Search

Tsontcho Ianchulev,1,&ast; Robert N Weinreb,2,&ast; Ernesto A Calvo,3,&ast; James Lewis,4,&ast; Gautam Kamthan,1,&ast; Arsham Sheybani,5,&ast; Douglas J Rhee,6,&ast; Iqbal K Ahmed7,&ast; 1Department of Ophthalmology, New York Eye and Ear of Mount Sinai, New York, NY, USA; 2Shiley Eye Institute, University of California San Diego, La Jolla, CA, USA; 3Clínica de Ojos Orillac-Calvo, Panama City, Panama; 4Cataract Philadelphia, Elkins Park, PA, USA; 5Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA; 6Department of Ophthalmology & Visual Sciences, University Hospitals, Case Western Reserve University, Cleveland, OH, USA; 7John Moran Eye Center, University of Utah, Salt Lake City, UT, USA&ast;These authors contributed equally to this workCorrespondence: Tsontcho Ianchulev, Ophthalmology, New York Eye and Ear of Mount Sinai, New York, NY, USA, Email tianchul@yahoo.comBackground: To evaluate the one-year safety and effectiveness of bio-interventional cyclodialysis and scleral reinforcement in open-angle glaucoma (OAG) patients undergoing cataract surgery.Methods: An ab-interno approach was used to create a sectoral cyclodialysis in OAG patients who were prospectively followed in a consecutive case series. Subsequent visco-cycloplasty with scleral reinforcement using homologous minimally modified allograft scaffold was completed to maintain patency of the cyclodialysis reservoir and increase uveoscleral outflow. Outcomes were mean medicated IOP and mean number of IOP-lowering medications. Safety outcomes were adverse events (AEs) and best-corrected visual acuity (BCVA) changes.Results: Successful cyclodialysis and allograft bio-scaffold reinforcement was achieved in 117 eyes. There was minimal intraoperatie bleeding and few post-operative adverse events. At baseline, mean BCVA was 0.48 (95% CI: 0.42‒0.54; 20/40 Snellen) and mean ± SD medicated IOP was 20.2 ± 6.0 mmHg on 1.4 ± 1.3 IOP-lowering medications. At 12 months, there was a 27.1% reduction from baseline mean medicated IOP. In eyes with medicated baseline IOP > 21 mmHg (n = 45), there was a 39.7% paired IOP reduction at 12 months with a concurrent reduction in the mean number of IOP lowering medications to 0.8 ± 0.9 which were statistically significant (p < 0.01). For all eyes, 81.9% achieved a medicated IOP ≤ 18 mmHg with no increase in medications at 12 months. To achieve target IOP control, secondary glaucoma surgery was performed in 3.2% of the cases.Conclusion: IOP lowering through uveoscleral outflow enhancement can be achieved by means of a bio-interventional cyclodialysis procedure with allograft scleral reinforcement.Keywords: glaucoma, open-angle, intraocular pressure, cataract, allografts

Ticiana De Francesco,1,2 Tsontcho Ianchulev,3 Douglas J Rhee,4 Ronald C Gentile,3,5 Louis R Pasquale,3 Iqbal Ike K Ahmed1,6,7 1John A. Moran Eye Center, University of Utah, Salt Lake City, UT, USA; 2Clinica de Olhos De Francesco, Fortaleza, Brazil; 3Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 4Department of Ophthalmology and Visual Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA; 5NYU Long Island School of Medicine, Department of Ophthalmology, Mineola, NY, USA; 6Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada; 7Prism Eye Institute, Mississauga, CanadaCorrespondence: Ticiana De Francesco, Tel +55 85 32192425, Email ticianadefrancesco@gmail.comAbstract: To review the latest surgical advances and evolving clinical use of scleral bio-tissue for reinforcement in the eye and review the published literature on novel surgical applications of scleral allograft bio-tissue. Conventional surgical procedures for scleral reinforcement using homologous scleral allograft have been traditionally ab-externo interventions comprising of anterior or posterior reinforcement of the sclera for clinical indications such as trauma, scleromalacia, glaucoma drainage device coverage, scleral perforation, buckle repair as well as posterior reinforcement for pathologic myopia and staphyloma. There have been a few novel ab-interno uses of scleral bio-tissue for reinforcement in both retina and glaucoma. Over the last decade, there has been an increase in peer-reviewed publications on scleral reinforcement, reflecting more interest in its clinical applications. With favorable biological and biomechanical properties, scleral allograft may be an ideal substrate for an array of new applications and surgical uses.Keywords: sclera, allograft, biotissue, glaucoma

Meenakashi Gupta,1 Jae Young Heo,2 Haiyan Gong,3 Elliot Cha,3 Mark Latina,4,5 Douglas J Rhee2 1Department of Ophthalmology, New York Eye & Ear Infirmary of Mt. Sinai, New York, NY, USA; 2Department of Ophthalmology & Visual Sciences, University Hospitals, Cleveland, OH, USA; 3Department of Ophthalmology, Boston University, Boston, MA, USA; 4Department of Ophthalmology, Massachusetts Eye & Ear Infirmary, Boston, MA, USA; 5Department of Ophthalmology, Advanced Glaucoma Specialists, Reading, MA, USACorrespondence: Douglas J Rhee, Department of Ophthalmology & Visual Sciences, 10900 Euclid Ave, Lakeside, 4129, Cleveland, OH, 44105, USA, Tel +1 216-844-8590, Fax +1 216-983-0544, Email douglas.rhee@uhhospitals.orgPurpose: Selective laser trabeculoplasty is a safe and effective procedure for reducing IOP, but its mechanism of action is not fully elucidated. We evaluated the morphologic and cellular changes as well as DNA synthesis after SLT treatment of human trabecular meshwork (TM) tissue explants.Methods: Corneoscleral rim tissues that underwent SLT treatment were compared to control segments that had no laser treatment. Light microscopy (LM), transmission electron microscopy (TEM), and scanning electron microscopy (SEM) were used to assess cell morphology. The Click-iT 5-ethynyl-2’-deoxyuridine (EdU) imaging kit was used to compare DNA synthesis/cell proliferation with a confocal microscope. All tissues were assessed for vitality.Results: SLT treatment does not reveal notable cell damage in the juxtacanalicular (JCT) region, but mildly disrupts superficial trabecular beams and uveal TM, ablates TM endothelial cells from the undamaged beams as detected by both LM and TEM. This superficial destruction was not observed in some SLT treatment spots on higher magnification by SEM. SLT treatment increased mitotic activity and DNA synthesis near the lining of Schlemm’s canal after several days.Conclusion: SLT treatment disrupts endothelial cells in the corneoscleral TM and causes superficial ultrastructural changes to the uveal TM. SLT treatment also shows a trend towards dynamic time-dependent changes in (DNA synthesis) with an increase in mitotic activity at 7 days cell proliferation.Keywords: DNA synthesis, electron microscopy, selective laser trabeculoplasty, glaucoma

This paper presents elite-based simplex-GA hybrid approach combined with multipop-GA (ESGA) to determining the location, size, and number of capacitors to improve voltage profile and minimize power losses in unbalanced distribution systems. One of the main obstacles in applying GA to complex problems has been the high computational cost due to their slow convergence rate. To alleviate this difficulty, ESGA hybrid approach was developed that combines elite-based simplex-GA hybrid approach with multipop-GA. The objective function formulated consists of two terms: cost for energy losses and cost related to capacitor purchase and capacitor installation. The cost function associated with capacitor placement is considered as a step function due to banks of standard discrete capacities. Its efficiency was proved through the application in IEEE 13-bus and 34-bus test systems and was compared with several methods using GA. [ABSTRACT FROM AUTHOR]

Meenakshi Chaku,1 Peter A Netland,2 Kyoko Ishida,3 Douglas J Rhee4 1Department of Ophthalmology, Loyola University Chicago, Maywood, IL, 2Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA; 3Department of Ophthalmology, Toho University, Tokyo, Japan; 4Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH, USA Purpose: The purpose of this study was to evaluate the risk factors for tube exposure after glaucoma drainage implant surgery.Patients and methods: This was a retrospective case-controlled observational study of 64 eyes from 64 patients. Thirty-two eyes of 32 patients with tube erosion requiring surgical revision were compared with 32 matched control eyes of 32 patients. Univariate and multivariate risk factor analyses were performed.Results: Mean age was significantly younger in the tube exposure group compared with the control group (48.2±28.1 years versus 67.3±18.0 years, respectively; P=0.003). The proportion of diabetic patients (12.5%) in the tube exposure group was significantly less (P=0.041) compared with the control group (37.5%). Comparisons of the type and position of the drainage implant were not significantly different between the two groups. The average time to tube exposure was 17.2±18.0 months after implantation of the drainage device. In both univariate and multivariate analyses, younger age (P=0.005 and P=0.027) and inflammation prior to tube exposure (P≤0.001 and P=0.004) were significant risk factors. Diabetes was a significant risk factor only in the univariate analysis (P=0.027).Conclusion: Younger age and inflammation were significant risk factors for tube exposure after drainage implant surgery. Keywords: glaucoma drainage implant complications, Ahmed Glaucoma Valve, Baerveldt implant, tube erosion, pericardial patch graft

In this study, the drainage efficiency of the multi-stage intake structure, which transports flood to the underground storage, was investigated from the laboratory experiments. The multi-stage intake structure was designed based on the tangential intake and the steps on the bed were purposes to decrease the energy of approaching flow. The experimental results show that the maximum water depth was effectively decreased in the entrance of the drop shaft. The measurements results of the air core width in the drop shaft show that the flow was stably drained without the choking. Furthermore, the air core width tends to increase with the Froude number, and these results indicate that the multi-stage intake structure is applicable to convey the approaching flow with relatively high velocity.

In this study, flow and pollutant transport simulations were conducted in the tidal reach of the Han River where the horizontal recirculation zone induced by the tidal cycle causes the storage effect. The flow analysis results show that the flow direction was repeatedly changed due to the downstream water level and the horizontal recirculation zone was occurred at the point where the flow direction was changed. Thus, the pollutant cloud was advected back and forth by the periodically occurred reversal flow. The storage effects of the horizontal recirculation zone cause that the concentration-time curve shows oscillatory increasing patterns, and the retention time of pollutant cloud was also increased.

Abstract Background Pseudoexfoliation syndrome is a major risk factor for glaucoma in many populations throughout the world. Using a U.S. clinic-based case control sample with broad ethnic diversity, we show that three common SNPs in LOXL1 previously associated with pseudoexfoliation in Nordic populations are significantly associated with pseudoexfoliation syndrome and pseudoexfoliation glaucoma. Methods Three LOXL1 SNPs were genotyped in a patient sample (206 pseudoexfoliation, 331 primary open angle glaucoma, and 88 controls) from the Glaucoma Consultation Service at the Massachusetts Eye and Ear Infirmary. The SNPs were evaluation for association with pseudeoexfoliation syndrome, pseudoexfoliation glaucoma, and primary open angle glaucoma. Results The strongest association was found for the G allele of marker rs3825942 (G153D) with a frequency of 99% in pseudoexfoliation patients (with and without glaucoma) compared with 79% in controls (p = 1.6 × 10-15; OR = 20.93, 95%CI: 8.06, 54.39). The homozygous GG genotype is also associated with pseudoexfoliation when compared to controls (p = 1.2 × 10-12; OR = 23.57, 95%CI: 7.95, 69.85). None of the SNPs were significantly associated with primary open angle glaucoma. Conclusion The pseudoexfoliation syndrome is a common cause of glaucoma. These results indicate that the G153D LOXL1 variant is significantly associated with an increased risk of pseudoexfoliation and pseudoexfoliation glaucoma in an ethnically diverse patient population from the Northeastern United States. Given the high prevalence of pseudooexfoliation in this geographic region, these results also indicate that the G153D LOXL1 variant is a significant risk factor for adult-onset glaucoma in this clinic based population.

Background: Learning complex navigation routes increases hippocampal volume in humans, but it is not clear whether this growth impacts behaviors outside the learning situation or what cellular mechanisms are involved., Methods: We trained rats with pharmacogenetic suppression of adult neurogenesis and littermate controls in 3 mazes over 3 weeks and tested novelty approach behavior several days after maze exposure. We then measured hippocampus and prelimbic cortex volumes using magnetic resonance imaging and assessed neuronal and astrocyte morphology. Finally, we investigated the activation and behavioral role of the ventral CA1 (vCA1)-to-prelimbic pathway using immediate-early genes and DREADDs (designer receptors exclusively activated by designer drugs)., Results: Maze training led to volume increase of both the vCA1 region of the hippocampus and the prelimbic region of the neocortex compared with rats that followed fixed paths. Growth was also apparent in individual neurons and astrocytes in these 2 regions, and behavioral testing showed increased novelty approach in maze-trained rats in 2 different tests. Suppressing adult neurogenesis prevented the effects on structure and approach behavior after maze training without affecting maze learning itself. The vCA1 neurons projecting to the prelimbic area were more activated by novelty in maze-trained animals, and suppression of this pathway decreased approach behavior., Conclusions: Rewarded navigational learning experiences induce volumetric and morphologic growth in the vCA1 and prelimbic cortex and enhance activation of the circuit connecting these 2 regions. Both the structural and behavioral effects of maze training require ongoing adult neurogenesis, suggesting a role for new neurons in experience-driven increases in novelty exploration.

Importance: Surgery is a foundational aspect to high functioning health care systems. In the wake of the Lancet Commission on Global Surgery, previous research has focused on defining the burden of surgical conditions among a pediatric population, however these studies often fail to include forced migrant or refugees. The goal of this study was to estimate the prevalence of pediatric surgical conditions among refugees in east Africa., Methods: We used the previously validated Surgeons OverSeas Assessment of Surgical Need (SOSAS) that utilizes cross-sectional design with random cluster sampling to assess prevalence of surgical disease among participants aged 0 to 18 years in Nyarugusu refugee camp, Tanzania. We used descriptive and multivariable analyses including an average marginal effects model., Results: A total of 1,658 participants were included in the study. The mean age of our sample was 8.3 ± 5.8 years. A total of 841 participants (50.7%) were male and 817 participants (49.3%) were female. A total of 513 (n = 30.9%) reported a history or presence of a problem that may be surgical in nature, and 280 (54.6%) of them reported the problem was ongoing or untreated. Overall, 16.9% had an ongoing problem that may be amenable to surgery. We found that increasing age and recent illness were associated with having a surgical problem on both our multivariable analyses., Conclusion: To our knowledge, this is the first and largest study of prevalence of surgical conditions among refugee children in sub-Saharan Africa. We found that over 16% (one-in-six) of refugee children have a problem that may be amenable to surgery. Our results provide a benchmark upon which other studies in conflict or post-conflict zones with refugee or forced migrant populations may be compared., (© 2022. The Author(s).)

Following the significant discovery of van der Waals (vdW) layered materials with diverse electronic properties over more than a decade ago, the scalable production of high-quality vdW layered materials has become a critical goal to enable the transformation of fundamental studies into practical applications in electronics. To this end, solution-based processing has been proposed as a promising technique to yield vdW layered materials in large quantities. Moreover, the resulting dispersions are compatible with cost-effective device fabrication processes such as inkjet printing and roll-to-roll manufacturing. Despite these advantages, earlier works on solution-based processing methods (i.e., direct liquid-phase exfoliation or alkali-metal intercalation) have several challenges in achieving high-performance electronic devices, such as structural polydispersity in thickness and lateral size or undesired phase transformation. These challenges hinder the utilization of the solution-processed materials in the limited fields of electronics such as electrodes and conductors. In the meantime, the groundbreaking discovery of another solution-based approach, molecular intercalation-based electrochemical exfoliation, has shown significant potential for the use of vdW layered materials in scalable electronics owing to the nearly ideal structure of the exfoliated samples. The resulting materials are highly monodispersed, atomically thin, and reasonably large, enabling the preparation of electronically active thin-film networks via successful vdW interface formation. The formation of vdW interfaces is highly important for efficient plane-to-plane charge transport and mechanical stability under various deformations, which are essential to high-performance, flexible electronics. In this Perspective, we survey the latest developments in solution-based processing of vdW layered materials and their electronic applications while also describing the field's future outlook in the context of its current challenges., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Due to their similarities in anatomy, physiology, and pharmacology to humans, mice are a valuable model system to study the generation and mechanisms modulating conventional outflow resistance and thus intraocular pressure. In addition, mouse models are critical for understanding the complex nature of conventional outflow homeostasis and dysfunction that results in ocular hypertension. In this review, we describe a set of minimum acceptable standards for developing, characterizing, and utilizing mouse models of open-angle ocular hypertension. We expect that this set of standard practices will increase scientific rigor when using mouse models and will better enable researchers to replicate and build upon previous findings.

Two-dimensional molybdenum disulfide (MoS 2 ) nanosheets have emerged as a promising material for transparent, flexible micro-supercapacitors, but their use in electrodes is hindered by their poor electrical conductivity and cycling stability because of restacking. In this paper, we report a novel electrode architecture to exploit electrochemical activity of MoS 2 nanosheets. Electrochemically exfoliated MoS 2 dispersion was spin coated on mesh-like silver networks encapsulated with a flexible conducting film exhibiting a pseudocapacitive behavior. MoS 2 nanosheets were electrochemically active over the whole electrode surface and the conductive layer provided a pathway to transport electrons between the MoS 2 and the electrolyte. As the result, the composite electrode achieved a large areal capacitance (89.44 mF cm -2 at 6 mA cm -2 ) and high energy and power densities (12.42 µWh cm -2 and P = 6043 µW cm -2 at 6 mA cm -2 ) in a symmetric cell configuration with 3 M KOH solution while exhibiting a high optical transmittance of ~80%. Because the system was stable against mechanical bending and charge/discharge cycles, a flexible micro-supercapacitor that can power electronics at different bending states was realized., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2021 The Author(s). Published by National Institute for Materials Science in partnership with Taylor & Francis Group.)

Memories do not persist in a permanent, static state but instead must be dynamically modified in response to new information. Although new memory formation is typically studied in a laboratory setting, most real-world associations are modifications to existing memories, particularly in the aging, experienced brain. To date, the field has lacked a simple behavioral paradigm that can measure whether original and updated information is remembered in a single test session. To address this gap, we have developed a novel memory updating paradigm, called the Objects in Updated Locations (OUL) task that is capable of assessing memory updating in a non-stressful task that is appropriate for both young and old rodents. We first show that young mice successfully remember both the original memory and the updated information in OUL. Next, we demonstrate that intrahippocampal infusion of the protein synthesis inhibitor anisomycin disrupts both the updated information and the original memory at test, suggesting that memory updating in OUL engages the original memory. To verify this, we used the Arc CatFISH technique to show that the OUL update session reactivates a largely overlapping set of neurons as the original memory. Finally, using OUL, we show that memory updating is impaired in aging, 18-m.o. mice. Together, these results demonstrate that hippocampal memory updating is impaired with aging and establish that the OUL paradigm is an effective, sensitive method of assessing memory updating in rodents.

Aging is accompanied by impairments in both circadian rhythmicity and long-term memory. Although it is clear that memory performance is affected by circadian cycling, it is unknown whether age-related disruption of the circadian clock causes impaired hippocampal memory. Here, we show that the repressive histone deacetylase HDAC3 restricts long-term memory, synaptic plasticity, and experience-induced expression of the circadian gene Per1 in the aging hippocampus without affecting rhythmic circadian activity patterns. We also demonstrate that hippocampal Per1 is critical for long-term memory formation. Together, our data challenge the traditional idea that alterations in the core circadian clock drive circadian-related changes in memory formation and instead argue for a more autonomous role for circadian clock gene function in hippocampal cells to gate the likelihood of long-term memory formation.

Nanostructured surfaces with quasi-random geometries can manipulate light over broadband wavelengths and wide ranges of angles. Optimization and realization of stochastic patterns have typically relied on serial, direct-write fabrication methods combined with real-space design. However, this approach is not suitable for customizable features or scalable nanomanufacturing. Moreover, trial-and-error processing cannot guarantee fabrication feasibility because processing-structure relations are not included in conventional designs. Here, we report wrinkle lithography integrated with concurrent design to produce quasi-random nanostructures in amorphous silicon at wafer scales that achieved over 160% light absorption enhancement from 800 to 1,200 nm. The quasi-periodicity of patterns, materials filling ratio, and feature depths could be independently controlled. We statistically represented the quasi-random patterns by Fourier spectral density functions (SDFs) that could bridge the processing-structure and structure-performance relations. Iterative search of the optimal structure via the SDF representation enabled concurrent design of nanostructures and processing., Competing Interests: The authors declare no conflict of interest.

Histone acetylation is a fundamental epigenetic mechanism that is dynamically regulated during memory formation. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) compete to modulate histone acetylation, allowing for rapid changes in acetylation in response to a learning event. HDACs are known to be powerful negative regulators of memory formation, but it is not clear whether this function depends on HDAC enzymatic activity per se. Here, we tested whether the enzymatic activity of an individual Class I HDAC, HDAC3, has a role in fear memory formation in subregions of the hippocampus and amygdala. We found that fear conditioning drove expression of the immediate early genes cFos and Nr4a2 in the hippocampus, which coincided with reduced HDAC3 occupancy at these promoters. Using a dominant-negative, deacetylase-dead point mutant virus (AAV-HDAC3(Y298H)-v5), we found that selectively blocking HDAC3 deacetylase activity in either the dorsal hippocampus or basal nucleus of the amygdala enhanced context fear without affecting tone fear. Blocking HDAC3 activity in the lateral nucleus of the amygdala, on the other hand, enhanced tone, but not context fear memory. These results show for the first time that the enzymatic activity of HDAC3 functions to negatively regulate fear memory formation. Further, HDAC3 activity regulates different aspects of fear memory in the basal and lateral subregions of the amygdala. Thus, the deacetylase activity of HDAC3 is a powerful negative regulator of fear memory formation in multiple subregions of the fear circuit.

This study aims to determine the course of vision loss after Baerveldt aqueous tube shunt placement and identify risk factors associated with unexplained severe long-term vision loss, or snuff-out. We retrospectively reviewed 247 eyes of 222 patients who underwent Baerveldt implantations at one of two academic institutions. Postoperative vision loss at 6 months following surgery was categorized as mild-to-moderate versus severe and long-term versus transient. Long-term vision loss, defined as 3 or more lines of Snellen visual acuity (VA) loss compared with preoperative VA, occurred in 63 of 247 eyes (25.5%), and 39 had mild-to-moderate and 24 had severe loss. Of these 63 eyes, 18 had no identifiable cause of vision loss. On multivariate analysis, poorer Snellen VA on postoperative day 1 (POD1) was found to be a significant risk factor for long-term vision loss ( p = 0.005). In addition, the negative change in preoperative versus POD1 Snellen VA ( p = 0.021) and the presence of split fixation involving the inferonasal quadrant on preoperative Humphrey visual field ( p = 0.044) were significant risk factors for snuff-out. Transient vision loss occurred in 76 of 242 eyes (30.8%). In conclusion, vision loss is not uncommon after Baerveldt surgery, with snuff-out occurring in 2.4% of cases in this study., Competing Interests: The authors have no financial interests in the topic of this manuscript.

Hypothermia is considered a useful intervention for limiting pathophysiological changes after brain injury. Local hypothermia is a relatively safe and convenient intervention that circumvents many of the complications associated with systemic hypothermia. However, successful hypothermia treatment requires careful consideration of several factors including its practicality, feasibility, and associated risks. Here, we review the protective effects-and the cellular mechanisms that underlie them-of delayed and prolonged local hypothermia in rodent and canine brain injury models. The data show that the protective effects of therapeutic hypothermia, which mainly result from the modulation of inflammatory glial dynamics, are limited. We argue that decompressive craniectomy can be used to overcome the limitations of local brain hypothermia without causing histological abnormalities or other detrimental effects to the cooled area. Therefore, delayed and prolonged local brain hypothermia at the site of craniectomy is a promising intervention that may prove effective in the clinical setting.

α-Synuclein is implicated both in physiological functions at neuronal synaptic terminals as well as in pathological processes in the context of Parkinson's disease. However, the molecular mechanisms for these apparently diverse roles are unclear. Here we show that specific RNA transcript isoforms of α-synuclein with an extended 3' untranslated region, termed aSynL, appear selectively linked to pathological processes, relative to shorter α-synuclein transcripts. Common variants in the aSynL 3' untranslated region associated with Parkinson's disease risk promote the accumulation and translation of aSynL transcripts. The presence of intracellular dopamine can further enhance the relative abundance of aSynL transcripts through alternative polyadenylation site selection. We demonstrate that the presence of the extended aSynL transcript 3' untranslated region impacts accumulation of α-synuclein protein, which appears redirected away from synaptic terminals and towards mitochondria, reminiscent of Parkinson's disease pathology. Taken together, these findings identify a novel mechanism for aSyn regulation in the context of Parkinson's disease-associated genetic and environmental variations.

Acinetobacter baumannii is emerging as an important nosocomial pathogen worldwide. We report molecular epidemiology of 65 carbapenem-nonsusceptible A. baumannii isolates identified from hospitals in New York, Pennsylvania, Florida, Missouri, Nevada, and California between 2008 and 2009. All isolates were subjected to pulsed-field gel electrophoresis (PFGE). Select isolates then underwent multilocus sequence typing (MLST). While the PFGE patterns tended to cluster within each hospital, sequence types (STs) belonging to the clonal complex 92 (CC92) and the pan-European clonal lineage II (EUII; worldwide clonal lineage 2) were predominant in all hospitals. Of them, ST122 and ST208 were the most common and were found in four of the six hospitals. Isolates belonging to the pan-European clonal lineages I and III were identified in one hospital each. Carbapenemase-encoding genes bla(OXA-23) and/or ISAba1-bla(OXA-51-like) were present among the majority of isolates. These findings suggest that carbapenem-nonsusceptible A. baumannii isolates found in U.S. hospitals constitute part of the global epidemic driven by CC92, but have unique STs other than ST92, which may be spreading by means of patient transfer between health care facilities within the United States.

Directed conversion of mature human cells, as from fibroblasts to neurons, is of potential clinical utility for neurological disease modeling as well as cell therapeutics. Here, we describe the efficient generation of human-induced neuronal (hiN) cells from adult skin fibroblasts of unaffected individuals and Alzheimer's patients, using virally transduced transcription regulators and extrinsic support factors. hiN cells from unaffected individuals display morphological, electrophysiological, and gene expression profiles that typify glutamatergic forebrain neurons and are competent to integrate functionally into the rodent CNS. hiN cells from familial Alzheimer disease (FAD) patients with presenilin-1 or -2 mutations exhibit altered processing and localization of amyloid precursor protein (APP) and increased production of Aβ, relative to the source patient fibroblasts or hiN cells from unaffected individuals. Together, our findings demonstrate directed conversion of human fibroblasts to a neuronal phenotype and reveal cell type-selective pathology in hiN cells derived from FAD patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: LOXL1 is a major genetic risk factor for exfoliation syndrome (ES) and exfoliation glaucoma (EG). Recent evidence documenting reversal of risk alleles for the disease-associated missense variants R141L and G153D suggests that these variants are not causative and that they may be proxies for other unknown functional LOXL1 variants. The purpose of this study was to investigate the disease association of LOXL1 variants spanning the gene region, including the 5' and 3' regulatory regions, in a U.S. Caucasian case-control sample., Methods: Twenty-five LOXL1 single-nucleotide polymorphisms (SNPs), distributed throughout the gene, were genotyped in 196 Caucasian patients with ES/EG and 201 matched controls. Genotype data were analyzed for single SNP associations, SNP interactions, and haplotype associations., Results: Promoter region haplotypes that included the risk alleles for rs12914489, a SNP located in the distal promoter region and independently associated with ES, and rs16958477, a SNP previously shown to affect gene transcription, were associated with increased disease risk (P=0.0008; odds ratio [OR], 2.34; 95% confidence interval [CI], 1.42-3.85) and with protective effects (P=2.3 × 10(-6); OR, 0.38; 95% CI, 0.25-0.57). Haplotypes containing rs12914489 and rs16958477 risk and protective alleles also significantly influenced the disease risk associated with missense alleles R141L and G153D., Conclusions: LOXL1 promoter haplotypes were identified that are significantly associated with ES/EG in a U.S. Caucasian population. These results suggest that promoter region SNPs can influence LOXL1 gene expression, potentially causing a reduction of enzyme activity that may predispose to disease., (Copyright 2011 The Association for Research in Vision and Ophthalmology, Inc.)

Background: Pseudoexfoliation syndrome is a major risk factor for glaucoma in many populations throughout the world. Using a U.S. clinic-based case control sample with broad ethnic diversity, we show that three common SNPs in LOXL1 previously associated with pseudoexfoliation in Nordic populations are significantly associated with pseudoexfoliation syndrome and pseudoexfoliation glaucoma., Methods: Three LOXL1 SNPs were genotyped in a patient sample (206 pseudoexfoliation, 331 primary open angle glaucoma, and 88 controls) from the Glaucoma Consultation Service at the Massachusetts Eye and Ear Infirmary. The SNPs were evaluation for association with pseudeoexfoliation syndrome, pseudoexfoliation glaucoma, and primary open angle glaucoma., Results: The strongest association was found for the G allele of marker rs3825942 (G153D) with a frequency of 99% in pseudoexfoliation patients (with and without glaucoma) compared with 79% in controls (p = 1.6 x 10-15; OR = 20.93, 95%CI: 8.06, 54.39). The homozygous GG genotype is also associated with pseudoexfoliation when compared to controls (p = 1.2 x 10-12; OR = 23.57, 95%CI: 7.95, 69.85). None of the SNPs were significantly associated with primary open angle glaucoma., Conclusion: The pseudoexfoliation syndrome is a common cause of glaucoma. These results indicate that the G153D LOXL1 variant is significantly associated with an increased risk of pseudoexfoliation and pseudoexfoliation glaucoma in an ethnically diverse patient population from the Northeastern United States. Given the high prevalence of pseudooexfoliation in this geographic region, these results also indicate that the G153D LOXL1 variant is a significant risk factor for adult-onset glaucoma in this clinic based population.

Purpose: To evaluate genes involved in homocysteine metabolism as secondary risk factors for pseudoexfoliation syndrome (PXFS) and the associated glaucoma (PXFG)., Methods: One hundred eighty-six unrelated patients with PXFS, including 140 patients with PXFG and 127 unrelated control subjects were recruited from the Massachusetts Eye and Ear Infirmary. All the patients and controls were Caucasian of European ancestry. Seventeen tag SNPs from 5 genes (methylenetetrahydrofolate reductase [MTHFR], methionine synthase [MTR], methionine synthase reductase [MTRR], methylenetetrahydrofolate dehydrogenase [MTHFD1], and cystathionine beta-synthase [CBS]) were genotyped. Single-SNP association was analyzed using Fisher's exact test (unconditional) or logistic regression after conditioning on the effects of age and three LOXL1 SNPs (rs1048661, rs3825942, and rs2165241). Interaction analysis was performed between the homocysteine and LOXL1 SNPs using logistic regression. Haplotype analysis and the set-based test were used to test for association of individual genes. Multiple comparisons were corrected using the Bonferroni method., Results: One SNP (rs8006686) in MTHFD1 showed a nominally significant association with PXFG (p=0.015, OR=2.23). None of the seventeen SNPs tested were significantly associated with PXFS or PXFG after correcting for multiple comparisons (Bonferroni corrected p>0.25). After controlling for the effects of age and three associated LOXL1 SNPs, none of the seventeen tested SNPs were associated with PXFS (p>0.12). No significant interaction effects on PXFS were identified between the homocysteine and LOXL1 SNPs (p>0.06). Haplotype analysis and the set-based test did not find significant association of individual genes with PXFS (p>0.23 and 0.20, respectively)., Conclusions: Five genes that are critical components of the homocysteine metabolism pathway were evaluated as secondary factors for PXFS and PXFG. Our results suggest that these genes are not significant risk factors for the development of these conditions.

Purpose: Although the genetic alterations in glioblastoma have been well characterized, reports regarding their prognostic effects have been inconsistent., Experimental Design: In this series of 140 consecutive cases of glioblastoma treated at a single center, we analyzed the frequency, age dependency and prognostic effects of TP53 mutation, CDKN2A/p16 deletion, EGFR amplification, as well as loss of chromosome 1p, chromosome 10q, and chromosome 19q. The complete set of genetic alterations was available on 60 of 140 patients., Results: In this cohort of glioblastoma cases, TP53 mutation was significantly associated with patient age. The prognostic effects of TP53 mutation, EGFR amplification, CDKN2A/p16 alterations, and loss of chromosome 1p were dependent on the age of the patient., Conclusions: This is the first observation that the prognostic effects of TP53, 1p, and CDKN2A/p16 alterations are dependent on patient age. These observations concerning the interactions of age and genetic changes in glioblastoma suggest that tumorigenic pathways to glioblastoma vary with the age of the patient and that future molecular marker studies should carefully evaluate the potential age-dependent prognostic effects of these biological variables. The inconsistent or negative prognostic effects of molecular markers reported in prior studies of glioblastoma may be because different effects at different ages may have resulted in a cancellation of an overall effect in the entire cohort.

Purpose: The major objective of this study was to test the reproducibility of a new method of estimating the amount of optic disc damage in patients with glaucoma., Methods: The Disc Damage Likelihood Scale (DDLS) is based on the appearance of the neuroretinal rim of the optic disc corrected for disc diameter. The eight stages, extending from no damage to far advanced damage, are based on the width of the neuroretinal rim or the circumferential extent of absence of neuroretinal rim. Reproducibility was measured by two masked observers staging 48 optic nerve stereoscopic photographs by two different methods, the cup/disc ratio (c/d) and the DDLS. Also, reproducibility was assessed by three observers examining 34 eyes of 24 patients., Results: With regard to the photographs, the intraobserver and interobserver reproducibility was better using the DDLS than the c/d ratio (98% versus 85% for intraobserver of reproducibility, and 85% versus 74% for interobserver reproducibility). The DDLS correlated better with the Humphrey Visual Field than did any Heidelberg Retina Tomograph parameter., Conclusion: In a clinical setting, the DDLS is as reproducible as, or more reproducible than, the c/d ratio system of estimating the amount of disc damage in patients with glaucoma.

GroEL is a major target of the immune defense in infection and seems to be negatively regulated by HrcA in gram-positive organisms. However, HrcA's mechanism has not been elucidated. To elucidate the role of groEL in Streptococcus pneumoniae, the groESL operon was cloned in Escherichia coli. The promoter region of the pneumococcal groESL operon contained a sigmaA type promoter and an inverted repeat (CIRCE). A Northern blot analysis of the groESL operon demonstrated that the groESL operon is transcribed as a bicistronic mRNA, and reached maximum expression 7.5 to 10 min after heat shock. A primer extension analysis showed a potential transcription start point at 155 bp upstream of the translation start site, preceding the groES gene. The putative negative regulator of the groEL gene, hrcA, of S. pneumoniae was recovered by PCR-based chromosomal walking from grpE locus. A sequence analysis showed a sigmaA type promoter flanked by 2 CIRCE elements. His-tagged HrcA was overexpressed as a soluble form in E. coli and bound to the CIRCE regions in the promoter of both groESL and dnaK operons in vitro. Additionally, a helix-loop helix motif, a putative DNA binding domain, was found at the C-terminal of HrcA. These results will help to determine the nature of HrcA in the groESL repression.