OBJECTIVE: In angiogenesis, circulating mononuclear cells are recruited to vascular lesions; however, the underlying mechanisms are poorly understood. APPROACH AND RESULTS: Here, we characterize the functional role of protein tyrosine kinase 7 (PTK7)-expressing CD11b(+) mononuclear cells in vitro and in vivo using a mouse model of angiogenesis. Although the frequencies of PTK7(+)CD11b(+) cells in the bone marrow remained similar after vascular endothelial growth factor-A-induced neovascularization, we observed an 11-fold increase in the cornea. Importantly, vascular endothelial growth factor-A-induced chemotaxis of PTK7(+) cells was mediated by vascular endothelial growth factor receptor 2. In a coculture with endothelial cells, PTK7(+)CD11b(+) cells stabilized the vascular network for 2 weeks by expressing high levels of angiopoietin-1. The enhanced vascular stability was abolished by knockdown of angiopoietin-1 in PTK7(+)CD11b(+) cells and could be restored by angiopoietin-1 treatment. CONCLUSIONS: We conclude that PTK7 expression in perivascular mononuclear cells induces vascular endothelial growth factor receptor 2 and angiopoietin-1 expression and thus contributes to vascular stabilization in angiogenesis.
PURPOSE: To investigate the effect of host immunity (allospecific) and surgical manipulation (non-allospecific) on corneal endothelial cells (CECs) in corneal transplantation. METHODS: Draining lymph nodes and grafted C57BL/6 corneas were harvested from syngeneic recipients, allograft acceptors, and allograft rejectors (BALB/c) 1, 3, and 8 weeks after transplantation. We analyzed CEC apoptosis using an ex vivo cornea-in-the-cup assay, and visualized cell-to-cell junctions using immunohistochemical staining (ZO-1). Automatic cell analysis using Confoscan software was used to measure CEC density as well as changes in CEC morphology by quantifying the coefficient of variation in cell size (polymegethism) and shape (pleomorphism). RESULTS: The cornea-in-the-cup assay showed that allogeneic acceptor T cells and to an even greater extent rejector T cells (but not syngeneic T cells) induced CEC apoptosis. CEC density after corneal transplantation was significantly reduced in allogeneic acceptors compared with syngeneic grafts (P<0.001), and CEC density was even further reduced in the allo-rejector group compared with the allo-acceptor group. Allogeneic grafts showed a greater increase in the coefficient of variation in cell size (polymegethism) when compared with syngeneic grafts 1 week after transplantation (P=P<0.001). However, pleomorphism was not significantly different between syngeneic and allo-acceptor grafts, indicating that polymegethism (but not pleomorphism or cell density) is a sensitive indicator of the effect of alloimmunity on CECs. CONCLUSIONS: Our data demonstrate that host alloimmunity rather than surgical manipulation alone is the major cause of CEC damage in corneal transplantation, and such morphologic changes of CECs can be detected before the clinically visible onset of allograft rejection.
OBJECTIVE: To design and implement a teaching skills curriculum that addressed the needs of an ophthalmology residency training program, to assess the effect of the curriculum, and to present important lessons learned. DESIGN: A teaching skills curriculum was designed for the Harvard Medical School (HMS) Residency Training Program in Ophthalmology. Results of a needs assessment survey were used to guide curriculum objectives. Overall, 3 teaching workshops were conducted between October 2012 and March 2013 that addressed areas of need, including procedural teaching. A postcurriculum survey was used to assess the effect of the curriculum. SETTING: Massachusetts Eye and Ear Infirmary, a tertiary care institution in Boston, MA. PARTICIPANTS: Overall, 24 residents in the HMS Residency Training Program in Ophthalmology were included. RESULTS: The needs assessment survey demonstrated that although most residents anticipated that teaching would be important in their future career, only one-third had prior formal training in teaching. All residents reported they found the teaching workshops to be either very or extremely useful. All residents reported they would like further training in teaching, with most residents requesting additional training in best procedural teaching practices for future sessions. CONCLUSIONS: The pilot year of the resident-as-teacher curriculum for the HMS Residency Training Program in Ophthalmology demonstrated a need for this curriculum and was perceived as beneficial by the residents, who reported increased comfort in their teaching skills after attending the workshops.
Fungal endophthalmitis is an important cause of vision loss worldwide with a large body of literature describing the treatment of the disease. The evidence supporting the use of pars plana vitrectomy in the management of fungal endophthalmitis is largely comprised of case reports and case series and demonstrates the important role of vitrectomy surgery. Vitrectomy can improve the likelihood of establishing the diagnosis, enhance the treatment of infection by removing fungal elements in the vitreous, aid in the removal of other inoculated intraocular structures, and is an important tool in the management of vision-threatening post-infectious sequelae like retinal detachment and epiretinal membrane.
BACKGROUND: Acute respiratory infections (ARI) are the major worldwide health problem associated with high morbidity and mortality rates. Human adenovirus (HAdV) is one of the most common pathogens associated with viral ARI, and thus calls for specific diagnosis and better understanding of the epidemiology and clinical characteristics. METHODS: Total 4,130 children with ARI requiring hospitalization from 2012 to 2013 were retrospectively studied. Throat swab specimens were collected from each patient. Fluorescence Quantitative PCR was performed to detect adenovirus as well as other common ARI-related pathogens. The seven HAdV hypervariable regions (HVRs) of the hexon gene from fifty-seven HAdVs-positive samples collected in the seasonal peaks were sequenced. Phylogenetic analysis of HVRs was also conducted to confirm the molecular types and genetic variation. In addition, epidemiological features and co-infection with other human respiratory pathogens were investigated and analyzed. RESULTS: Of 4,130 hospitalized pediatric patients tested, the positive rates of respiratory syncytial virus (RSV), Mycoplasma pneumoniae (MP), and HAdV were 13.7%, 13.2%, and 12.0%, respectively. The HAdV positive patients accounted for 7.9%, 17.2%, 17.5% and 10.7% in age groups <1, 1-3, 3-6 and 6-14 years, respectively. Eighty-four HAdV positive children were co-infected with other respiratory pathogens (84/495, 17.0%). The most common co-infection pathogens with HAdV were MP (57.1%) and Human Bocavirus (HBoV) (16.7%). The majority of HAdV infected patients were totally recovered (96.9%, 480/495); However, four (0.8%) patients, who were previously healthy and at the age of 2 years or younger died of pneumonia. Seasonal peaks of HAdV infection occurred in the summer season of 2012 and 2013; the predominant HAdV type was HAdV-3 (70%), followed by HAdV-7 (28%). These epidemiological features were different from those in Northern China. The HAdV-55 was identified and reported for the first time in Guangzhou metropolitan area. Phylogenetic analysis indicated that all the HVR sequences of the hexon gene of HAdV-3 and -7 strains have high similarity within their individual types, and these strains were also similar to those circulating in China currently, indicating the conservation of hexon genes of both HAdV-3 and HAdV-7. CONCLUSIONS: Knowledge of the epidemiological features and molecular types of HAdV, a major pathogen of pediatric ARI, as well as other co-infected respiratory pathogens circulating in Guangzhou, southern China, is vital to predict and prevent future disease outbreaks in children. This study will certainly facilitate HAdV vaccine development and treatment of HAdV infections in children.
OBJECTIVE: To examine effects of phacoemulsification on longer-term intraocular pressure (IOP) in patients with medically treated primary open-angle glaucoma (POAG; including normal-tension glaucoma), pseudoexfoliation glaucoma (PXG), or primary angle-closure glaucoma (PACG), without prior or concurrent incisional glaucoma surgery. METHODS: PubMed and Cochrane database searches, last conducted in December 2014, yielded 541 unique citations. Panel members reviewed titles and abstracts and selected 86 for further review. The panel reviewed these articles and identified 32 studies meeting the inclusion criteria, for which the panel methodologist assigned a level of evidence based on standardized grading adopted by the American Academy of Ophthalmology. One, 15, and 16 studies were rated as providing level I, II, and III evidence, respectively. RESULTS: All follow-up, IOP, and medication data listed are weighted means. In general, the studies reported on patients using few glaucoma medications (1.5-1.9 before surgery among the different diagnoses). For POAG, 9 studies (total, 461 patients; follow-up, 17 months) showed that phacoemulsification reduced IOP by 13% and glaucoma medications by 12%. For PXG, 5 studies (total, 132 patients; follow-up, 34 months) showed phacoemulsification reduced IOP by 20% and glaucoma medications by 35%. For chronic PACG, 12 studies (total, 495 patients; follow-up, 16 months) showed phacoemulsification reduced IOP by 30% and glaucoma medications by 58%. Patients with acute PACG (4 studies; total, 119 patients; follow-up, 24 months) had a 71% reduction from presenting IOP and rarely required long-term glaucoma medications when phacoemulsification was performed soon after medical reduction of IOP. Trabeculectomy after phacoemulsification was uncommon; the median rate reported within 6 to 24 months of follow-up in patients with controlled POAG, PXG, or PACG was 0% and was 7% in patients with uncontrolled chronic PACG. CONCLUSIONS: Phacoemulsification typically results in small, moderate, and marked reductions of IOP and medications for patients with POAG, PXG, and PACG, respectively, and using 1 to 2 medications before surgery. Trabeculectomy within 6 to 24 months after phacoemulsification is rare in such patients. However, reports on its effects in eyes with advanced disease or poor IOP control before surgery are few, particularly for POAG and PXG.
OBJECTIVE: To review the current published literature to evaluate the success rates and long-term problems associated with surgery for pediatric glaucoma.
METHODS: Literature searches of the PubMed and Cochrane Library databases were last conducted in May 2012. The search yielded 838 potentially relevant citations, of which 273 were in non-English languages. The titles and abstracts of these articles were reviewed by the authors, and 364 were selected for possible further review. Members of the Ophthalmic Technology Assessment Committee Glaucoma Panel reviewed the full text of these articles and used the 36 that met inclusion and exclusion criteria for this Ophthalmic Technology Assessment. There were no studies on the topic that provided level I evidence. The assessment included only level II and level III studies.
RESULTS: Surgeons treat pediatric glaucoma most commonly with goniotomy, trabeculotomy, trabeculectomy, combined trabeculotomy and trabeculectomy, tube shunt surgery, cyclodestruction, and deep sclerectomy. Certain surgical options seem better for specific diagnoses, such as primary congenital glaucoma, aphakic glaucoma, and glaucomas associated with other ocular or systemic anomalies.
CONCLUSIONS: There are many surgical options for the treatment of the pediatric glaucomas. The relative efficacy of these various procedures for particular diagnoses and clinical situations should be weighed against the specific risks associated with the procedures for individual patients.
Th17 cells are principal mediators of many autoimmune conditions. Recently, memory Th17 cells have been revealed as crucial in mediating the chronicity of various refractory autoimmune disorders; however, the underlying mechanisms maintaining memory Th17 cells have remained elusive. Here, using a preclinical model of ocular autoimmune disease we show that both IL-7 and IL-15 are critical for maintaining pathogenic memory Th17 cells. Neutralization of these cytokines leads to substantial reduction of memory Th17 cells; both IL-7 and IL-15 provide survival signals via activating STAT5, and IL-15 provides additional proliferation signals via activating both STAT5 and Akt. Topical neutralization of ocular IL-7 or IL-15 effectively reduces memory Th17 cells at the inflammatory site and draining lymphoid tissues, while topical neutralization of IL-17 alone, the major pathogenic cytokine secreted by Th17 cells, does not diminish memory Th17 cells at the draining lymphoid tissues. Our results suggest that the effective removal of pathogenic memory Th17 cells via abolishing environmental IL-7 or IL-15 is likely to be a novel strategy in the treatment of autoimmune diseases.
Shorter axial length observed in patients with primary angle closure glaucoma (PACG) might be due to altered matrix metalloproteinase-9 (MMP9) activity resulting in ECM remodeling during eye growth and development. This study aimed to evaluate common variants in MMP9 for association with PACG. Six tag SNPs of MMP9 were genotyped in a Chinese sample of 1,030 cases, including 572 PACG and 458 primary angle closure (PAC), and 499 controls. None of 6 SNPs were significantly associated with overall PAC/PACG (P > 0.07) or with PAC/PACG subgroups (Pc > 0.18). Meta-analysis of two non-Chinese studies revealed significant association between rs17576 and PACG (ORs = 0.56, P < 0.0001); however, meta-analysis of our dataset with 4 Chinese datasets did not replicate this association (ORs = 1.23, P = 0.29). Prior significant association for rs3918249 in one Caucasian study (OR = 0.63, P = 0.006) was not replicated in meta-analysis of 3 Chinese studies including this study (ORs = 0.91, P = 0.13). Significant heterogeneity between non-Chinese and Chinese datasets precluded overall meta-analysis for rs17576 and rs3918249 (Q = 0.001 and 0.04 respectively). rs17577 was nominally associated with PACG in one Caucasian study (OR = 1.71, P = 0.02), but not in 3 Chinese studies including our study (ORs = 1.20, P = 0.07). Overall meta-analysis revealed nominal association for rs17577 and PAC/PACG (ORs = 1.26, Pc = 0.05). Meta-analysis did not show significant association between the other SNPs and PAC/PACG (P > 0.47). The largest association study to date did not find significant association between MMP9 and PAC/PACG in Chinese; meta-analysis with other Chinese datasets did not produce significant association. In most instances combination with non-Chinese datasets was not possible except for one variant showing nominally significant association. More work is needed to define the role of MMP9 variants in PACG.
Lymphedema is caused by defective drainage of the lymphatic system. In Melkersson-Rosenthal syndrome, involvement is predominantly of the lumens with blockage of lymphatic channels by histiocytic-epithelioid cell clusters accompanied by dermal granulomas and lymphocytes. It is a localized, painless, nonitching, and nonpitting form of lymphedema. Besides the eyelids, the disease can cause lip edema, facial palsy, and/or fissured tongue. It is rare and has received little attention in the ophthalmic literature, either in its complete triadic form, or more frequently, in its monosymptomatic forms. Pathogenesis is not well understood, and there is no effective therapy. The authors describe a case of Melkesson-Rosenthal syndrome in a 45-year-old Hispanic man with isolated unilateral upper eyelid edema. Histopathological and immunohistochemical evaluations of an eyelid biopsy specimen revealed intravascular and extravascular clusters of histiocytic-epithelioid cells that were CD68/163-positive. Variable numbers of mostly T-lymphocytes were found in the epidermis, dermis, and orbicularis muscle and by virtue of the associated granulomas established the diagnosis of Melkersson-Rosenthal syndrome. CD4 helper and CD8 suppressor T-lymphocytes were equally represented. CD20 B-lymphocytes were exceedingly sparse. Conspicuous CD1a-positive Langerhans' cells were present in the epidermis, sometimes formed subepithelial loose aggregates and were also incorporated in the granulomas. The differential diagnosis includes the far more common condition of acne rosacea. Management of Melkersson-Rosenthal syndrome, and of angioedema in general, is reviewed.
Fenofibrate, a specific agonist of peroxisome proliferator-activated receptor alpha (PPARα), displays robust therapeutic effects on diabetic retinopathy (DR) in type 2 diabetic patients. Our recent studies have shown that PPARα is down-regulated in the diabetic retina, which contributes to the pathogenesis of DR. However, the mechanism for diabetes-induced down-regulation of PPARα remains unknown. We investigated the role of microRNA-21 (miR-21) in regulating PPARα in DR. MiR-21 was over-expressed, while PPARα levels were decreased in the retina of db/db mice, a type 2 diabetic model. Such alterations were also observed in palmitate-treated retinal endothelial cells. MiR-21 targeted PPARα by inhibiting its mRNA translation. Knockout of miR-21 prevented the decrease of PPARα, alleviated microvascular damage, ameliorated inflammation and reduced cell apoptosis in the retina of db/db mice. Intravitreal injection of miR-21 inhibitor attenuated PPARα down-regulation and ameliorated retinal inflammation in db/db mice. Further, retinal miR-21 levels were increased, while PPARα levels were decreased in oxygen-induced retinopathy (OIR). Knockout of miR-21 prevented PPARα down-regulation and ameliorated retinal neovascularization and inflammation in OIR retinas. In conclusion, diabetes-induced over-expression of miR-21 in the retina is responsible, at least in part, for PPARα down-regulation in DR. Targeting miR-21 may represent a novel therapeutic strategy for DR.
PURPOSE: To report 2 immunocompromised patients with sino-orbital necrotizing pseudomonas infections and review the literature. METHODS: This is a noncomparative, retrospective case series, and review. The clinical data of 2 patients with histopathologic and microbiologic diagnoses of pseudomonas sinus infections causing orbital cellulitis were obtained from medical records. A retrospective literature review was performed on all reported cases of periorbital pseudomonas infections. RESULTS: One patient with acquired immune deficiency syndrome was noted to have orbital cellulitis with clear visualization of eschar in the middle turbinate on nasal endoscopy. A second patient also had orbital cellulitis with ophthalmoplegia and presence of eschar in the sinus. Both patients had some degree of erosion through the lamina papyracea found on orbital imaging and both had intact vision without optic neuropathy. Pseudomonas infection was confirmed in both cases with permanent histopathology and cultures from conservative sinus debridement. CONCLUSIONS: Pseudomonas sino-orbital infections must be considered in the differential diagnosis in cases of eschar and orbital wall erosion especially when vision is preserved in immunocompromised individuals. This finding obviates the need for radical debridement including orbital exenteration, which can be indicated in cases of invasive fungal disease.
UNLABELLED: We present a case of corneal perforation secondary to an intrastromal astigmatic keratotomy performed with an optical coherence tomography-guided femtosecond laser. The keratotomy was concomitant with cataract surgery and resulted in a flat anterior chamber prior to the start of lens extraction. Interrupted nylon sutures were placed to seal the keratotomy prior to phacoemulsification. Escape of cavitation bubbles into the anterior chamber or the liquid interface can alert the surgeon to the possibility of unintended perforation of the endothelium or the epithelium, respectively. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned.
Mucormycosis is a rare often fatal opportunistic fungal infection. It is typically described in patients with diabetes in ketoacidotic status and is rare in renal transplant recipients. Calciphylaxis is a rare and highly morbid disease of vascular calcification affecting patients with end-stage renal disease (ESRD). The first case of a renal transplant recipient who was inflicted with both rhinoorbitocerebral mucormycosis and calciphylaxis is reported. A 45-year-old man presented with 2-day history of left upper blepharoptosis, periorbital pain, left-sided headache, binocular diplopia, and left V2 numbness. He had undergone renal transplant for ESRD 7 months earlier with resultant immunosuppressive therapy. MRI and nasal biopsy confirmed rhinoorbitocerebral mucormycosis. Immunosuppressive therapy was stopped and antifungal therapy begun. He had orbital exenteration for progressive rhinoorbitocerebral mucormycosis. Two months later, the patient reported new-onset intermittent bitemporal headache and bilateral swollen, tender temporal arteries. Temporal artery biopsy revealed features consistent with calciphylaxis. Clinical presentation, treatment course, and follow up are discussed.
PURPOSE: To describe the clinical course of uveitis-associated inflammatory papillitis and evaluate the utility and reproducibility of optic nerve spectral domain optical coherence tomography (SD-OCT). METHODS: Data on 22 eyes of 14 patients with uveitis-related papillitis and optic nerve imaging were reviewed. SD-OCT measure reproducibility was determined and parameters were compared in active vs. inactive uveitis. RESULTS: Papillitis resolution lagged behind uveitis resolution in three patients. For SD-OCT measures, the intraclass correlation coefficients were 99.1-100% and 86.9-100% for intraobserver and interobserver reproducibility, respectively. All SD-OCT optic nerve measures except inferior and nasal peripapillary retinal thicknesses were significantly higher in active vs. inactive uveitis after correction for multiple hypotheses testing. Mean optic nerve central thickness decreased from 545.1 to 362.9 µm (p = 0.01). CONCLUSIONS: Resolution of inflammatory papillitis can lag behind resolution of uveitis. SD-OCT assessment of papillitis is reproducible and correlates with presence vs. resolution of uveitis.
PURPOSE: To study the clinical features of endogenous endophthalmitis (EE) in sample patient populations from the USA and South Korea over an 8-year period. METHODS: We reviewed data from 128 eyes of 60 American and 48 Korean patients diagnosed with EE and compared their clinical characteristics. RESULTS: Fungemia and liver abscess were the most common extraocular infection sources among American (26.7%) and Korean patients (33.3%), respectively. Klebsiella pneumoniae and Candida species were the most common pathogens of EE in the Korean and the American patients, respectively. Endophthalmitis caused by fungi had a better visual prognosis than that caused by bacteria (p = 0.001). Vitrectomy was beneficial for eyes with EE due to virulent bacteria presenting with worse than counting finger vision. CONCLUSIONS: The predisposing conditions and responsible organisms for EE vary in different regions of the world. The visual prognosis was strongly influenced by the underlying pathogen.
PURPOSE: To evaluate the effect of camera flash position on the measurement of photographic margin reflex distances (MRD). METHODS: Subjects without any ophthalmic disease were prospectively enrolled after institutional review board approval. Clinical measurements of MRD1 and interpalpebral fissure were obtained. Photographs were then taken with a digital single lens reflex with built-in pop-up flash (dSLR-pop), a dSLR with lens-mounted ring flash (dSLR-ring), a point-and-shoot camera, and a smartphone, each in 4 positions: with the camera upright, rotated 90°, 180°, and 270°. The images were analyzed using ImageJ software to measure MRD1, interpalpebral fissure, horizontal white-to-white, and distance from nasal limbus to the corneal light reflex. RESULTS: Thirty-two eyes of 16 subjects were included (ages 27-65). When using the dSLR-ring, point-and-shoot, and smartphone, the difference between clinical and photographic MRD1 did not reach statistical significance. There was, however, a statistically significant difference in the upright position with dSLR-pop (mean difference 0.703 mm, σ = 0.984 mm, p = 0.0008). For dSLR-pop, photographic MRD1 in upright versus inverted position differed significantly (mean difference -0.562 mm, σ =0.348 mm, p < 0.0001). Photographic MRD1 between dSLR-pop and dSLR-ring showed significant difference in upright position (mean difference -0.572 mm, σ = 0.701 mm, p = 0.0002). There were no statistically significant differences between clinical and photographic interpalpebral fissure, and among white-to-white and nasal limbus to light reflex measurements in any position in all 4 cameras. CONCLUSIONS: When using photographs for measurement of MRD1, cameras with a near-coaxial light source and aperture have values that are most similar to clinical measurements.