Zaina Al-Mohtaseb

Protein Interactome Reveals Converging Molecular Pathways Among Autism Disorders

We developed an autism protein interaction network that provides a framework for studying autism pathogenesis and reveals shared molecular pathways among distinct autism spectrum disorders. Building Connections in Autism Autism is a collection of neurodevelopmental disorders characterized by impaired social skills, delayed language development, and repetitive behaviors. In classic (idiopathic) autism, these three characteristics predominate, whereas in syndromic autism disorders, these characteristics are part of a much larger set of symptoms. Clearly, common molecular pathways should underlie these similar disorders but trying to identify these pathways has proved difficult. Genetic studies have implicated genes mutated in syndromic autism disorders such as fragile X syndrome, Angelman syndrome, and Rett syndrome. Meanwhile, recent genome-wide association studies have pinpointed a large number of susceptibility loci that may contribute to autism spectrum disorders. Now, Zoghbi and her team turn their attention from genes associated with autism to the proteins they encode. These authors have compiled a network of protein-protein interactions based on autism-associated genes with the aim of finding common molecular pathways that underpin both classic and syndromic autism. The authors divided autism-associated genes into three groups and then used a yeast two-hybrid screen of a human complementary DNA library to obtain interacting partners for the products of 26 autism-associated genes. They then built a protein-protein interaction network and from it pulled out very highly connected proteins such as those known to be mutated in fragile X syndrome. Their network showed that two proteins, SHANK3 and PSD95, located in the postsynaptic region of neurons and known to be associated with classic autism interact with each other and share nine common protein binding partners. SHANK3 also interacts with the TSC1 protein mutated in a form of syndromic autism called tuberous sclerosis complex, and these two proteins share 21 binding partners. SHANK3 and TSC1 also associate with two other postsynaptic proteins, ACTN1 and HOMER3. With their protein interaction network as a guide, the authors then performed microarray-based comparative genome hybridization for genes encoding 627 proteins in the network using DNA from 288 patients with classic autism. They discovered four new gene mutations including a mutation in the FLNA gene encoding a protein that turns out to bind to SHANK3. This new protein-protein interaction network provides a starting point for elucidating the common molecular pathways that may underlie both classic and syndromic autism. It also provides a framework on which to build a much bigger autism interactome that could be used to develop drugs with potential for treating several different forms of autism. To uncover shared pathogenic mechanisms among the highly heterogeneous autism spectrum disorders (ASDs), we developed a protein interaction network that identified hundreds of new interactions among proteins encoded by ASD-associated genes. We discovered unexpectedly high connectivity between SHANK and TSC1, previously implicated in syndromic autism, suggesting that common molecular pathways underlie autistic phenotypes in distinct syndromes. ASD patients were more likely to harbor copy number variations that encompass network genes than were control subjects. We also identified, in patients with idiopathic ASD, three de novo lesions (deletions in 16q23.3 and 15q22 and one duplication in Xq28) that involve three network genes (NECAB2, PKM2, and FLNA). The protein interaction network thus provides a framework for identifying causes of idiopathic autism and for understanding molecular pathways that underpin both syndromic and idiopathic ASDs.

Accuracy of toric intraocular lens axis alignment using a 3-dimensional computer-guided visualization system

Purpose To evaluate the accuracy of toric intraocular lens (IOL) alignment in femtosecond laser–assisted cataract surgery using the Truevision 3‐dimensional (3‐D) computer‐guided visualization system compared with a manual marking method. Setting Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA. Design Retrospective comparative case series. Methods Preoperatively, all patients had corneal topography measurements with a color light‐emitting diode topographer. The 3‐D system used the anterior keratometry values to create an optimized plan for the toric IOL alignment. Intrastromal marks were created by the femtosecond laser at the intended toric meridian, guided by manual ink marks placed at the 3 o’clock and 9 o’clock limbus with the patient sitting upright. Intraoperatively, the 3‐D system was used to align the IOL and measure the angular position of the femtosecond marks relative to the IOL meridian. Three weeks postoperatively, the manifest refraction, corrected distance visual acuity, and toric IOL alignment were recorded. Results The mean 3‐D imaging error was −0.58 degrees ± 3.90 (SD) (range −9 to 5 degrees), and the mean manual ink error was −0.27 ± 3.65 degrees (range −8 to 5 degrees); neither was statistically significantly different from zero (P = .28 and P = .76, respectively). The mean absolute errors were 2.96 ± 2.54 degrees and 2.88 ± 2.18 degrees, respectively. Conclusion The 3‐D computer‐guided system and manual marking combined with femtosecond laser marks were similar in accuracy for toric alignment. Financial Disclosures Dr. Wang received research support from Ziemer USA, Inc. Dr. Weikert is a consultant to Ziemer USA, Inc. Dr. Koch is a consultant to Alcon Laboratories, Inc., and Abbott Medical Optics, Inc., and received research support from Ziemer USA, Inc., i‐Optics Corp, and Truevision Systems. None of the other authors has a financial or proprietary interest in any material or method mentioned.

Repeatability and comparability of corneal power and corneal astigmatism obtained from a point-source color light-emitting diode topographer, a Placido-based corneal topographer, and a low-coherence reflectometer.

Purpose To assess the repeatability and agreement of corneal power and astigmatism obtained from the Cassini point‐source color light–emitting diode (LED) topographer, Humphrey Atlas 9000 Placido–based corneal topographer, and Lenstar LS‐900 low‐coherence reflectometer in normal eyes. Setting Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA. Design Evaluation of diagnostic test or technology. Methods Consecutively enrolled patients with normal corneas were enrolled. Three sets of measurements were obtained using the color‐LED topographer, the Placido topographer, and the reflectometer. Vector analysis was used in the astigmatism analysis. The repeatability was evaluated using the within‐subject standard deviation, coefficient of variation (CoV), and intraclass correlation coefficient (ICC). Agreement was verified using Bland‐Altman plots. The paired Student t test was used to assess statistical significance. Results Thirty‐two eyes (32 patients) were evaluated. All devices provided highly repeatable corneal power and astigmatism measurements (ICC > 0.9) except for the Placido topographer with regard to J45 (ICC = 0.721). The color‐LED topographer and the reflectometer obtained similar mean values of corneal power, astigmatism magnitude, J0, and J45 (P > .05), which was also true when comparing the color‐LED topographer and the Placido topographer, except for the mean corneal power (P = .0007). The Bland‐Altman plots showed a wide data spread for all analyzed variables. Conclusions The color‐LED topographer provided highly repeatable corneal power and astigmatism measurements. Even though it obtained values similar to those of the reflectometer and the Placido topographer, the wide data spread discourages their interchangeable use to assess corneal power and astigmatism. Financial Disclosure Drs. Wang, Koch, and Weikert are consultants to Ziemer USA, Inc. Dr. Koch is a consultant to Abbott Medical Optics, Inc., Alcon Surgical, Inc., and i‐Optics, Corp. Drs. Ventura and Al‐Mohtaseb have no financial or proprietary interest in any material or method mentioned.

Evolving risk factors and antibiotic sensitivity patterns for microbial keratitis at a large county hospital

Purpose: To identify the risk factors, causative organisms, antimicrobial susceptibility and outcomes of microbial keratitis in a large county hospital in Houston, Texas. Design: Case series. Methods Setting: A large county hospital in Houston, Texas. Study Population: Patients with known diagnosis of microbial keratitis from January 2011 to May 2015. Observation Procedure: Retrospective chart review. Main Outcomes: Epidemiology, risk factors, outcomes and antibiotic susceptibility of microbial keratitis. Results The most commonly identified risk factors were contact lens use (34.4%), ocular trauma (26.3%), diabetes mellitus (16.7%), ocular surgery (13.5%), ocular surface diseases (11.5%), previous keratitis (10.4%), glaucoma (6.3%), cocaine use (5.2%) and HIV-positive status (4.2%). Eyes with positive cultures (61.5%) were associated with worse visual outcomes (p=0.019) and a higher number of follow-up visits (p=0.007) than eyes with negative cultures (38.5%). Corneal perforation was the most common complication (11.5%). Gram-negative organisms (21.9%) were all susceptible to ceftazidime, tobramycin and fluoroquinolones. Gram-positive organisms (33.3%) had worse outcomes than Gram-negative organisms (21.9%) and exhibited a wide spectrum of antibiotic resistance, but all were susceptible to vancomycin. Twenty-seven per cent of the coagulase-negative Staphylococci were resistant to fluoroquinolones. Conclusion This study identified a recent shift in risk factors and antibiotic resistance patterns in microbial keratitis at a County Hospital in Houston, Texas. In our patient population, fluoroquinolone monotherapy is not recommended for severe corneal ulcers. On the basis of these results, vancomycin and tobramycin should be used for empirical therapy until microbial identity and sensitivity results are available.

Anterior capsulotomy outcomes: A comparison between two femtosecond laser cataract surgery platforms

PURPOSE To compare capsulotomy outcomes between two femtosecond laser platforms for cataract surgery. METHODS This retrospective case series included 205 eyes of 162 consecutive patients (75 male and 87 female) aged 68.32 ± 10.27 years (range: 38 to 92 years) who underwent femtosecond laser-assisted cataract surgery (FLACS) using either the LenSx (Alcon Laboratories, Inc., Fort Worth, TX) or the Catalys (Abbott Medical Optics, Abbott Park, IL) laser platform. Intraoperative assessment of the capsulotomy was performed and graded as one of the following four types: complete treatment pattern (type 1), microadhesions (type 2), incomplete treatment pattern (type 3), and complete pattern but not continuous (type 4). RESULTS Ninety-seven eyes underwent FLACS using the LenSx platform and 108 eyes using the Catalys platform. Ninety-four capsulotomies in the LenSx group were graded as type 1 (96.91%), and three were graded as type 2 (3.09%); all capsulotomies in the Catalys group were graded as type 1 (100%). There was no statistically significant difference between the LenSx and Catalys groups (P > .05). No intraoperative complications (specifically, no posterior capsular extension or vitreous loss) were noticed in any of the eyes included in the study. CONCLUSIONS The LenSx and Catalys laser platforms demonstrate similar capsulotomy outcomes. The microadhesions that were demonstrated in three cases in the LenSx group did not lead to intraoperative or postoperative complications.

Congenital optic disc anomalies.

A congenital optic disc anomaly may be an isolated ocular abnormality or occur as part of a systemic disorder. Congenital optic disc anomalies may also occur with other disorders of central nervous system development. Initially the embryonic optic vesicle develops. Then, an invagination of the anterior wall of the vesicle forms the optic cup and the embryonic fissure. The fissure, which is located inferiorly and ventrally, provides an opening through the optic stalk for the retinal nerve fibers to pass from the ganglion cell layer of the retina to the brain. The optic nerve develops from the embryonic optic stalk. The optic stalk is the communication between the cavity of the optic vesicle and the ventricle of the diencephalon in early development. At 6-weeks gestation, the first nerve fibers form from the retinal ganglion cells. These course through the optic stalk to the brain. Nerve parenchyma slowly replaces the lumen of the optic stalk. Myelination occurs in the opposite direction, beginning centrally in the brain and progressing toward the eye then terminating at the lamina cribrosa. Fusion of the embryonic fissure leads to the closure of the cleft and the formation of an intact globe.

LASER demarcation photocoagulation for rhegmatogenous retinal detachments

PurposeTo evaluate demarcation laser photocoagulation (DLP) for macula-sparing rhegmatogenous retinal detachments (RRD) with and without symptoms of posterior vitreous separation or progressive visual field defect.MethodsRetrospective, interventional, single surgeon case series of consecutive patients with RRD treated with demarcation laser photocoagulation between March 1999 and February 2008 at an academic center. The null hypothesis was that there exists no difference in the rate of progression for retinal detachment irrespective of the presence (‘symptomatic’) or absence (‘asymptomatic’) of symptoms of posterior vitreous separation or visual field defect at presentation.ResultsA total of 27 eyes of 26 patients were included in the study. In all, 22 of the 27 eyes (81.4%) did not require additional treatment and remained attached during mean follow-up of 38.4 months. None of the 14 asymptomatic patients required surgery (0%) whereas 5 out of the 13 patients (38.5%) who were symptomatic at presentation required further intervention (p=0.016): one patient required additional laser only and four patients required scleral buckling or vitrectomy. Pre- and post- DLP logMAR visual acuity was 0.15 and 0.14, respectively.ConclusionDemarcation laser photocoagulation is an effective alternative to scleral buckling or vitrectomy for treating asymptomatic RRDs. It has a high failure rate among eyes with symptomatic RRD.

Lens Placement in the Absence of Capsular Support: Scleral-fixated Versus Iris-fixated IOL Versus ACIOL.

Cataract surgery is one of the most commonly performed surgical procedures in the United States, and the prevalence of cataracts is projected to further increase to 30 million by 2020. Ideally, the cataract is extracted and an intraocular lens (IOL) is implanted in the native capsular bag or ciliary sulcus in a single procedure. However, the absence of adequate capsular support necessitates alternative surgical approaches, which include scleral-fixation, iris-fixation, or placement in the anterior chamber angle. Although each method offers unique advantages and disadvantages regarding surgical complexity, operative duration, and complications, there is still no clear consensus on the optimal approach. Early closed-loop anterior chamber intraocular lenses (ACIOLs) were initially reported to have good short-term results, but were later found to be associated with several complications, including cystoid macular edema (CME), glaucoma, uveitis, hyphema, irreversible endothelial cell loss, and corneal decompensation. However, new and improved open-loop ACIOL designs have eliminated the vast majority of these complications. As an alternative, scleral and iris fixation methods were also developed. In 1976, uveal fixation sutures were first used to stabilize posterior chamber intraocular lenses (PCIOLs). In 1983, transsulcus suture fixation of a PCIOL to the sclera was first reported. Other techniques such as sutureless scleral fixation and iris claw IOLs soon followed.

Comparison of corneal endothelial cell loss between two femtosecond laser platforms and standard phacoemulsification

PURPOSE To analyze and compare the changes in endothelial cell density (ECD) and cumulative dissipated energy (CDE) in patients having cataract surgery with two different femtosecond laser platforms and standard phacoemulsification. METHODS This prospective non-randomized comparative study included patients scheduled to undergo cataract extraction using femtosecond laser-assisted cataract surgery (FLACS) (60 eyes) or standard phacoemulsification (60 eyes) between September 2013 and March 2016. The main outcome measures were CDE and percentage of endothelial cell loss. Comparative analysis of CDE and percentage of endothelial cell loss between the two phacoemulsification platforms with respect to conventional and FLACS techniques was performed. RESULTS The CDE and the 1-month mean percentage of endothelial cell loss was 6.11 ± 3.52 and 9.06% ± 8.77% in the standard phacoemulsification group and 4.65 ± 3.61 and 6.00% ± 8.02% in the FLACS group, respectively (P = .039). In the subgroup analysis based on cataract grading, the CDE was significantly less in the FLACS group compared to the standard phacoemulsification group in both the early and advanced cataract group (P = .002). The percent decrease in endothelial cell loss was statistically lower in the FLACS group when compared to the standard phacoemulsification group in the advanced cataract subgroup (P = .02). CONCLUSIONS FLACS pretreatment resulted in a decrease in CDE and less endothelial cell loss when compared to standard phacoemulsification. The decrease in endothelial cell loss was more prominent in the denser cataract group; thus, FLACS may be most beneficial in those cases. There was no significant difference in results between the two laser platforms. [J Refract Surg. 2017;33(10):708-712.].

Nocardia asteroides Keratitis Resistant to Amikacin.

Purpose: To describe 2 cases of Nocardia keratitis resistant to topical compounded amikacin therapy. Methods: A 24-year-old woman presented with a corneal infiltrate. Cultures were taken, and topical moxifloxacin was administered. Corneal biopsy was performed when clinical status deteriorated, which confirmed infection with Nocardia. The patient was administered topical compounded amikacin. When clinical status further deteriorated, she was switched to compounded trimethoprim–sulfamethoxazole, which resulted in rapid resolution. Separately, a 22-year-old woman presented with contact lens–related keratitis that grew Nocardia asteroides. Corneal cultures and drug sensitivity testing revealed a strain of N. asteroides resistant to amikacin and imipenem, but sensitive to tobramycin. After a protracted clinical course, the keratitis ultimately responded to topical tobramycin leaving the patient with a pericentral corneal scar. Conclusions: Nocardia keratitis is an atypical infection for which standard management algorithms exist. However, atypical cases require that these patients be followed closely for the response to therapy.