 0.001 and OR = 0.50, p < 0.001 respectively). We identified an association between the risk of cataract and several food groups and nutrients. Diets rich in fruits, vegetables, fish, pulses and starchy foods may protect against cataract. In addition, high intake of vitamins C and E and carotene with reduction of intake in total fat and cholesterol may be beneficial. Dietary advice along these lines may provide adequate public health guidelines for the delay of age-related cataract.
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http://dx.doi.org/10.1007/s10792-013-9795-6DOI Listing
February 2014

Dry eye in Graves ophthalmopathy: correlation with corneal hypoesthesia.

Eur J Ophthalmol 2013 Jul-Aug;23(4):473-9. Epub 2013 Mar 4.

2nd Department of Ophthalmology, "Attikon" University Hospital, University of Athens, Athens, Greece.

Purpose: To evaluate dry eye disease and corneal sensitivity in patients with early and active Graves ophthalmopathy (GO).

Methods: A total of 52 eyes of 26 patients with early GO and 74 eyes of 37 age- and sex-matched controls were included in our study. Dry eye disease was assessed based on the criteria of the 
International Dry Eye Workshop. Diagnosis of early GO was based on the European Group on Graves' Orbitopathy consensus statement. Clinical Activity Score (CAS) and Werner-NOSPECS Score were determined. Corneal sensitivity was assessed using a Cochet-Bonnet aesthesiometer.

Results: A total of 67.8% of patients with early GO and 13.5% of healthy controls had ocular surface dryness (p<0.001). The mean Schirmer test score was significantly lower in patients with early GO (12.88 ± 7.94 mm [right eyes] and 14.04 ± 9.00 mm [left eyes]) than in controls (18.08 ± 7.26 mm [right eyes] and 18.05 ± 7.50 mm [left eyes] [p<0.05]). The tear film break-up time was lower in patients by 5.46 seconds and 5.74 seconds in right and left eyes (p<0.001). We also found a significant reduction in corneal sensitivity in patients with early GO (4.16 ± 0.68 [right eyes] and 4.10 ± 0.89 [left eyes]) than in controls (4.70 ± 0.34 [right eyes] and 4.72 ± 0.34 [left eyes] [p<0.05]). The CAS correlated significantly with the Schirmer test (r = -0.60, p = 0.003).

Conclusion: Dry eye is common in early GO even in the absence of apparent exophthalmos and is associated with CAS and reduced corneal sensitivity.
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http://dx.doi.org/10.5301/ejo.5000259DOI Listing
February 2014

Triamcinolone acetonide as an adjuvant to membrane peeling surgery: a pilot study.

Ophthalmic Surg Lasers Imaging Retina 2013 Jan-Feb;44(1):41-5

Case Western Reserve University, Cleveland, Ohio, USA.

Background And Objective: To evaluate the clinical outcome and complications of intravitreal injections of triamcinolone acetonide as adjuvant to reduce postoperative macular edema in patients undergoing pars plana vitrectomy for epiretinal membranes.

Patients And Methods: This retrospective comparative study included 22 patients (22 eyes) who underwent pars plana vitrectomy with membrane peeling for the treatment of idiopathic epiretinal membrane. Fifteen eyes (15 patients) received an intravitreal injection of 4 mg (0.1 cc) of triamcinolone acetonide at the end of surgery, and no injection was performed for 7 eyes (7 patients). Main outcome measures were visual acuity and intraocular pressure. Minimum follow-up was 3 months.

Results: Twenty-two eyes of 22 patients were included in the study. The follow-up ranged from 3 to 12 months. Visual acuity improved in both groups at 3 months: logarithm of the minimum angle of resolution -0.26 ± 0.19 in the triamcinolone acetonide group (P = .001) and -0.26 ± 0.13 in the control group (P = .002). However, there was no statistically significant difference in visual acuity improvement 1, 3, and 12 months postoperatively in the triamcinolone acetonide group compared with the control group (P = .79, = .94, and = .21, respectively). There was no significant difference in intraocular pressure change between the two groups during the follow-up period (P > .05).

Conclusion: The current pilot study suggests that postoperative intravitreal injection of triamcinolone acetonide does not lead to better visual outcomes in patients undergoing pars plana vitrectomy for the treatment of idiopathic epiretinal membranes.
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http://dx.doi.org/10.3928/23258160-20121221-11DOI Listing
July 2013

Aminoimidazole carboxamide ribonucleotide (AICAR) inhibits the growth of retinoblastoma in vivo by decreasing angiogenesis and inducing apoptosis.

PLoS One 2013 3;8(1):e52852. Epub 2013 Jan 3.

Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Retina Service, Harvard Medical School, Boston, Massachusetts, United States of America.

5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR), an analog of AMP is widely used as an activator of AMP-kinase (AMPK), a protein that regulates the responses of the cell to energy change. Recently, we showed that AICAR-induced AMPK activation inhibits the growth of retinoblastoma cells in vitro by decreasing cyclins and by inducing apoptosis and S-phase arrest. In this study, we investigated the effects of AMPK activator AICAR on the growth of retinoblastoma in vivo. Intraperitoneal injection of AICAR resulted in 48% growth inhibition of Y79 retinoblastoma cell tumors in mice. Tumors isolated from mice treated with AICAR had decreased expression of Ki67 and increased apoptotic cells (TUNEL positive) compared with the control. In addition, AICAR treatment suppressed significantly tumor vessel density and macrophage infiltration. We also showed that AICAR administration resulted in AMPK activation and mTOR pathway inhibition. Paradoxically observed down-regulation of p21, which indicates that p21 may have a novel function of an oncogene in retinoblastoma tumor. Our results indicate that AICAR treatment inhibited the growth of retinoblastoma tumor in vivo via AMPK/mTORC1 pathway and by apoptogenic, anti-proliferative, anti-angiogenesis mechanism. AICAR is a promising novel non-chemotherapeutic drug that may be effective as an adjuvant in treating Retinoblastoma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0052852PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536763PMC
August 2013

Atypical toxoplasmic retinochoroiditis.

BMJ Case Rep 2012 May 30;2012. Epub 2012 May 30.

Department of Ophthalmology, Princess Alexandra Eye Pavilion, Edinburgh, UK.

We report a case of re-activation of Toxoplasma gondii as a cause of atypical retinal necrosis in an immunocompetent individual. The rapid development of necrotising confluent retinochoroiditis and vitreous inflammation necessitated urgent aqueous humor PCR analysis, which was positive for T gondii. The patient was treated with two intravitreal injections of clindamycin, along with oral sulphadiazine, pyrimethamine, folinic acid and prednisolone. He developed central retinal arterial occlusion, as a complication of toxoplasmic retinochoroiditis, and immediate anterior chamber paracentesis was performed with visual recovery. The injection of intravitreal clindamycin with concomitant oral therapy was associated with control of toxoplasmic retinochoroiditis and resolution of vitreous inflammation.
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http://dx.doi.org/10.1136/bcr.12.2011.5419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543018PMC
May 2012

Vascular endothelial growth factor inhibitors for treatment of corneal neovascularization: a meta-analysis.

Cornea 2013 Apr;32(4):435-44

2nd Department of Ophthalmology, Attikon University Hospital, Athens, Greece.

Purpose: To evaluate the therapeutic effect of bevacizumab (Avastin) on corneal neovascularization (NV).

Methods: Systematic review and meta-analysis of the literature was performed. Seven eligible clinical human studies and 18 eligible experimental animal studies examining the effectiveness of bevacizumab treatment on corneal NV were included in the meta-analysis. Pertinent publications were identified through a systematic search of PubMed. All references of relevant reviews and eligible articles were also screened, and data were extracted from each eligible study. The random-effects model (of DerSimonian and Laird) was used to combine the results from the selected studies. Heterogeneity was explored using available data. Publication bias was also assessed.

Results: A significant reduction of corneal neovascularized area was seen in clinical human studies, with a pooled reduction of 36% [95% confidence interval (CI), 18%-54%] overall, of 32% (95% CI, 10%-54%) for subconjunctival anti-vascular endothelial growth factor injections, and 48% (95% CI, 32%-65%) for topical treatment. Pooled mean change in best-corrected visual acuity showed an improvement in best-corrected visual acuity by 0.04. The summary standardized mean difference in animal studies indicated a statistically significant reduction in the area of corneal NV when treated with bevacizumab compared with the control group by -1.71 (95% CI, -2.12 to -1.30). The subtotal pooled standardized mean differences were -1.83 (95% CI, -2.38 to -1.28) for subconjunctival anti-vascular endothelial growth factor injections and -1.50 (95% CI, -1.88 to -1.12) for topical treatment.

Conclusion: Our results suggest that both topical and subconjunctival bevacizumab achieve significant reduction in the area of corneal NV. This meta-analysis provides an evidential basis for the new therapeutic concept of treating corneal NV with antiangiogenic therapy.
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http://dx.doi.org/10.1097/ICO.0b013e3182542613DOI Listing
April 2013

The effect of alpha antagonists on pupil dynamics: implications for the diagnosis of intraoperative floppy iris syndrome.

Am J Ophthalmol 2012 Apr 21;153(4):620-6. Epub 2012 Jan 21.

2nd Department of Ophthalmology, Attikon University Hospital, University of Athens, Athens, Greece.

Purpose: To assess pupil dynamics quantitatively in relation to the use of α1-adrenoceptor antagonists, which contribute to the features of intraoperative floppy iris syndrome, using a new, hand-held, digital pupillometer.

Design: Prospective case-control study.

Methods: We studied 15 and 25 patients administered tamsulosin and alfuzosin, respectively, as well as 25 control patients. Resting pupil diameter and subsequent contraction, latency, constriction velocity, and dilation velocity were recorded using an electronic pupillometer. All pupil measurements were performed before and after pharmacologic dilation.

Results: In predilation pupillary measurements, we detected a significant decrease in maximum pupillary diameter by 0.50±0.19 mm (P=.011) and in the mean percentage of diameter reduction after stimulation (5.23±2.42%, P=.035) in the tamsulosin group. Alfuzosin also induced a significant decrease in maximum pupillary diameter (0.49±0.17 mm, P=.005). Constriction velocity was significantly reduced by 0.70±0.20 m/s (P=.001) in the tamsulosin group and by 0.54±0.18 m/s (P=.004) in the alfuzosin group. In terms of postdilation measurements, maximum and minimum pupil diameters were reduced significantly only in the tamsulosin group (by 1.09±0.31 mm [P=.001] and by 0.89±0.36 mm [P=.016], respectively).

Conclusions: We describe a reliable, accurate, and rapid method to acquire quantitative pupil measurements and identify the tendency for intraoperative floppy iris syndrome before cataract surgery after the use of alfuzosin and tamsulosin. This investigation also analyzed the similarities and differences induced by the 2 drugs in predilation and postdilation pupil dynamics, demonstrating that tamsulosin is more potent than alfuzosin in inducing intraoperative floppy iris syndrome.
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http://dx.doi.org/10.1016/j.ajo.2011.09.030DOI Listing
April 2012

Hemodialysis-induced alterations in macular thickness measured by optical coherence tomography in diabetic patients with end-stage renal disease.

Ophthalmologica 2012 15;227(2):90-4. Epub 2011 Sep 15.

Second Department of Ophthalmology, University of Athens, Athens, Greece. patheo @ med.uoa.gr

Background/aims: To evaluate changes in macular thickness measured by optical coherence tomography (OCT) during a hemodialysis (HD) session in diabetic patients with end-stage renal disease.

Methods: 72 eyes of 36 diabetic patients with and without macular edema were evaluated before and immediately after an HD session. Average and maximum macular thicknesses in the central disk (6 mm in diameter) and total macular volume were measured.

Results: In the eyes with diabetic macular edema, maximum macular thickness within the central disk of 6 mm, and mainly in its peripheral parts, was significantly reduced by 31.18 ± 4.18 μm after HD (p < 0.001). Average macular thickness and total macular volume were also significantly reduced (p = 0.003 and 0.015, respectively). In diabetic eyes without edema, maximum macular thickness decreased significantly by 11.21 ± 1.98 μm after HD (p < 0.001), while average macular thickness and total macular volume decreased slightly (p = 0.034, p = 0.043). Best-corrected visual acuity failed to change. We found a significant association of macular thickness changes with osmolality reduction and the presence of macular edema.

Conclusion: HD decreases macular thickness in diabetic patients with macular edema, while there exists a less-pronounced effect in diabetic eyes without edema.
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http://dx.doi.org/10.1159/000331321DOI Listing
April 2012

Heat shock protein 70 (HSP70) is critical for the photoreceptor stress response after retinal detachment via modulating anti-apoptotic Akt kinase.

Am J Pathol 2011 Mar;178(3):1080-91

Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, and the Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, USA.

Photoreceptor apoptosis is a major cause of vision loss in many ocular diseases. Significant progress has been made to elucidate the molecular pathways involved in this process, yet little is known about proteins counteracting these apoptotic pathways. It is established that heat shock proteins (HSPs) function as molecular helper proteins (chaperones) by preventing protein aggregation and facilitating refolding of dysfunctional proteins, critical to the survival of all organisms. Here, we investigated the role of HSP70 on photoreceptor survival after experimental retinal detachment (RD) in mice and rats. We found that HSP70 was up-regulated after RD and associated with phosphorylated Akt, thereby preventing its dephosphorylation and further activation of cell death pathways. Administration of quercetin, which inhibits HSP70 and suppresses Akt phosphorylation significantly increased photoreceptor apoptosis. Similarly, RD-induced photoreceptor apoptosis was augmented in mice carrying hypomorphic mutations of the genes encoding HSP70. On the other hand, administration of geranylgeranylacetone, which induces an increase in HSP70 significantly decreased photoreceptor apoptosis after RD through prolonged activation of Akt pathway. Thus, HSP70 may be a favorable potential target to increase photoreceptor cell survival after RD.
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http://dx.doi.org/10.1016/j.ajpath.2010.11.072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069883PMC
March 2011