Residency, Byers Eye Institute, Stanford University School of Medicine
Internship, Berkshire Medical Center, MA
PhD, Boston University School of Medicine, MA
MPH, Northeastern University, MA
Research Fellowship (Retina), Massachusetts Eye and Ear, Harvard Medical School
MD, Damascus Medical School, Syria
Telegenetics for inherited retinal diseases in the COVID-19 environment.
International journal of retina and vitreous
2021; 7 (1): 25
Inherited retinal diseases (IRDs) are visually debilitating conditions that affect families worldwide. They require extensive clinical testing, examination, and patient and family counseling, which are frequently accomplished over single-day extended clinic visits. However, the COVID-19 pandemic has limited the number of patients and staff allowed in clinics, leading to interruptions in care. We therefore developed telehealth management protocols for complete or hybrid virtual visits. The three main components of our telegenetics approach included reviewing the diagnostic tests results remotely, in-person or virtual video visits with a retina specialist, and virtual genetic testing using saliva kits. During the first 5months of the program, telegenetic care was provided for 80 patients, including 3 international patients, and a spectrum of retinal dystrophies were diagnosed and managed. In conclusion, telegenetic virtual visits ensure continuity of care while reducing patient and provider exposure to SARS-CoV-2 and may continue and expand into other medical genetic conditions long after the pandemic.
View details for DOI 10.1186/s40942-021-00301-z
View details for PubMedID 33781332
Key factors in a rigorous longitudinal image-based assessment of retinopathy of prematurity.
2021; 11 (1): 5369
To describe a database of longitudinally graded telemedicine retinal images to be used as a comparator for future studies assessing grader recall bias and ability to detect typical progression (e.g. International Classification of Retinopathy of Prematurity (ICROP) stages) as well as incremental changes in retinopathy of prematurity (ROP). Cohort comprised of retinal images from 84 eyes of 42 patients who were sequentially screened for ROP over 6 consecutive weeks in a telemedicine program and then followed to vascular maturation or treatment, and then disease stabilization. De-identified retinal images across the 6 weekly exams (2520 total images) were graded by an ROP expert based on whether ROP had improved, worsened, or stayed the same compared to the prior week's images, corresponding to an overall clinical "gestalt" score. Subsequently, we examined which parameters might have influenced the examiner's ability to detect longitudinal change; images were graded by the same ROP expert by image view (central, inferior, nasal, superior, temporal) and by retinal components (vascular tortuosity, vascular dilation, stage, hemorrhage, vessel growth), again determining if each particular retinal component or ROP in each image view had improved, worsened, or stayed the same compared to the prior week's images. Agreement between gestalt scores and view, component, and component by view scores was assessed using percent agreement, absolute agreement, and Cohen's weighted kappa statistic to determine if any of the hypothesized image features correlated with the ability to predict ROP disease trajectory in patients. The central view showed substantial agreement with gestalt scores (kappa=0.63), with moderate agreement in the remaining views. Of retinal components, vascular tortuosity showed the most overall agreement with gestalt (kappa=0.42-0.61), with only slight to fair agreement for all other components. This is a well-defined ROP database graded by one expert in a real-world setting in a masked fashion that correlated with the actual (remote in time) exams and known outcomes. This provides a foundation for subsequent study of telemedicine's ability to longitudinally assess ROP disease trajectory, as well as for potential artificial intelligence approaches to retinal image grading, in order to expand patient access to timely, accurate ROP screening.
View details for DOI 10.1038/s41598-021-84723-7
View details for PubMedID 33686091
Reperfusion of retinal ischemia in retinal occlusive vasculitis with nicotinic acid and infliximab in Adamantiades-Behcet's disease.
American journal of ophthalmology case reports
2021; 21: 101027
To describe a case of ischemic retinal vasculitis in Adamantiades-Behcet disease (ABD) that demonstrated significant resolution of retinal ischemia following treatment with nicotinic acid and infliximab.Observations: A 12-year-old male with a history of recurrent oral ulcers, fevers, and failure to thrive was admitted to the hospital with fever, oral and perirectal mucositis, and poor oral intake one month before presentation to uveitis clinic. He was suspected to have ABD and was treated with three doses of intravenous (IV) methylprednisolone (30 mg/kg/day) which led to improvement in his systemic symptoms. One week after admission, he complained of decreased vision in both eyes (OU), during which he was found to have anterior uveitis in OU and was referred to the Uveitis Clinic. Upon examination, his visual acuity was 20/80 in OU. Intraocular pressures were within normal limits. Anterior chamber evaluation revealed 0.5+ cells and 1.5+ flare in OU. Posterior examination revealed pale optic nerve, sclerosis and vascular sheathing of retinal arteries, and collateral vessels in OU. Fluorescein angiography (FA) showed optic disc leakage and widespread retinal ischemia in OU. The patient was diagnosed with retinal occlusive vasculitis associated with ABD. He was initially treated with infliximab (5 mg/kg), systemic methylprednisolone, and mycophenolate mofetil. Three months later, his BCVA improved to 20/70 OU with slight improvement of retinal ischemia on FA. Nicotinic acid was added to his treatment regimen. Due to logistic challenges, he did not receive infliximab treatment during the subsequent three months. However, three months after beginning nicotinic acid therapy, FA revealed significant improvement of his retinal ischemia OU. Conclusion: To our knowledge, the index report is the first to show that nicotinic acid may improve retinal ischemia in vaso-occlusive retinal vasculitis and be an integral part of the treatment regimen of this sight-threatening condition.
View details for DOI 10.1016/j.ajoc.2021.101027
View details for PubMedID 33615039
Higher prevalence of fundus haemorrhages in early-screened (NEST Study) as compared to late-screened (SUNDROP Study) newborn populations.
The British journal of ophthalmology
BACKGROUND/AIMS: To determine whether timing of ophthalmic screening influences prevalence of neonatal fundus haemorrhages. We compared the prevalence of fundus haemorrhages in two populations: term newborns screened early (less than 72 hours) and preterm newborns screened late (4-11 weeks). Additionally, we reviewed the literature on timing and prevalence of newborn haemorrhages.METHODS: Retrospective observational cohort study. Infants who underwent wide-angle ophthalmic digital imaging over one overlapping year in the Newborn Eye Screen Testing (NEST) or Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP) programme were included. The PubMed database was filtered to include English-language articles dating back to 1950. Nine articles were selected for review based on inclusion of the prevalence of newborn fundus haemorrhages at multiple time points.RESULTS: A total of 202 patients received early imaging in the NEST cohort and 73 patients received late imaging in the SUNDROP cohort. In the NEST cohort, 20.2% of newborns had haemorrhages. In contrast, we found haemorrhages in only one case or 1.4% of the SUNDROP cohort. Using prevalence data from nine additional studies, we developed a predicted probabilities model of newborn haemorrhages. Per this model, the probability of seeing a haemorrhage if you screen an infant at 1 hour is 18.8%, at 2 weeks is 2.9% and at 1 month is 0.28%.CONCLUSION: We found a significant difference in the prevalence of fundus haemorrhages between the early-screened NEST cohort and the late-screened, preterm SUNDROP cohort. Likely, this difference is due to the transient nature of most newborn haemorrhages.
View details for DOI 10.1136/bjophthalmol-2020-317908
View details for PubMedID 33514529
Risk of Retinal Artery Occlusion in Patients with Migraine.
American journal of ophthalmology
PURPOSE: To determine if migraine is associated with increased risk of retinal artery occlusion (RAO).DESIGN: Retrospective cohort study METHODS: Setting: A large insurance claims database.PARTICIPANTS: Patients with migraine and matched controls without migraine between 2007 to 2016.PROCEDURES: Cox proportional hazard regression models were used to investigate the association between migraine and risk of all RAO, central RAO (CRAO), branch RAO (BRAO), and "other" RAO, which includes transient and partial RAO.MAIN OUTCOME MEASURES: Incidence of all RAO, including CRAO, BRAO, and other RAO, following first migraine diagnosis.RESULT: There were 418,965 patients with migraine who met study criteria and were included in the analysis with the appropriate matched controls. Among the 418,965 patients with migraine, 1,060 (0.25%) were subsequently diagnosed with RAO, whereas only 335 (0.08%) of the patients without migraine were diagnosed with RAO. The hazard ratio (HR) for incident all RAO in patients with migraine compared with those without migraine was 3.48 (95% Confidence Interval (CI): 3.07 - 3.94; P <0.0001]. This association was consistent across all types of RAO, including CRAO (HR = 1.62; 95% CI: 1.15 - 2.28; P=0.004) BRAO (HR 2.09; 95% CI 1.60 - 2.72; P <0.001), and other types of RAO (HR 4.61; 95% CI 3.94 - 5.38; P <0.001). Patients with migraine with aura had a higher risk for incident RAO compared with those with migraine without aura (HR = 1.58; 95% CI: 1.40 - 1.79; P <0.001). This association was consistent for BRAO (HR = 1.43; 95% CI 1.04 - 1.97; P <0.03) and other types of RAO (HR = 1.67; 95% CI 1.45 - 1.91; P <0.001), but was not statistically significant for CRAO (HR = 1.18; 95% CI 0.75 - 1.87; P = 0.475). Significant risk factors for this association included increased age, male sex, acute coronary syndrome, valvular disease, carotid disease, hyperlipidemia, hypertension, retinal vasculitis and/or inflammation, and systemic lupus erythematosus.CONCLUSIONS: Migraine is associated with increased risk of all types of RAO and migraine with aura is associated with increased risk of RAO compared with migraine without aura.
View details for DOI 10.1016/j.ajo.2020.11.004
View details for PubMedID 33359716
Morning glory optic nerve in Aicardi syndrome: Report of a case with fluorescein angiography.
European journal of ophthalmology
BACKGROUND: Aicardi syndrome is an X-linked condition that is associated with multiple ophthalmic malformations. Here, we report the first published fluorescein angiography (FA) study of a morning glory optic nerve in a patient with Aicardi syndrome and contralateral persistent fetal vasculature (PFV).CASE DESCRIPTION: A 12-day old full-term baby girl with a normal neurological exam was referred for evaluation of microphthalmia. The posterior segment of the right eye demonstrated chorioretinal lacunae typical of Aicardi syndrome and microphthalmos with a stalk consistent with PFV. The right eye imaging could not be captured due to the severe microphthalmos and cataract, however, fluorescein angioscopy was performed. The left eye demonstrated a morning glory appearing optic disc with peripapillary chorioretinal lacunae. Fluorescein angiography of the eye showed and late staining in the areas of ellipsoid chorioretinal lacunae emanating from the optic nerve and extensive peripapillary staining and late leakage of the optic nerve.CONCLUSION: Patients with Aicardi syndrome can have morning glory optic nerve anomaly and PFV. Using FA under anesthesia to detect these abnormalities help in estimating the extend of the disease and its complications, which allows for better management of the complications.
View details for DOI 10.1177/1120672120942702
View details for PubMedID 32674592
Exudative Retinal Detachment in Ocular Inflammatory Diseases: Risk and Predictive Factors.
American journal of ophthalmology
PURPOSE: To evaluate the risk/risk factors for exudative retinal detachment (ERD) in ocular inflammatory diseases.DESIGN: Retrospective cohort study.METHODS: Patients with non-infectious ocular inflammation had been followed longitudinally between 1978-2007 at four US subspecialty uveitis centers. The main outcome measures were ERD occurrence and its predictive factors.RESULTS: One hundred seventy-six of 14,612 eyes with ocular inflammation presented with ERD. Among uveitis cases, Vogt-Koyanagi-Harada syndrome (VKH) (OR=109), undifferentiated choroiditis (OR=9.18), sympathetic ophthalmia (OR=8.43), primary or secondary panuveitis (OR=7.09), multifocal choroiditis with panuveitis (OR=4.51), and "other" forms of posterior uveitis (OR=16.9) were associated with a higher prevalence of ERD. Among the 9,209 uveitic or scleritic eyes initially free of ERD and followed-up, 137 incident ERD cases were observed over 28,949 eye-years at risk (incidence rate=0.47% (0.40%-0.56%)/eye-year). VKH (HR=13.2), sympathetic ophthalmia (HR=5.82), undifferentiated choroiditis (HR=6.03), primary or secondary panuveitis (HR=4.21), and rheumatoid arthritis (HR=3.30) were significantly associated with incident ERD. A significant dose-response relationship with ERD prevalence and incidence was observed for anterior chamber cells and vitreous cell activity. African Americans had significantly higher prevalence and incidence of ERD.CONCLUSIONS: Other ocular inflammatory conditions besides VKH and posterior scleritis were associated with increased ERD risk, indicating that ERD does not necessarily dictate a diagnosis of VKH or posterior scleritis. In addition, the relationship of ERD with inflammatory severity factors implies that inflammation is a key predictive factor that is associated with developing ERD and requires early and vigorous control.
View details for DOI 10.1016/j.ajo.2020.06.019
View details for PubMedID 32621891
- Retinopathy of prematurity and neurodevelopmental outcomes in premature infants. Eye (London, England) 2020
Resolution of optic disc pit-associated macular retinoschisis after topical carbonic anhydrase inhibitor treatment: Report of a case.
European journal of ophthalmology
BACKGROUND: Optic disc pits frequently lead to visual deterioration due to macular retinoschisis or serous retinal detachment. Here, we report a case of optic disc pit-associated macular retinoschisis due to intraretinal fluid accumulation that resolved with improvement in visual acuity after treatment with topical dorzolamide.CASE DESCRIPTION: A 56-year-old otherwise healthy female with no ocular history presented with 2weeks of slowly worsening blurry vision in her right eye. Visual acuity was 20/30 in the right eye. Posterior segment examination revealed posterior vitreous detachment, an optic disc pit at 9 o'clock, macular edema and foveoschisis with fluid extending from the optic nerve, and a normal peripheral retina. Optical coherence tomography imaging of the macula showed central subfield thickness of 526m. The patient preferred no surgical intervention, so topical dorzolamide 2% three times daily was initiated. Over the next 2 years, the central subfield thickness steadily declined from 526 to 262m, and her vision improved to 20/20 with improvement in the macular retinoschisis.CONCLUSION: Our report presents a case of resolution of optic disc pit-associated macular retinoschisis due to intraretinal fluid accumulation with possible role for dorzolamide as a potential treatment option.
View details for DOI 10.1177/1120672120904664
View details for PubMedID 32019335
Timing and Reoperation Rate of Rhegmatogenous Retinal Detachments Occurring During Major Ophthalmology Meetings.
Ophthalmic surgery, lasers & imaging retina
2020; 51 (6): 328–37
To investigate whether surgical management of newly diagnosed rhegmatogenous retinal detachment (RRD) varies if patients are diagnosed during a major national ophthalmology conference.This retrospective cohort study included 34,759 patients with incident RRD, of whom, 1,246 (3.6%) were diagnosed during dates of three national ophthalmology conferences, and 1,170 (3.4%) underwent surgery during conference dates. The authors identified patients with primary repair with cryotherapy, laser, scleral buckle, pneumatic retinopexy, or pars plana vitrectomy. Multinomial logistic regression models were used to determine patients' likelihood of receiving each type of repair within 30 days of their diagnosis depending on whether they were diagnosed during a national ophthalmology conference. Linear regression models were used to determine the relationship between the date patients were diagnosed and how long they waited to receive a repair. Main outcome measures included days between diagnosis with RRD and RRD repair, receiving repair on the same day of diagnosis, and reoperation rate within 30 days of the primary repair.Mean time from diagnosis to repair was 1.5 days (standard deviation: ± 2.4 days), and 71% of patients underwent repair within a day of diagnosis. Repairs were followed by a second surgery within 30 days in 11.1% of patients. Patients diagnosed during conferences waited 0.23 days longer between diagnosis and repair compared with patients diagnosed outside of conference dates (P = .001). Patients diagnosed with RRD during conferences were less likely to receive surgical repair within a day of diagnosis compared to patients diagnosed during non-conference dates (P = .037). Patients who were diagnosed with RRD during a conference date and also received surgery during a conference date were more likely to undergo a second surgery within 30 days of the primary procedure (P = .006) CONCLUSIONS: Patients diagnosed with RRD during national ophthalmology conference dates waited slightly longer for surgery, were slightly less likely to receive surgery within a day, and were more likely to undergo a second surgery within 30 days of the primary procedure. The "national meeting effect" phenomenon is present in ophthalmology, albeit to a lesser degree that is likely not visually significant. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:328-337.].
View details for DOI 10.3928/23258160-20200603-03
View details for PubMedID 32579691
Impending central retinal vein occlusion in patient with idiopathic cutaneous leukocytoclastic vasculitis.
American journal of ophthalmology case reports
2020; 20: 100934
To report a case of impending central retinal vein occlusion (CRVO) associated with idiopathic cutaneous leukocytoclastic vasculitis (LCV) that demonstrated significant resolution following treatment with intravenous (IV) methylprednisolone.A 27-year-old man presented to a tertiary Uveitis Clinic with a five-day history of blurry vision in the right eye (OD). He had a history of a purpuric rash and arthralgias five years ago and a biopsy-confirmed diagnosis of LCV controlled with colchicine two years ago in India. Recently, he presented with a recurrent rash and severe abdominal pain. After being evaluated by rheumatology and gastroenterology, he was placed on Helicobacter pylori treatment and high dose oral prednisone, which improved his skin and gastrointestinal symptoms. At the first ophthalmic exam, his systemic findings included lower extremity purpura. His best-corrected visual acuity (BCVA) was 20/20 in both eyes (OU). Slit-lamp examination revealed no cells or flare in OU. Dilated fundus exam showed mild enlarged, tortuous veins, optic nerve hemorrhage, and intraretinal hemorrhages temporal to the macula in OD. Spectral-domain optical coherence tomography (SD-OCT) demonstrated multiple hyper-reflective, plaque-like lesions involving the inner nuclear layer, consistent with paracentral acute middle maculopathy (PAMM). The patient was diagnosed with impending central retinal vein occlusion (CRVO) in OD. Laboratory evaluations were unremarkable. Aspirin was initially started for the patient but was later held due to the worsening of retinal hemorrhage and retinal vein tortuosity at the one-week follow-up. The patient then received three doses of intravenous methylprednisolone, followed by systemic oral prednisone and mycophenolate mofetil. One month later, retinal hemorrhages, venous stasis, and skin manifestations resolved.Ocular involvement in LCV is rare and may present with different manifestations. The index case is the first report of impending CRVO in a patient with idiopathic LCV and without any other known risk factors for CRVO. Our report not only describes the unique course of LCV-related ocular involvement, but also introduces and underscores a potentially effective therapeutic plan.
View details for DOI 10.1016/j.ajoc.2020.100934
View details for PubMedID 33015410
View details for PubMedCentralID PMC7522751
Sex Differences in the Repair of Retinal Detachments in the United States.
American journal of ophthalmology
To determine differences between women and men in the repair of rhegmatogenous retinal detachments (RRD) in the United States.Retrospective cohort study.SETTING: A large insurance claims database.Subjects with an incident RRD between 2007-2015.Demographic data, comorbid ocular conditions associated with RRD,systemic comorbidities,and surgical intervention (pneumatic retinopexy (PR), pars plana vitrectomy (PPV), laser barricade, or scleral buckle (SB)) were collected.Odds of receipt of surgical intervention for incident RRD, time to repair, type of intervention, and the rate of reoperation by sex.The study period included 133 million eligible records with 61,071 cases of incident RRD meeting inclusion criteria among which 43% (n = 26,289) were women. Women had 34% reduced odds of receipt of surgical repairof an RRD (OR 0.66, 95% CI 0.59 - 0.73, p<0.001) after adjusting for confounders. This effect persisted in all sensitivity models. Among patients that received repair, women were more often delayed (0.17 days, p = 0.04). Women were more likely to undergo primary laser barricade (RRR 1.68, p < 0.001), primary SB (RRR 1.15, p < 0.001), and PR (RRR 1.07, p < 0.04) than men. The odds of reoperation were lower in women (OR 0.91, 95% CI 0.85 - 0.96, p=0.002) after adjustment.Insured women are less likely than insured men to receive surgical intervention for an RRD. If the odds of repair were equal between women and men in the U.S. then 781 more women would receive surgery each year, or 7,029 more during the study period. Women are more likely to have the repair performed with scleral buckle and laser barricade. The reason for thesesex differences in RRD repair remains unknown and requires further investigation.
View details for DOI 10.1016/j.ajo.2020.06.039
View details for PubMedID 32640255
Receptor interacting protein kinase 3 (RIP3) regulates iPSCs generation through modulating cell cycle progression genes.
Stem cell research
2019; 35: 101387
The molecular mechanisms involved in induced pluripotent stem cells (iPSCs) generation are poorly understood. The cell death machinery of apoptosis-inducing caspases have been shown to facilitate the process of iPSCs reprogramming. However, the effect of other cell death processes, such as programmed necrosis (necroptosis), on iPSCs induction has not been studied. In this study, we investigated the role of receptor-interacting protein kinase 3 (RIP3), an essential regulator of necroptosis, in reprogramming mouse embryonic fibroblast cells (MEFs) into iPSCs. RIP3 was found to be upregulated in iPSCs compared to MEFs. Deletion of RIP3 dramatically suppressed the reprogramming of iPSCs (~82%). RNA-seq analysis and qRT-PCR showed that RIP3 KO MEFs expressed lower levels of genes that control cell cycle progression and cell division and higher levels of extracellular matrix-regulating genes. The growth rate of RIP3 KO MEFs was significantly slower than WT MEFs. These findings can partially explain the inhibitory effects of RIP3 deletion on iPSCs generation and show for the first time that the necroptosis kinase RIP3 plays an important role in iPSC reprogramming. In contrast to RIP3, the kinase and scaffolding functions of RIPK1 appeared to have distinct effects on reprogramming.
View details for DOI 10.1016/j.scr.2019.101387
View details for PubMedID 30703581
View details for PubMedCentralID PMC7375132
Boston keratoprosthesis type I in the elderly.
The British journal of ophthalmology
2017; 101 (4): 514–18
To determine the outcomes of Boston type I keratoprosthesis implanted in elderly patients.A retrospective case series was performed on patients at least 75 years old who received the Boston type I keratoprosthesis between 1 January 2007 and 31 December 2012. Preoperative diagnosis, interval visual acuity, keratoprosthesis retention and postoperative complications were recorded for each patient.Forty-four Boston type I keratoprostheses were implanted in 44 eyes of 43 patients. The most common indication for surgery was corneal graft failure (n=23; 52.3%) followed by corneal scar (n=8; 18.2%) and limbal stem cell dysfunction (n=8; 18.2%). All patients had preoperative visual acuity of ≤20/200. Thirty-six of 44 (82%) patients achieved visual acuity of 20/200 or better postoperatively, and 20 of those (55.6%) maintained 20/200 or better for 1 year after surgery. The median length of follow-up was 825 days (range: 27-2193 days), and at the last follow-up visit, 20 of 44 (45.5%) had 20/200 or better vision. The median best-corrected visual acuity (logMAR) improved from 2.6 preoperatively to 1.0 at 1 year postoperative (p<0.00001). Device retention at 1 year postoperative was 88.9%. The most common postoperative complications were retroprosthetic membrane formation in 20 patients (45.5%) and cystoid macular oedema in six patients (13.6%). One patient developed keratitis and consecutive endophthalmitis 2 months after surgery and required enucleation.Boston type I keratoprosthesis is an effective modality in corneal blindness in elderly patients. Failure to restore or maintain ambulatory vision was typically due to non-corneal comorbidities, often unrelated to the keratoprosthesis.
View details for DOI 10.1136/bjophthalmol-2015-307868
View details for PubMedID 27381593
Verteporfin inhibits growth of human glioma in vitro without light activation.
2017; 7 (1): 7602
Verteporfin (VP), a light-activated drug used in photodynamic therapy for the treatment of choroidal neovascular membranes, has also been shown to be an effective inhibitor of malignant cells. Recently, studies have demonstrated that, even without photo-activation, VP may still inhibit certain tumor cell lines, including ovarian cancer, hepatocarcinoma and retinoblastoma, through the inhibition of the YAP-TEAD complex. In this study, we examined the effects of VP without light activation on human glioma cell lines (LN229 and SNB19). Through western blot analysis, we identified that human glioma cells that were exposed to VP without light activation demonstrated a downregulation of YAP-TEAD-associated downstream signaling molecules, including c-myc, axl, CTGF, cyr61 and survivin and upregulation of the tumor growth inhibitor molecule p38 MAPK. In addition, we observed that expression of VEGFA and the pluripotent marker Oct-4 were also decreased. Verteporfin did not alter the Akt survival pathway or the mTor pathway but there was a modest increase in LC3-IIB, a marker of autophagosome biogenesis. This study suggests that verteporfin should be further explored as an adjuvant therapy for the treatment of glioblastoma.
View details for DOI 10.1038/s41598-017-07632-8
View details for PubMedID 28790340
View details for PubMedCentralID PMC5548915
Atorvastatin Promotes Phagocytosis and Attenuates Pro-Inflammatory Response in Human Retinal Pigment Epithelial Cells.
2017; 7 (1): 2329
Phagocytosis of daily shed photoreceptor outer segments is an important function of the retinal pigment epithelium (RPE) and it is essential for retinal homeostasis. RPE dysfunction, especially impairment of its phagocytic ability, plays an essential role in the pathogenesis of age-related macular degeneration (AMD). Statins, or HMG CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors, are drugs with multiple properties that have been extensively used to treat hyperlipidemia. However, their effect on RPE cells has not been fully elucidated. Here we report that high dose atorvastatin increased the phagocytic function of ARPE-19 cells, as well as rescue the cells from the phagocytic dysfunction induced by cholesterol crystals and oxidized low-density lipoproteins (ox-LDL), potentially by increasing the cellular membrane fluidity. Similar effects were observed when evaluating two other hydrophobic statins, lovastatin and simvastatin. Furthermore, atorvastatin was able to block the induction of interleukins IL-6 and IL-8 triggered by pathologic stimuli relevant to AMD, such as cholesterol crystals and ox-LDL. Our study shows that statins, a well-tolerated class of drugs with rare serious adverse effects, help preserve the phagocytic function of the RPE while also exhibiting anti-inflammatory properties. Both characteristics make statins a potential effective medication for the prevention and treatment of AMD.
View details for DOI 10.1038/s41598-017-02407-7
View details for PubMedID 28539592
View details for PubMedCentralID PMC5443823
Verteporfin-induced formation of protein cross-linked oligomers and high molecular weight complexes is mediated by light and leads to cell toxicity.
2017; 7: 46581
Verteporfin (VP) was first used in Photodynamic therapy, where a non-thermal laser light (689 nm) in the presence of oxygen activates the drug to produce highly reactive oxygen radicals, resulting in local cell and tissue damage. However, it has also been shown that Verteporfin can have non-photoactivated effects such as interference with the YAP-TEAD complex of the HIPPO pathway, resulting in growth inhibition of several neoplasias. More recently, it was proposed that, another non-light mediated effect of VP is the formation of cross-linked oligomers and high molecular weight protein complexes (HMWC) that are hypothesized to interfere with autophagy and cell growth. Here, in a series of experiments, using human uveal melanoma cells (MEL 270), human embryonic kidney cells (HEK) and breast cancer cells (MCF7) we showed that Verteporfin-induced HMWC require the presence of light. Furthermore, we showed that the mechanism of this cross-linking, which involves both singlet oxygen and radical generation, can occur very efficiently even after lysis of the cells, if the lysate is not protected from ambient light. This work offers a better understanding regarding VP's mechanisms of action and suggests caution when one studies the non-light mediated actions of this drug.
View details for DOI 10.1038/srep46581
View details for PubMedID 28429726
View details for PubMedCentralID PMC5399488
Fornix-Based Versus Limbal-Based Conjunctival Trabeculectomy Flaps for Glaucoma: Findings From a Cochrane Systematic Review.
American journal of ophthalmology
2017; 174: 33–41
To compare effectiveness of fornix- and limbal-based conjunctival flaps in trabeculectomy surgery.Systematic review.Setting: CENTRAL, MEDLINE, LILACS, ISRCTN registry, ClinicalTrials.gov, WHO, and ICTRP were searched to identify eligible randomized controlled trials (RCTs).RCTs in which benefits and complications of fornix- vs limbal-based trabeculectomy for glaucoma were compared in adult glaucoma patients.We followed Cochrane methodology for data extraction.Proportion of failed trabeculectomies at 24 months, defined as the need for repeat surgery or uncontrolled intraocular pressure (IOP) >22 mm Hg, despite topical/systemic medications.The review included 6 trials with a total of 361 participants, showing no difference in effectiveness between fornix-based vs limbal-based trabeculectomy surgery, although with a high level of uncertainty owing to low event rates. In the fornix-based and limbal-based surgery, mean IOP at 12 months was similar, with ranges of 12.5-15.5 mm Hg and 11.7-15.1 mm Hg, respectively. Mean difference was 0.44 mm Hg (95% CI -0.45 to 1.33) and 0.86 mm Hg (95% CI -0.52 to 2.24) at 12 and 24 months of follow-up, respectively. Mean number of postoperative glaucoma medications was similar between the 2 groups. Mean difference was 0.02 (95% CI -0.15 to 0.19) at 12 months. As far as postoperative complications, an increased risk of shallow anterior chamber was observed in the limbal-based group.Similar efficacy of trabeculectomy surgery with respect to bleb failure or IOP control was observed in both types of conjunctival flap incisions. A significant difference was detected in the risk of postoperative shallow anterior chamber, which was increased in the limbal-based group.
View details for DOI 10.1016/j.ajo.2016.10.006
View details for PubMedID 27794426
View details for PubMedCentralID PMC5321540
AMPK-Activated Protein Kinase Suppresses Ccr2 Expression by Inhibiting the NF-κB Pathway in RAW264.7 Macrophages.
2016; 11 (1): e0147279
C-C chemokine receptor 2 (Ccr2) is a key pro-inflammatory marker of classic (M1) macrophage activation. Although Ccr2 is known to be expressed both constitutively and inductively, the full regulatory mechanism of its expression remains unclear. AMP-activated protein kinase (AMPK) is not only a master regulator of energy homeostasis but also a central regulator of inflammation. In this study, we sought to assess AMPK's role in regulating RAW264.7 macrophage Ccr2 protein levels in resting (M0) or LPS-induced M1 states. In both M0 and M1 RAW264.7 macrophages, knockdown of the AMPKα1 subunit by siRNA led to increased Ccr2 levels whereas pharmacologic (A769662) activation of AMPK, attenuated LPS-induced increases in Ccr2 expression in an AMPK dependent fashion. The increases in Ccr2 levels by AMPK downregulation were partially reversed by NF-κB inhibition whereas TNF-a inhibition had minimal effects. Our results indicate that AMPK is a negative regulator of Ccr2 expression in RAW264.7 macrophages, and that the mechanism of action of AMPK inhibition of Ccr2 is mediated, in part, through the NF-κB pathway.
View details for DOI 10.1371/journal.pone.0147279
View details for PubMedID 26799633
View details for PubMedCentralID PMC4723067
- Outcomes of an algorithmic approach to treating mild ocular alkali burns. JAMA ophthalmology 2015; 133 (10): 1214–16
Fornix-based versus limbal-based conjunctival trabeculectomy flaps for glaucoma.
The Cochrane database of systematic reviews
Glaucoma is one of the leading largely preventable causes of blindness in the world. It usually is addressed first medically with topical intraocular pressure-lowering drops or by laser trabeculoplasty. In cases where such treatment fails, glaucoma-filtering surgery is considered, most commonly trabeculectomy surgery with variations in technique, for example, the type of conjunctival flap (fornix- or limbal-based). In a fornix-based flap, the surgical wound is performed at the corneal limbus; while in a limbal-based flap, the incision is further away. Many studies in the literature compare fornix- and limbal-based trabeculectomy with respect to outcomes and complications.To assess the comparative effectiveness of fornix- versus limbal-based conjunctival flaps in trabeculectomy for adult glaucoma, with a specific focus on intraocular pressure (IOP) control and complications (adverse effects).We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2015, Issue 9), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to October 2015), EMBASE (January 1980 to October 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to October 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 23 October 2015.We reviewed the bibliographic references of identified randomised controlled trials (RCTs) in order to find trials not identified by the electronic searches. We contacted researchers and practitioners active in the field of glaucoma to identify other published and unpublished trials.We included RCTs comparing the benefits and complications of fornix- versus limbal-based trabeculectomy for glaucoma, irrespective of glaucoma type, publication status, and language. We excluded studies on children less than 18 years of age, since wound healing is different in this age group and the rate of bleb scarring postoperatively is high.Two review authors independently extracted data and assessed trial quality. We contacted study authors for additional information.The primary outcome was the proportion of failed trabeculectomies at 24 months. Failure was defined as the need for repeat surgery or uncontrolled IOP (more than 22 mmHg), despite additional topical/systemic medications. Needling and 5-fluorouracil (5-FU) injections were allowed only during the first six months postoperatively; additional needling or 5-FU injections were considered as failure. Mean post-operative IOP at 12 and 24 months also was recorded.The review included six trials with a total of 361 participants. Two studies were conducted in America and one each in Germany, Greece, India, and Saudi Arabia. The participants of four trials had open-angle glaucoma; one study included participants with primary open-angle or primary closed-angle glaucoma, and one study did not specify the type of glaucoma. Three studies used a combined procedure (phacotrabeculectomy). Trabeculectomy with mitomycin C (MMC) was performed in four studies, and trabeculectomy with 5-fluorouracil (5-FU) was performed in only one study.None of the included trials reported trabeculectomy failure at 24 months. Only one trial reported the failure rate of trabeculectomy as a late complication. Failure was higher among participants randomised to the limbal-based surgery: 1/50 eyes failed trabeculectomy in the fornix group compared with 3/50 in the limbal group (risk ratio (RR) 0.33, 95% confidence interval (95% CI) 0.04 to 3.10); therefore we are very uncertain as to the relative effect of the two procedures on failure rate.Four studies including 252 participants provided measures of mean IOP at 12 months. In the fornix-based surgeries, mean IOP ranged from 12.5 to 15.5 mmHg and similar results were noted in limbal-based surgeries with mean IOP ranging from 11.7 to 15.1 mmHg without significant difference. Mean difference was 0.44 mmHg (95% CI -0.45 to 1.33) and 0.86 mmHg, (95% CI -0.52 to 2.24) at 12 and 24 months of follow-up, respectively. Neither of these pooled analyses showed a statistically significant difference in IOP between groups (moderate quality of evidence).One trial reported number of anti-glaucoma medications at 24 months of follow-up with no difference noted between surgical groups. However, three trials reported the mean number of anti-glaucoma medications at 12 months of follow-up without significant difference in the mean number of postoperative IOP-lowering medications between the two surgical techniques. Mean difference was 0.02, (95% CI -0.15 to 0.19) at 12 months of follow-up (high quality of evidence).Because of the small numbers of events and total participants, the risk of many reported adverse events were uncertain and those that were found to be statistically significant may have been due to chance.For risk of bias assessment: although all six trials were randomised selection bias was mostly unclear, with unclear random sequence generation in four of the six studies and unclear allocation concealment in five of the six studies. Attrition bias was encountered in only one trial which also suffered from reporting bias. All other trials had an unclear risk of reporting bias as there was no access to study protocols. All included trials were judged to have high risk of detection bias due to lack of masking of the outcomes. Trabeculectomy is quite a standard procedure and unlikely to induce bias due to surgeon 'performance', hence performance bias was not evaluated.The main result of this review was that there was uncertainty as to the difference between fornix- and limbal-based trabeculectomy surgeries due to the small number of events and confidence intervals that cross the null. This also applied to postoperative complications, but without any impact on long-term failure rate between the two surgical techniques.
View details for DOI 10.1002/14651858.CD009380.pub2
View details for PubMedID 26599668
View details for PubMedCentralID PMC4734381
Uveal melanoma cell growth is inhibited by aminoimidazole carboxamide ribonucleotide (AICAR) partially through activation of AMP-dependent kinase.
Investigative ophthalmology & visual science
2014; 55 (7): 4175–85
To evaluate the effects and mechanism of aminoimidazole carboxamide ribonucleotide (AICAR), an AMP-dependent kinase (AMPK) activator, on the growth of uveal melanoma cell lines.Four different cell lines were treated with AICAR (1-4 mM). Cell growth was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay. Cell cycle analysis was conducted by flow cytometry; additionally, expression of cell-cycle control proteins, cell growth transcription factors, and downstream effectors of AMPK were determined by RT-PCR and Western blot.Aminoimidazole carboxamide ribonucleotide inhibited cell growth, induced S-phase arrest, and led to AMPK activation. Aminoimidazole carboxamide ribonucleotide treatment was associated with inhibition of eukaryotic translation initiation factor 4E-BP1 phosphorylation, a marker of mammalian target of rapamycin (mTOR) pathway activity. Aminoimidazole carboxamide ribonucleotide treatment was also associated with downregulation of cyclins A and D, but had minimal effects on the phosphorylation of ribosomal protein S6 or levels of the macroautophagy marker LC3B. The effects of AICAR were abolished by treatment with dipyridamole, an adenosine transporter inhibitor that blocks the entry of AICAR into cells. Treatment with adenosine kinase inhibitor 5-iodotubericidin, which inhibits the conversion of AICAR to its 5'-phosphorylated ribotide 5-aminoimidazole-4-carboxamide-1-D-ribofuranosyl-5'-monophosphate (ZMP; the direct activator of AMPK), reversed most of the growth-inhibitory effects, indicating that some of AICAR's antiproliferative effects are mediated at least partially through AMPK activation.Aminoimidazole carboxamide ribonucleotide inhibited uveal melanoma cell proliferation partially through activation of the AMPK pathway and downregulation of cyclins A1 and D1.
View details for DOI 10.1167/iovs.13-12856
View details for PubMedID 24781943
View details for PubMedCentralID PMC4089421
The clinically used photosensitizer Verteporfin (VP) inhibits YAP-TEAD and human retinoblastoma cell growth in vitro without light activation.
Experimental eye research
2014; 124: 67–73
Verteporfin (VP), a benzoporphyrin derivative, is clinically used in photodynamic therapy for neovascular macular degeneration. Recent studies indicate that VP may inhibit growth of hepatoma cells without photoactivation through inhibition of YAP-TEAD complex. In this study, we examined the effects of VP without light activation on human retinoblastoma cell lines. Verteporfin but not vehicle control inhibited the growth, proliferation and viability of human retinoblastoma cell lines (Y79 and WERI) in a dose-dependent manner and was associated with downregulation of YAP-TEAD associated downstream proto-oncogenes such as c-myc, Axl, and surviving. In addition VP affected signals involved in cell migration and angiogenesis such as CTGF, cyr61, and VEGF-A but was not associated with significant effect on the mTOR/autophagy pathway. Of interest the pluripotency marker Oct4 were downregulated by Verteporfin treatment. Our results indicate that the clinically used photosensitizer VP is a potent inhibitor of cell growth in retinoblastoma cells, disrupting YAP-TEAD signaling and pluripotential marker OCT4. This study highlights for the first time the role of the YAP-TEAD pathway in Retinoblastoma and suggests that VP may be a useful adjuvant therapeutic tool in treating Rb patients.
View details for DOI 10.1016/j.exer.2014.04.011
View details for PubMedID 24837142
View details for PubMedCentralID PMC4135181
An albumin leader sequence coupled with a cleavage site modification enhances the yield of recombinant C-terminal Mullerian Inhibiting Substance.
Technology (Elmsford, N.Y.)
2013; 1 (1): 63–71
Mullerian Inhibiting Substance (MIS) has been shown to inhibit ovarian cancer cells both in-vitro and in-vivo. Furthermore, recent evidence suggests that MIS may effectively target a putative ovarian cancer progenitor cell population enriched by a panel of CD44+, CD24+, Ep-CAM+, and E-cadherin-cell surface markers. In order to accommodate clinical testing of MIS in ovarian cancer patients, the production of recombinant human MIS must be optimized to increase yield and purity. Here we show that, compared to wild type, the substitution of the MIS leader sequence to that of human serum albumin, combined with a modification of the endogenous cleavage site from RAQR/S to a furin/kex2 RARR/S consensus site results in high expression, increased C-terminus cleavage and a reduction in unwanted cryptic internal cleavage products when produced in CHO cells. Purified MIS containing these alterations retains its capacity to induce regression of the Mullerian duct in fetal rat embryonic urogenital ridge assays.
View details for DOI 10.1142/S2339547813500076
View details for PubMedID 24729676
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War-related ocular injuries in Damascus during the Syrian Crisis.
BACKGROUND: . Ocular injuries constitute a major cause of visual morbidity, and they have a significant socioeconomic impact worldwide. We aimed to document the types and causes of Syrian War related ocular injuries in Damascus, Syria.METHODS: . Medical records were retrospectively reviewed to evaluate all patients in Al-Mouwasat University Hospital and Damascus Hospital, whose ocular injuries were caused by war-related activities during the period extending between January of 2016 and December 2017.RESULTS: . 150 eye injuries in 127 patients were reviewed, in which 46 (31%) were bilateral and 87 (58%) were open globe injuries. The leading cause of the observed ocular injuries was improvised explosive devices (IED) [37 eyes (41%)]. The majority of patients presented with an initial best corrected visual acuity (BCVA) of "light perception" (LP) to "hand movement" (HM) [51 eyes (34%)]. Information on the final BCVA was available for 69 injured eyes only, and it was "no light perception" (NLP) in 20 eyes (29%).CONCLUSION: . Explosive weaponry is the main culprit in most war-related ocular injuries in Syria. The high incidence of open globe injuries caused many of the cases to be severe in nature. Education on the precautionary measures that protect the eyes such as the use of combat eye protection during wartimes ought to be enforced, so that future ocular injuries can be prevented.
View details for DOI 10.1016/j.injury.2020.11.069
View details for PubMedID 33408056
- Avicenna Journal of Medicine: 5-year milestones. Avicenna journal of medicine ; 6 (1): 1–2
Attitudes, barriers, and practices toward research and publication among medical students at the University of Damascus, Syria.
Avicenna journal of medicine
; 8 (1): 24–33
Research is crucial for health-care delivery. However, medical students may not participate in research during their training, which might negatively affect their understanding of the importance of research and their future ability to conduct research projects. This is more prominent in developing countries. We aim to assess the attitudes of a sample of Syrian medical students toward research and suggest plausible solutions to reduce their self-reported barriers.A cross-sectional study was conducted using a self-administered, pretested questionnaire.Three hundred and twenty-three responses were included. Most students demonstrated positive attitudes toward research. However, most of the responses indicated that they did not receive any training in academic writing or research and therefore did not have the opportunity to participate in formal research projects or scholarly writing. Students reported various types of barriers that challenged their progress in the field of research. Students who reported being encouraged by their professors to participate in research and writing/publishing scientific papers or reported receiving training about these activities were more likely to participate in research projects or writing scientific articles.Students have positive attitudes toward research and publication while they reported poor education, limited participation, and presence of many barriers that impede their participation in such activities.
View details for DOI 10.4103/ajm.AJM_116_17
View details for PubMedID 29404270
View details for PubMedCentralID PMC5782417
An online academic writing and publishing skills course: Help Syrians find their voice.
Avicenna journal of medicine
; 7 (3): 103–9
A group of Arab-American physicians and researchers in the United States organized a blended online course in academic writing and publishing in medicine targeting medical students and physicians in war-torn Syria. This was an effort to address one of the reasons behind the poor quantity and quality of scientific research papers in Syria and the Arab region. In this paper, we report on the design, conduct, and outcome of this course and attempt to evaluate its effectiveness.The educational intervention was a 2-month blended online course. We administered a questionnaire to assess satisfaction and self-reported improvement in knowledge, confidence, and skills of academic writing and publishing.The course succeeded in reaching more than 2588 physicians and medical students from the region; 159 of them completed most of the course. Eighty-three percent of the participants felt that they were confident enough to write an academic paper after the course and 95% felt the learning objectives were achieved with an average student satisfaction of 8.4 out of 10.Physicians in Syria and neighboring countries are in need of training to become an active part of the global scientific community and to document and communicate the crisis their countries are going through from a medical perspective. Low-cost online educational initiatives help respond, at least partially, to those needs.
View details for DOI 10.4103/ajm.AJM_204_16
View details for PubMedID 28791242
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Muslim patients in Ramadan: A review for primary care physicians.
Avicenna journal of medicine
; 7 (3): 81–87
Fasting Ramadan, in which Muslims abstain from specific habits and behaviors from dawn to sunset, is one of the five Pillars of Islam. While there are several exemptions from fasting, many Muslim patients with acute or chronic medical conditions still choose to fast, which may adversely affect their health if not addressed properly. Some patients may not be well educated about the effects of some medical treatments and procedures on the validity of their fast, which can unnecessarily lead to suboptimal management of their conditions or treatment nonadherence. Since spirituality, religiosity, and personal beliefs affect patients' health behaviors and adherence to treatments, health-care providers need to learn how fasting Ramadan can affect the health of their Muslim patients, especially those with chronic medical conditions, and how to help them achieve safe fasting. This article aims to provide an overview of the main topics that primary care physicians may need to know in order to improve their cultural competence when caring for their fasting Muslim patients.
View details for DOI 10.4103/ajm.AJM_76_17
View details for PubMedID 28791239
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Polio in Syria: Problem still not solved.
Avicenna journal of medicine
; 7 (2): 64–66
The reappearance of polio in Syria in mid-2013, 18 years after it was eliminated from the country, manifests the public health catastrophe brought on by the civil war. Among the lessons learned, this outbreak emphasizes the importance of increasing the international financial and logistical support for vaccine and immunization efforts, especially in countries suffering from conflicts. The lack of access to polio accredited laboratory or outright lack of laboratories in settings of conflict should be recognized allowing international surveillance to be strengthened by supplementing the laboratory definition with the clinical definition. In addition, it illustrates the imperative for the United Nations (UN) agencies involved in global health to be able to operate independently from governments during conflicts in order to provide adequate and efficient medical and humanitarian relief for civilians. Proper communicable disease surveillance and control, delivery of vaccinations, and other pivotal healthcare services to these areas require independence from governments and all military actors involved. Moreover, it shows the necessity to adequately support and fund the front-line nongovernmental organizations (NGOs) that are implementing the delivery of medical and humanitarian aid in Syria.
View details for DOI 10.4103/ajm.AJM_173_16
View details for PubMedID 28469988
View details for PubMedCentralID PMC5398005
Progression of Dry to Wet Age-related Macular Degeneration in Patients Receiving Intensive Statin Treatment
ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2020
View details for Web of Science ID 000554495703257
Absolute Risk of Rhegmatogenous Retinal Detachment in High Myopes in the United States
ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2020
View details for Web of Science ID 000554495702305
Impact of Obstructive Sleep Apnea Treatment on Choroidal Thickness in Patients with Central Serous Chorioretinopathy
ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2020
View details for Web of Science ID 000554528301035
Evidence-based medicine: a persisting desire under fire.
2017; 22 (1): 9–11
Healthcare infrastructure and medical schools in Syria have been greatly compromised by military conflict and humanitarian disaster. Medical students and healthcare professionals reached out for remote learning opportunities. Surprisingly, they desired a curriculum in evidence-based medicine. We report on a curriculum that was delivered to 126 learners using an online remote delivery platform. This experience demonstrates the feasibility of this approach in disaster-stricken areas and underscores the importance of evidence-based medicine even under such conditions.
View details for DOI 10.1136/ebmed-2016-110608
View details for PubMedID 27965267
- Syrians' alternative to a health care system: "field hospitals". Avicenna journal of medicine 2014; 4 (3): 51–52