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A role for cystatin C (CysC) in the pathogenesis of Alzheimer's disease (AD) has been suggested by the genetic linkage of a CysC gene (CST3) polymorphism with late-onset AD, the co-localization of CysC with amyloid-beta (Abeta) in AD brains, and binding of CysC to soluble Abeta in vitro and in mouse models of AD. This study investigates the binding between Abeta and CysC in the human central nervous system. While CysC binding to soluble Abeta was observed in AD patients and controls, a SDS-resistant CysC/Abeta complex was detected exclusively in brains of neuropathologically normal controls, but not in AD cases. The association of CysC with Abeta in brain from control individuals and in cerebrospinal fluid reveals an interaction of these two polypeptides in their soluble form. The association between Abeta and CysC prevented Abeta accumulation and fibrillogenesis in experimental systems, arguing that CysC plays a protective role in the pathogenesis of AD in humans and explains why decreases in CysC concentration caused by the CST3 polymorphism or by specific presenilin 2 mutations can lead to the development of the disease. Thus, enhancing CysC expression or modulating CysC binding to Abeta have important disease-modifying effects, suggesting a novel therapeutic intervention for AD. [ABSTRACT FROM AUTHOR]

Dysfunction of the endolysosomal system within neurons is a prominent feature of Alzheimer's disease (AD) pathology. Multiple AD-risk factors are known to cause hyper-activity of the early-endosome small GTPase rab5, resulting in neuronal endosomal pathway disruption. APPL1, an important rab5 effector protein, is an interface between endosomal and neuronal function through a rab5-activating interaction with the BACE1-generated C-terminal fragment (βCTF or C99) of the amyloid precursor protein (APP), a pathogenic APP fragment generated within endolysosomal compartments. To better understand the role of APPL1 in the AD endosomal phenotype, we generated a transgenic mouse model over-expressing human APPL1 within neurons (Thy1-APPL1 mice). Consistent with the important endosomal regulatory role of APPL1, Thy1-APPL1 mice have enlarged neuronal early endosomes and increased synaptic endocytosis due to increased rab5 activation. We additionally demonstrate pathological consequences of APPL1 overexpression, including functional changes in hippocampal long-term potentiation (LTP) and long-term depression (LTD), as well as degeneration of the large projection cholinergic neurons of the basal forebrain and impairment of hippocampal-dependent memory. Our findings show that increased neuronal APPL1 levels lead to a cascade of pathological effects within neurons, including early endosomal alterations, synaptic dysfunction, and neurodegeneration. Multiple risk factors and molecular regulators, including APPL1 activity, are known to contribute to the endosomal dysregulation seen in the early stages of AD, and these findings further highlight the shared pathobiology and consequences to a neuron of early endosomal pathway disruption., Significance Statement: Dysfunction in the endolysosomal system within neurons is a key feature of Alzheimer's disease (AD). Multiple AD risk factors lead to hyperactivity of the early-endosome GTPase rab5, disrupting neuronal pathways including the cholinergic circuits involved early in memory decline. APPL1, a crucial rab5 effector, connects endosomal and neuronal functions through its interaction with a specific amyloid precursor protein (APP) fragment generated within endosomes. To understand APPL1's role, a transgenic mouse model over-expressing human APPL1 in neurons (Thy1-APPL1 mice) was developed. These mice show enlarged early endosomes and increased synaptic endocytosis due to rab5 activation, resulting in impaired hippocampal long-term potentiation and depression, the degeneration of basal forebrain cholinergic neurons, and memory deficits, highlighting a pathological cascade mediated through APPL1 at the early endosome.

Objective: To assess the feasibility of using artificial intelligence (AI) to improve readability of online cataract surgery patient education materials (PEMs) in English and Spanish., Participants: Websites with information dedicated to educating patients about cataract surgery., Design: Comparative cross-sectional study., Methods: The first 50 patient-oriented websites containing PEMs related to cataract surgery were identified through online search. Website authorship was categorized as an institution, private practice, or medical organization. Websites were assessed qualitatively for information accuracy, the presence of narrative video content, and multilingual availability. Readability of PEMs was assessed using five validated reading formulas. A natural language processing platform was used to simplify PEMs in English and Spanish. Converted PEMs were reassessed for readability and accuracy., Results: A total of 32 institution, 7 private practice, and 11 medical organization sites were included. The overall average original reading grade level was 11.68 ± 1.59. After conversion, overall reading grade level improved to 7.94 ± 0.82 (p < 0.01). The first 10 results had better readability (10.40 ± 1.59) and reading ease (57.51 ± 9.24) compared to the subsequent 40 results (11.99 ± 1.43; p = 0.01; 47.64 ± 8.59; p < 0.01). Converted simplified Spanish text had an average reading ease score of 61.17 ± 5.39 (8-9th grade level). Native Spanish text reading ease improved from 57.41 ± 5.24 to 71.78 ± 5.24 (p < 0.01) following conversion (7th-grade level)., Conclusion: AI conversion can enhance the readability of online PEMs on cataract surgery, while maintaining accuracy and content integrity, thereby improving accessibility and comprehensibility for a wider audience., (Copyright © 2024 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate subjective and objective outcomes after combined implantation of an extended depth-of-focus (EDOF) intraocular lens (IOL) and a combined technology multifocal lens (CT-IOL)., Setting: 2 clinical practices (Carolina Eyecare Physicians, Center For Sight) in the United States., Design: Prospective, unmasked, multicenter, nonrandomized bilateral eye study., Methods: Patients interested in reducing their dependence on spectacles were implanted with an EDOF IOL in the dominant eye and a CT-IOL in the nondominant eye. Refractive and visual acuity (VA) data at various distances (4 m, 66 cm, 40 cm, and 33 cm) were collected 3 months postsurgery, along with the distance-corrected binocular defocus curve and responses to questionnaires related to spectacle independence, visual disturbances, and overall visual function., Results: Data from 37 participants were analyzed. The distance-corrected binocular defocus curve showed a mean VA better than 0.1 logMAR (20/25) at all vergences from +1.00 to -2.50 diopters (D). 36 participants (97%) had an uncorrected binocular VA of 0.3 logMAR or better, at all test distances. 70% of participants (26/37) reported never wearing spectacles at any distance, and 84% (31/37) were "completely" or "mostly" satisfied with their overall vision after surgery. Halos were the disturbance reported most frequently and reported as most bothersome, with difficulty driving at night the most common visual function issue. Difficulty reading was the next most reported issue. Overall eyesight was rated as "excellent" or "good" by 92% (34/37) of participants., Conclusions: This combined EDOF/CT-IOL approach was well-tolerated by participants and provided some potential benefits relative to bilateral implantation of either lens., (Copyright © 2024 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

Purpose: ChatGPT is a commonly used source of information by patients and clinicians. However, it can be prone to error and requires validation. We sought to assess the quality and accuracy of information regarding corneal transplantation and Fuchs dystrophy from 2 iterations of ChatGPT, and whether its answers improve over time., Methods: A total of 10 corneal specialists collaborated to assess responses of the algorithm to 10 commonly asked questions related to endothelial keratoplasty and Fuchs dystrophy. These questions were asked from both ChatGPT-3.5 and its newer generation, GPT-4. Assessments tested quality, safety, accuracy, and bias of information. Chi-squared, Fisher exact tests, and regression analyses were conducted., Results: We analyzed 180 valid responses. On a 1 (A+) to 5 (F) scale, the average score given by all specialists across questions was 2.5 for ChatGPT-3.5 and 1.4 for GPT-4, a significant improvement ( P < 0.0001). Most responses by both ChatGPT-3.5 (61%) and GPT-4 (89%) used correct facts, a proportion that significantly improved across iterations ( P < 0.00001). Approximately a third (35%) of responses from ChatGPT-3.5 were considered against the scientific consensus, a notable rate of error that decreased to only 5% of answers from GPT-4 ( P < 0.00001)., Conclusions: The quality of responses in ChatGPT significantly improved between versions 3.5 and 4, and the odds of providing information against the scientific consensus decreased. However, the technology is still capable of producing inaccurate statements. Corneal specialists are uniquely positioned to assist users to discern the veracity and application of such information., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The polymorphic APOE gene is the greatest genetic determinant of sporadic Alzheimer's disease risk: the APOE4 allele increases risk, while the APOE2 allele is neuroprotective compared with the risk-neutral APOE3 allele. The neuronal endosomal system is inherently vulnerable during aging, and APOE4 exacerbates this vulnerability by driving an enlargement of early endosomes and reducing exosome release in the brain of humans and mice. We hypothesized that the protective effects of APOE2 are, in part, mediated through the endosomal pathway. Messenger RNA analyses showed that APOE2 leads to an enrichment of endosomal pathways in the brain when compared with both APOE3 and APOE4. Moreover, we show age-dependent alterations in the recruitment of key endosomal regulatory proteins to vesicle compartments when comparing APOE2 to APOE3. In contrast to the early endosome enlargement previously shown in Alzheimer's disease and APOE4 models, we detected similar morphology and abundance of early endosomes and retromer-associated vesicles within cortical neurons of aged APOE2 targeted-replacement mice compared with APOE3. Additionally, we observed increased brain extracellular levels of endosome-derived exosomes in APOE2 compared with APOE3 mice during aging, consistent with enhanced endosomal cargo clearance by exosomes to the extracellular space. Our findings thus demonstrate that APOE2 enhances an endosomal clearance pathway, which has been shown to be impaired by APOE4 and which may be protective due to APOE2 expression during brain aging., (© 2024 The Authors. Traffic published by John Wiley & Sons Ltd.)

Purpose: To assess the web accessibility and readability of patient-oriented educational websites for cataract surgery., Design: Cross-sectional electronic survey., Participants: Websites with information dedicated to educating patients about cataract surgery., Methods: An incognito search for "cataract surgery" was performed using a popular search engine. The top 100 patient-oriented cataract surgery websites that came up were included and categorized as institutional, private practice, or medical organization according to authorship. Each site was assessed for readability using 4 standardized reading grade-level formulas. Accessibility was assessed through multilingual availability, accessibility menu availability, complementary educational video availability, and conformance and adherence to the Web Content Accessibility Guidelines (WCAG) 2.0. A standard t test and chi-square analysis were performed to assess the significance of differences with regard to readability and accessibility among the 3 authorship categories., Main Outcome Measures: The main outcome measures were the website's average reading grade level, number of accessibility violations, multilingual availability, accessibility menu availability, complementary educational video availability, accessibility conformance level, and violation of the perceivable, operable, understandable, and robust (POUR) principles according to the WCAG 2.0., Results: A total of 32, 55, and 13 sites were affiliated with institutions, private practice, and other medical organizations, respectively. The overall mean reading grade was 11.8 ± 1.6, with higher reading levels observed in private practice websites compared with institutions and medical organizations combined (12.1 vs. 11.4; P = 0.03). Fewer private practice websites had multiple language options compared with institutional and medical organization websites combined (5.5% vs. 20.0%; P = 0.03). More private practice websites had accessibility menus than institutions and medical organizations combined (27.3% vs. 8.9%; P = 0.038). The overall mean number of WCAG 2.0 POUR principle violations was 17.1 ± 23.1 with no significant difference among groups. Eighty-five percent of websites violated the perceivable principle., Conclusions: Available patient-oriented online information for cataract surgery may not be comprehensible to the general public. Readability and accessibility aspects should be considered when designing these resources., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To report the heterogeneity in methodology of clinical trials submitted to the US Food and Drug Administration (FDA) for approval of topical dry eye treatments., Design: Comparative analysis of clinical trials' methods., Methods: We reviewed the online, publicly available FDA database, application review files, ClinicalTrials.gov registry records, and journal articles for each FDA-approved topical dry eye treatment. For each trial, we extracted information about the study, patient demographics, treatment names and doses, sample size in each arm, and the measurement instrument in a systematic fashion., Results: Fourteen trials were included that assessed 5 topical treatments for dry eye (cyclosporine 0.05%, cyclosporine 0.09%, lifitegrast 5%, and loteprednol 0.25% eye drops and varenicline 0.03-mg nasal spray). Median treatment duration was 12 weeks (range, 2-24 weeks). In all trials, treatments, including varying concentrations of the same treatment, were compared with vehicle. Twelve trials (85.7%) evaluated a primary clinician-measured clinical sign, and 10 trials (71.4%) evaluated a primary patient-reported symptom. Corneal staining was the most frequently evaluated clinical sign primary outcome, reported in half (6 of 12) of the trials, and was graded using 4 different scoring systems. Conjunctival staining, conjunctival hyperemia, and tear production were each measured using 2 different scoring systems. Ocular discomfort, the only patient-reported symptom primary outcome, was measured using 5 different instruments., Conclusion: A variety of outcome measures were used in these clinical trials. Clinically meaningful dry eye outcome measures and standardized measurements can optimize the assessment of and comparison of therapeutic benefits., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Human apolipoprotein E (APOE) is the greatest determinant of genetic risk for memory deficits and Alzheimer's disease (AD). While APOE4 drives memory loss and high AD risk, APOE2 leads to healthy brain aging and reduced AD risk compared to the common APOE3 variant. We examined brain APOE protein levels in humanized mice homozygous for these alleles and found baseline levels to be age- and isoform-dependent: APOE2 levels were greater than APOE3, which were greater than APOE4. Despite the understanding that APOE lipoparticles do not traverse the blood-brain barrier, we show that brain APOE levels are responsive to dietary fat intake. Challenging mice for 6 months on a Western diet high in fat and cholesterol increased APOE protein levels in an allele-dependent fashion with a much greater increase within blood plasma than within the brain. In the brain, APOE2 levels responded most to the Western diet challenge, increasing by 20 % to 30 %. While increased lipoparticles are generally deleterious in the periphery, we propose that higher brain APOE2 levels may represent a readily available pool of beneficial lipid particles for neurons., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Inc.)

Purpose: To investigate health disparities in racial and ethnic minorities with dry eye., Methods: Medical records were reviewed for demographics, socioeconomic factors, treatments, and objective dry eye parameters. Race/ethnicity was self-reported as delineated by the U.S. Census. The reference group comprised of randomly selected White patients, with number equal to the largest minority group., Results: The study included 465 patients (157 Black, 157 White, 85 Asian, and 66 Hispanic). Compared to White (3.2%) patients, larger proportion of minorities used Medicaid or lacked health insurance (Black 8.3%, P = .054; Asian 10.6%, P = .019; Hispanic 18.2%, P < .001). Black and Hispanic patients had lower estimated median household income than Whites (White $98,472, Black $75,554, P < .001; Asian $105,503, P = .088; Hispanic $86,839, P = .030). Prior to presentation, fewer minority patients received prescription treatments or procedures (White 61.8%; Black 30.6%, P < .001; Asian 43.5%, P = .006; Hispanic 43.9%, P = .014). Although at baseline visit minorities had worse mean conjunctival (White, 1.7; Black 2.2, P = .136, Asian 2.4, P = .022; Hispanic 2.6, P = .005) and corneal staining scores (White, 1.6; Black 2.5, P < .001; Asian 2.3, P = .003; Hispanic 2.4, P = .001), no differences were noted at final visit., Conclusion: Minorities presented with worse objective dry eye parameters, and less prior dry eye care. Income and health care access may not fully explain the observed undertreatment at presentation. Differential management by eye care providers and patient attitudes warrant further investigation.

Background: To compare the clinical outcomes of patients undergoing sequential pars plana vitrectomy (PPV) followed by cataract extraction surgery (CE) [PPV/CE], simultaneous PPV and CE (PPV + CE), and sequential CE followed by PPV [CE/PPV]., Methods: A retrospective observational cohort study of 427 eyes of 404 patients who underwent either sequential or simultaneous PPV and CE surgery between March 2016 and May 2021. Pre-operative and post-operative assessments (up to 2 years of follow-up visits) of uncorrected visual acuity (UCVA), corrected distance visual acuity (CDVA), spherical equivalent (SEQ), and refractive prediction error (RPE) was done. Main outcome measures were both visual (UCVA, CDVA) and refractive (RPE, SEQ)., Results: There was a statistically significant difference in CDVA of the PPV/CE, PPV + CE, CE/PPV groups (logMAR 0.34 ± 0.40, 0.65 ± 0.61, and 0.55 ± 0.60, respectively) at one month postoperatively (POM1) (P < 0.001), and at the POM12 visits (logMAR 0.25 ± 0.34, 0.53 ± 0.68, and 0.44 ± 0.48; P = 0.04). In the subgroup analysis of patients with a diagnosis of either epiretinal membrane or vitreous opacities, there was no statistically significant difference in SEQ (P = 0.09) and RPE (P = 0.13) at the combined 1 month and 3 month visits., Conclusion: Simultaneous PPV and cataract surgery demonstrated similar improvements in visual acuity and refractive outcomes, as well as comparable intraoperative and postoperative complication profiles to sequential surgery., (© 2023. The Author(s).)

The 3 human apolipoprotein E (APOE) gene alleles modify an individual's risk of developing Alzheimer's disease (AD): compared to the risk-neutral APOE ε3 allele, the ε4 allele (APOE4) is strongly associated with increased AD risk while the ε2 allele is protective. Multiple mechanisms have been shown to link APOE4 expression and AD risk, including the possibility that APOE4 increases the expression of the amyloid precursor protein (APP) (Y-W.A. Huang, B. Zhou, A.M. Nabet, M. Wernig, T.C. Südhof, 2019). In this study, we investigated the impact of APOE genotype on the expression, and proteolytic processing of endogenously expressed APP in the brains of mice humanized for the 3 APOE alleles. In contrast to prior studies using neuronal cultures, we found in the brain that both App gene expression, and the levels of APP holoprotein were not affected by APOE genotype. Additionally, our analysis of APP fragments showed that APOE genotype does not impact APP processing in the brain: the levels of both α- and β-cleaved soluble APP fragments (sAPPs) were similar across genotypes, as were the levels of the membrane-associated α- and β-cleaved C-terminal fragments (CTFs) of APP. Lastly, APOE genotype did not impact the level of soluble amyloid beta (Aβ). These findings argue that the APOE-allele-dependent AD risk is independent of the brain expression and processing of APP., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Innate immunity against Mycobacterium tuberculosis is a critical early response to prevent the establishment of the infection. Despite recent advances in understanding the host-pathogen dialogue in the early stages of tuberculosis (TB), much has yet to be learnt. The nature and consequences of this dialogue ultimately determine the path of infection: namely, either early clearance of M. tuberculosis, or establishment of M. tuberculosis infection leading to active TB disease and/or latent TB infection. On the frontline in innate immunity are pattern recognition receptors (PRRs), with soluble factors (e.g. collectins and complement) and cell surface factors (e.g. Toll-like receptors and other C-type lectin receptors (Dectin 1/2, Nod-like receptors, DC-SIGN, Mincle, mannose receptor, and MCL) that play a central role in recognising M. tuberculosis and facilitating its clearance. However, in a 'double-edged sword' scenario, these factors can also be involved in enhancement of pathogenesis as well. Furthermore, innate immunity is also a critical bridge in establishing the subsequent adaptive immune response, which is also responsible for granuloma formation that cordons off M. tuberculosis infection, establishing latency and acting as a reservoir for bacterial persistence and dissemination of future disease. This chapter discusses the current understanding of pattern recognition of M. tuberculosis by innate immunity and the role this plays in the pathogenesis and protection against TB., (© 2021. Springer Nature Switzerland AG.)

Leprosy is an ancient insidious disease caused by Mycobacterium leprae, where the skin and peripheral nerves undergo chronic granulomatous infections, leading to sensory and motor impairment with characteristic deformities. Susceptibility to leprosy and its disease state are determined by the manifestation of innate immune resistance mediated by cells of monocyte lineage. Due to insufficient innate resistance, granulomatous infection is established, influencing the specific cellular immunity. The clinical presentation of leprosy ranges between two stable polar forms (tuberculoid to lepromatous) and three unstable borderline forms. The tuberculoid form involves Th1 response, characterized by a well demarcated granuloma, infiltrated by CD4 + T lymphocytes, containing epitheloid and multinucleated giant cells. In the lepromatous leprosy, there is no characteristic granuloma but only unstructured accumulation of ineffective macrophages containing engulfed pathogens. Th1 response, characterised by IFN-γ and IL-2 production, activates macrophages in order to kill intracellular pathogens. Conversely, a Th2 response, characterized by the production of IL-4, IL-5 and IL-10, helps in antibody production and consequently downregulates the cell-mediated immunity induced by the Th1 response. M. lepare has a long generation time and its inability to grow in culture under laboratory conditions makes its study challenging. The nine-banded armadillo still remains the best clinical and immunological model to study host-pathogen interaction in leprosy. In this chapter, we present cellular morphology and the genomic uniqueness of M. leprae, and how the pathogen shows tropism for Schwann cells, macrophages and dendritic cells., (© 2021. Springer Nature Switzerland AG.)

The current coronavirus pandemic, COVID-19, is the third outbreak of disease caused by the coronavirus family, after Severe Acute Respiratory Syndrome and Middle East Respiratory Syndrome. It is an acute infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This severe disease is characterised by acute respiratory distress syndrome, septic shock, metabolic acidosis, coagulation dysfunction, and multiple organ dysfunction syndromes. Currently, no drugs or vaccines exist against the disease and the only course of treatment is symptom management involving mechanical ventilation, immune suppressants, and repurposed drugs. The severe form of the disease has a relatively high mortality rate. The last six months have seen an explosion of information related to the host receptors, virus transmission, virus structure-function relationships, pathophysiology, co-morbidities, immune response, treatment and the most promising vaccines. This review takes a critically comprehensive look at various aspects of the host-pathogen interaction in COVID-19. We examine the genomic aspects of SARS-CoV-2, modulation of innate and adaptive immunity, complement-triggered microangiopathy, and host transmission modalities. We also examine its pathophysiological impact during pregnancy, in addition to emphasizing various gaps in our knowledge. The lessons learnt from various clinical trials involving repurposed drugs have been summarised. We also highlight the rationale and likely success of the most promising vaccine candidates., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Purpose: To report the significance of extraglandular ocular involvement and long-term systemic morbidity and mortality in primary Sjögren's Syndrome (SS)., Methods: This retrospective, longitudinal cohort study included consecutive patients with primary SS evaluated at a tertiary referral center. An electronic chart review was performed and all available data were extracted from clinic visits between October 1999 and March 2019. The primary outcome measures included occurrence of extraglandular ocular manifestations of SS, serological markers, prevalence of malignancy, and incidence of death., Results: One hundred and twenty-six SS patients with minimum 3 years of follow-up (median 9.6, range 3.0-15.9 years, total of 1,235 patient-years) were included. Of those, 10 patients with inflammatory keratolysis or scleritis had 2.3 times greater likelihood of death compared to the rest of the cohort (OR = 2.3, 95% confidence interval [CI] 0.5 to 4.0, p = 0.01) due to SS related complications. The lifetime prevalence of any malignancy in the entire cohort was 15.5%. The most common hematologic malignancy was non-Hodgkin's lymphoma (4.8%) and the most common solid malignancy was breast cancer (6.0%). Men SS patients were more likely to have a history of or concurrent malignancy compared to women (30.0% versus 13.7%, p = 0.16) and double the mortality (OR = 2.1, 95% CI 0.09 to 1.4, p = 0.04), independent of malignancy., Conclusions: SS patients with serious ocular manifestations, particularly men, may be at greater risk for mortality due to SS complications. The eye seems to be the barometer of systemic disease activity., Competing Interests: The authors have declared that no competing interests exist. Dr. Akpek is an unpaid member of the Sjögren’s Foundation.

Purpose: To assess the effects of sustained gazing on visual function of dry eye patients., Design: Prospective, comparative before-and-after study., Methods: A total of 176 patients with dry eye and 33 control subjects ≥50 years old were included. Dry eye symptomatology along and clinical parameters were assessed. Out-loud reading speed was measured using the International Reading Speed Test (IReST) as words per minute (wpm). Reading speed was repeated using different IReST excerpts following 30-minute silent reading., Results: At baseline, there were no differences between dry eye patients and control subjects with respect to reading speed (172 vs 180 wpm, respectively; P = 0.21) or the time to read the excerpt (33 vs 30 seconds, respectively; P = 0.17). After silent reading, the dry eye patients had decreased reading speed and increases in the length of time to read the passage compared to baseline (161 vs 172 wpm, respectively; P = 0.002; and 38 vs 33 seconds, respectively; P < 0.001). The control subjects did not show significant differences for either parameter. There were significant differences with respect to both parameters between the dry eye and control groups after sustained gazing (161 vs 188 wpm, respectively; P = 0.006; and 38 vs 31 seconds, respectively; P = 0.003). Each 1-point increase in baseline corneal staining score (0-6) led to a 5-wpm reduction in reading speed (95% confidence interval, -8 to -1; P = 0.01)., Conclusions: Sustained gazing, such as in silent reading, has a measurable negative impact on visual performance of dry eye patients. Corneal staining represents a clinical parameter relevant to visual function., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Dysfunction of the endosomal-lysosomal system is a prominent pathogenic factor in Alzheimer's disease (AD) and other neurodevelopmental and neurodegenerative disorders. We and others have extensively characterized the neuronal endosomal pathway pathology that results from either triplication of the amyloid-β precursor protein (APP) gene in Down syndrome (DS) or from expression of the apolipoprotein E ε4 allele (APOE4), the greatest genetic risk factor for late-onset AD. More recently brain exosomes, extracellular vesicles that are generated within and released from endosomal compartments, have been shown to be altered in DS and by APOE4 expression. In this review, we discuss the emerging data arguing for an interdependence between exosome production and endosomal pathway integrity in the brain. In vitro and in vivo studies indicate that altered trafficking through the endosomal pathway or compromised cargo turnover within lysosomes can affect the production, secretion, and content of exosomes. Conversely, exosome biogenesis can affect the endosomal-lysosomal system. Indeed, we propose that efficient exosome release helps to modulate flux through the neuronal endosomal pathway by decompressing potential "traffic jams." Exosome secretion may have the added benefit of unburdening the neuron's lysosomal system by delivering endosomal-lysosomal material into the extracellular space, where other cell types may contribute to the degradation of neuronal debris. Thus, maintaining robust neuronal exosome production may prevent or mitigate endosomal and lysosomal abnormalities linked to aging and neurodegenerative diseases. While the current evidence suggests that the exosomal system in the brain can be modulated both by membrane lipid composition and the expression of key proteins that contribute to the formation and secretion of exosomes, how exosomal pathway-regulatory elements sense and respond to perturbations in the endosomal pathway is not well understood. Based upon findings from the extensively studied DS and APOE4 models, we propose that enhanced neuronal exosome secretion can be a protective response, reducing pathological disruption of the endosomal-lysosomal system in disease-vulnerable neurons. Developing therapeutic approaches that help to maintain or enhance neuronal exosome biogenesis and release may be beneficial in a range of disorders of the central nervous system., (Copyright © 2019 Mathews and Levy.)

Objective: To report long-term clinical outcomes of gamma-irradiated corneal lenticules in partial and full-thickness keratoplasty., Methods and Analysis: This multicentre, retrospective case series includes 23 patients who underwent surgery at three centres (India, Guatemala, and USA) between May 2009 and March 2018. The main outcome measures were epithelialization and retention for therapeutic keratoplasty and best spectacle-corrected visual acuity (BSCVA) for optical keratoplasty., Results: Patients were categorised according to primary aetiology requiring corneal transplantation: non-inflammatory conditions, infectious keratitis and sterile keratolysis. Nine patients with non-inflammatory conditions underwent anterior lamellar keratoplasty (n=7) and Boston type 1 keratoprosthesis (n=2). All nine grafts remained intact and epithelialized during follow-up (median 24 months). In the seven patients who underwent anterior keratoplasty, the graft stayed optically clear during follow-up (median 12 months), with BSCVA between 20/20 and 20/40 in all but one patient who developed cataract. Nine patients with severe infectious keratitis had emergency patch grafting. Six of those grafts epithelialized and remained intact over a median of 30 months, providing tectonic support until optical keratoplasty with fresh tissue could be performed. Three grafts had recurrent infectious keratitis 1-3 months postoperatively, two of which underwent tectonic keratoplasty with fresh tissue which also eventually became infected during follow-up. In five additional patients with sterile keratolysis who underwent lamellar patch graft, two grafts remained intact during follow-up (median 36 months). Two patients had recurrent corneal melt within 1 month, and both had subsequent corneal surgery with fresh tissue which also failed. There were no donor-related complications., Conclusion: Gamma-irradiated sterile corneal stromal lenticules can be considered as a viable alternative to fresh tissue in various clinical settings., Competing Interests: Competing interests: PMM: WL Gore & Associates: consultant/advisor. EKA: Allergan, WL Gore & Associates: institutional grant support; CorneaGen and KeraLink: medical director; Novaliq, Clementia, Novartis Pharma AG, Shire, EpiTech, Takeda: consultant/advisor; Dompe: ad board; Sjogren's Syndrome Foundation: unpaid member of the Board of Directors; Up-To-Date: royalty., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To determine the prevalence and risk factors of exposure keratopathy (EK) across different intensive care units (ICU) at Columbia University Medical Center, including the Pediatric ICU (PICU), Medical ICU (MICU), and Neurologic ICU (NICU)., Methods: In this prospective cohort study, 65 patients were examined daily during their admission in the PICU (27 patients), MICU (15 patients), and NICU (23 patients). Data on eyelid position, conjunctival and corneal changes, Bell's and blink reflexes, medications, Glasgow Coma Scale rating, and ventilation type were collected., Results: Overall EK percentages were as follows: PICU 19%, MICU 60%, and NICU 48%. The prevalence of EK was lowest in the PICU (P = 0.013). Factors associated with EK were lagophthalmos (P < 0.001), an absent Bell's reflex (P = 0.003), an absent blink reflex (P < 0.001), conjunctival injection (P < 0.001), a low Glasgow Coma Scale score (P < 0.001), intubation (P < 0.001), surgery before examination (P < 0.001), dialysis (P = 0.002), and administration of opioid (P < 0.001), sedative (P < 0.001), and neuromuscular blocking medications (P = 0.006)., Conclusions: This is the first study to examine the rates and risk factors of EK across different ICU settings. The prevalence of EK was lowest in the PICU, which may partly be explained by the increased number of PICU patients receiving noninvasive ventilation and the absence of conjunctival chemosis.

BACE1 is a transmembrane aspartic protease that cleaves various substrates and it is required for normal brain function. BACE1 expression is high during early development, but it is reduced in adulthood. Under conditions of stress and injury, BACE1 levels are increased; however, the underlying mechanisms that drive BACE1 elevation are not well understood. One mechanism associated with brain injury is the activation of injurious p75 neurotrophin receptor (p75), which can trigger pathological signals. Here we report that within 72 h after controlled cortical impact (CCI) or laser injury, BACE1 and p75 are increased and tightly co-expressed in cortical neurons of mouse brain. Additionally, BACE1 is not up-regulated in p75 null mice in response to focal cortical injury, while p75 over-expression results in BACE1 augmentation in HEK-293 and SY5Y cell lines. A luciferase assay conducted in SY5Y cell line revealed that BACE1 expression is regulated at the transcriptional level in response to p75 transfection. Interestingly, this effect does not appear to be dependent upon p75 ligands including mature and pro-neurotrophins. In addition, BACE1 activity on amyloid precursor protein (APP) is enhanced in SY5Y-APP cells transfected with a p75 construct. Lastly, we found that the activation of c-jun n-terminal kinase (JNK) by p75 contributes to BACE1 up-regulation. This study explores how two injury-induced molecules are intimately connected and suggests a potential link between p75 signaling and the expression of BACE1 after brain injury., (Copyright © 2019. Published by Elsevier Inc.)

Background: It is now widely recognized that endogenous, picomolar concentrations of the 42 amino acid long peptide, amyloid-β (Aβ 42 ) is secreted under normal physiological conditions and exerts important functional activity throughout neuronal intracellular compartments. Transgenic animal models that overexpress Aβ 42 and its precursor, amyloid precursor protein (APP), have not provided predictive value in testing new treatments for Alzheimer's disease (AD), resulting in failed clinical trials. While these results are discouraging, they underscore the need to understand the physiological roles of Aβ 42 and APP under normal conditions as well as at early pre- symptomatic stages of AD. New method: We describe the use of acrolein-perfusion in immunoelectron microscopy in combination with novel antibodies directed against endogenous murine Aβ 42 and APP fragments to study abnormalities in the endolysosomal system at early stages of disease. The specific requirements, limitations and advantages of novel antibodies directed against human and murine Aβ 42 , APP and APP fragments are discussed as well as parameters for ultrastructural analysis of endolysosomal compartments., Results: Novel antibodies and a detailed protocol for immunoelectron microscopy using acrolein as a fixative are described. Acrolein is shown to preserve intraneuronal Aβ 42 species, as opposed to paraformaldehyde fixed tissue, which primarily preserves membrane bound species. Comparison with existing method(s): Technology sensitive enough to detect endogenous Aβ 42 under physiological conditions has not been widely available. We describe a number of novel and highly sensitive antibodies have recently been developed that may facilitate the analysis of endogenous Aβ 42 ., Conclusions: Using novel and highly specific antibodies in combination with electron microscopy may reveal important information about the timing of aberrant protein accumulation, as well as the progression of abnormalities in the endolysosomal systems that sort and clear these peptides., (Copyright © 2018. Published by Elsevier B.V.)

In addition to being the greatest genetic risk factor for Alzheimer's disease, expression of the ɛ4 allele of apolipoprotein E can lead to cognitive decline during ageing that is independent of Alzheimer's amyloid-β and tau pathology. In human post-mortem tissue and mouse models humanized for apolipoprotein E, we examined the impact of apolipoprotein E4 expression on brain exosomes, vesicles that are produced within and secreted from late-endocytic multivesicular bodies. Compared to humans or mice homozygous for the risk-neutral ɛ3 allele we show that the ɛ4 allele, whether homozygous or heterozygous with an ɛ3 allele, drives lower exosome levels in the brain extracellular space. In mice, we show that the apolipoprotein E4-driven change in brain exosome levels is age-dependent: while not present at age 6 months, it is detectable at 12 months of age. Expression levels of the exosome pathway regulators tumor susceptibility gene 101 (TSG101) and Ras-related protein Rab35 (RAB35) were found to be reduced in the brain at the protein and mRNA levels, arguing that apolipoprotein E4 genotype leads to a downregulation of exosome biosynthesis and release. Compromised exosome production is likely to have adverse effects, including diminishing a cell's ability to eliminate materials from the endosomal-lysosomal system. This reduction in brain exosome levels in 12-month-old apolipoprotein E4 mice occurs earlier than our previously reported brain endosomal pathway changes, arguing that an apolipoprotein E4-driven failure in exosome production plays a primary role in endosomal and lysosomal deficits that occur in apolipoprotein E4 mouse and human brains. Disruption of these interdependent endosomal-exosomal-lysosomal systems in apolipoprotein E4-expressing individuals may contribute to amyloidogenic amyloid-β precursor protein processing, compromise trophic signalling and synaptic function, and interfere with a neuron's ability to degrade material, all of which are events that lead to neuronal vulnerability and higher risk of Alzheimer's disease development. Together, these data suggest that exosome pathway dysfunction is a previously unappreciated component of the brain pathologies that occur as a result of apolipoprotein E4 expression.

Significance: Patients with dry eye frequently report difficulty with reading. However, the impact of dry eye on reading has not been studied in detail. This study shows the unfavorable effect of dry eye on reading speed and offers mechanisms that may be responsible., Purpose: The purpose of this study was to evaluate the impact of dry eye signs as well as symptoms on both short-duration out-loud and prolonged silent reading., Methods: This study included 116 patients with clinically significant dry eye, 39 patients with dry eye symptoms only, and 31 controls, 50 years or older. After the Ocular Surface Disease Index (OSDI) questionnaire, objective testing of dry eye (tear film stability studies, Schirmer's test, and ocular surface staining) was performed. Total OSDI score and two subscores (vision related and discomfort related) were calculated. A short-duration out-loud reading test and a 30-minute sustained silent reading test were performed. Reading speed for each test was calculated as words per minute (wpm) and compared across the three groups., Results: Patients with clinically significant dry eye read slower than controls measured with sustained silent reading test (240 vs. 272 wpm, P = .04), but not with short-duration out-loud reading test (146 vs. 153 wpm, P = .47). Patients with dry eye symptoms only did not have slower reading speed measured using either reading test as compared with controls. However, vision-related OSDI subscore independently was associated with slower reading speed (P = .02). Multivariable regression models demonstrated that each 1-point (between 0 and 6) increase in corneal staining score led to a 10-wpm decrease in sustained silent reading speed (P = .01)., Conclusions: This study demonstrates a significant negative impact of dry eye (particularly presence of corneal staining) on prolonged reading. Prolonged reading task may serve as an objective clinically relevant test to measure the impact of dry eye on vision-related quality of life.

Background: Corneal collagen crosslinking (CXL) is a widely used treatment for halting the progression of keratoconus. Although initial studies of CXL were performed with a riboflavin solution containing dextran, recent protocols for CXL have indicated the use of a riboflavin solution containing isotonic hydroxypropyl methylcellulose (HPMC). This study was performed to investigate differences in visual outcomes and Scheimpflug (Pentacam) analysis in patients who have undergone epithelium-off CXL with riboflavin solution containing either 20% dextran versus 1.1% HPMC., Methods: All patients in this non-randomized, non-masked, retrospective cohort analysis were treated at Edward S. Harkness Eye Institute, Columbia University Medical Center, New York, NY, USA. Thirty-seven eyes of 33 patients were crosslinked with a dextran solution and 19 eyes of 19 patients crosslinked with an isotonic HPMC solution, both using an epithelium-off 30-min, 3 mW/cm 2 protocol. All patients had a diagnosis of keratoconus or post-refractive surgery ectasia. Best spectacle corrected visual acuity (BSCVA) and Pentacam parameters were compared at all follow up visits (1, 6, 12, and 24 months). Differences between groups treated with HPMC and dextran were compared using student's t-test. Differences between treated eye and fellow eye were calculated and compared between HPMC and dextran groups using paired t-test., Results: Patients treated with a dextran solution had significantly greater improvement in BSCVA at 1, 6, and 24 months ( p  < 0.05) compared to the isotonic HPMC-treated group. Kmax increased in both groups at 1 month; however, HPMC-treated patients had a greater increase compared to dextran-treated patients ( p  = 0.01). Kmax decreased in both groups at 6 and 12 months, although this finding was only significant in the HPMC-treated group at 12 months., Conclusions: Our data suggest that crosslinking with the dextran solution may result in significantly better visual outcomes (demonstrated by visual acuity) compared to the isotonic HPMC riboflavin solution. Dextran solutions may have other potential advantages intrinsic to its biochemical properties facilitating more efficient crosslinking. Further research and long-term evidence regarding the use of dextran versus HPMC riboflavin solutions in collagen crosslinking is necessary., Competing Interests: The study protocol was approved by the Columbia University Institutional Review Board in accordance with the Declaration of Helsinki and was Health Insurance and Portability Accountability Act (HIPAA) compliant. Surgeons discussed risks and benefits with patients prior to obtaining written consent for CXL procedure and research participation.Not applicable.ST is a member of Avedro’s Medical Advisory Board.

Purpose: The purpose of this focused review was to explore the etiologies of corneal blindness worldwide and compare them with the indications and type of keratoplasties (eg, full-thickness penetrating keratoplasty, anterior lamellar keratoplasty, or endothelial keratoplasty) performed., Methods: A literature search of the articles published in the top 10 journals (based on the Altmetrics score) relevant to corneal transplantation within the past 20 years was performed to determine how the focus within corneal transplantation has changed over time. These data were compared with the prevalence and etiology of corneal blindness in each respective region worldwide., Results: The leading etiologies of corneal blindness worldwide are primarily due to anterior corneal pathology with a normal endothelium, and the prevalence is highest in developing countries. In addition, the number and type of corneal transplantations performed globally indicate that current practices are disproportionately skewed in favor of endothelial keratoplasty, which is targeted for the pathology prevalent in developed countries. Despite the large number of individuals who would benefit from anterior lamellar keratoplasty, this technique seems to be infrequently performed., Conclusions: Most corneal blindness worldwide is secondary to anterior corneal pathology because of infections and trauma. However, this does not align with the current trends and practices in the field of corneal transplantation. We discuss potential solutions to address the current leading causes of global corneal blindness, including increasing the number of anterior lamellar keratoplasties performed, using long-term preserved corneas by trained surgeons, and improving eye bank handling and distribution of procured tissues.

Purpose: To characterize changes in densitometry after corneal crosslinking (CXL) and correlate it with visual outcomes., Setting: Tertiary referral academic medical center, New York, New York, USA., Design: Retrospective case series., Methods: Patients with progressive keratoconus or post-laser in situ keratomileusis ectasia had CXL following the Dresden protocol. The corrected distance visual acuity (CDVA) and Pentacam imaging were obtained at baseline and follow-up visits., Results: Fifty-seven patients were followed for a mean of 15 months (range 1 to 24 months) after CXL. The CDVA improved significantly from baseline to 6, 12, 18, and 24 months postoperatively. The change in densitometry of the mid-stromal layer, 2.0 to 6.0 mm annulus, at 6 months was correlated with the improvement in CDVA at 6, 12, and 24 months (all P < .10). The increase in densitometry of the mid-stromal layer, centermost 0.0 to 2.0 mm annulus, at 6 months was significantly associated with the decrease in maximum keratometry (K) at 6 and 12 months (both P < .05). Last, the change in densitometry at 6 months was significantly correlated with the decrease in specific higher-order aberrations (HOAs) (P < .05)., Conclusions: Although the greatest and most durable post-CXL densitometry change was in the anterior layer, the degree of increased densitometry haze in the mid-stromal layer was most associated with and possibly predictive of improvement in CDVA, maximum K, and HOAs. The persistence of corneal haze at 6 months, measured by increased densitometry, might be a prognostic marker for CXL effectiveness., (Copyright © 2018 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.)

Human surfactant protein D (SP-D) is a potent innate immune molecule, which is emerging as a key molecule in the recognition and clearance of altered and non-self targets. Previous studies have shown that a recombinant fragment of human SP-D (rfhSP-D) induced apoptosis via p53-mediated apoptosis pathway in an eosinophilic leukemic cell line, AML14.3D10. Here, we report the ability of rfhSP-D to induce apoptosis via TNF-α/Fas-mediated pathway regardless of the p53 status in human pancreatic adenocarcinoma using Panc-1 (p53 mt ), MiaPaCa-2 (p53 mt ), and Capan-2 (p53 wt ) cell lines. Treatment of these cell lines with rfhSP-D for 24 h caused growth arrest in G1 cell cycle phase and triggered transcriptional upregulation of pro-apoptotic factors such as TNF-α and NF-κB. Translocation of NF-κB from the cytoplasm into the nucleus of pancreatic cancer cell lines was observed via immunofluorescence microscopy following treatment with rfhSP-D as compared to the untreated cells. The rfhSP-D treatment caused upregulation of pro-apoptotic marker Fas, as analyzed via qPCR and western blot, which then triggered caspase cascade, as evident from cleavage of caspase 8 and 3 analyzed via western blot at 48 h. The cell number following the rfhSP-D treatment was reduced in the order of Panc-1 (~67%) > MiaPaCa-2 (~60%) > Capan-2 (~35%). This study appears to suggest that rfhSP-D can potentially be used to therapeutically target pancreatic cancer cells irrespective of their p53 phenotype.

Apolipoprotein E (ApoE) is an important lipid carrier in both the periphery and the brain. The ApoE ε4 allele (ApoE4) is the single most important genetic risk-factor for Alzheimer's disease (AD) while the ε2 allele (ApoE2) is associated with a lower risk of AD-related neurodegeneration compared to the most common variant, ε3 (ApoE3). ApoE genotype affects a variety of neural circuits; however, the olfactory system appears to provide early biomarkers of ApoE genotype effects. Here, we directly compared olfactory behavior and olfactory system physiology across all three ApoE genotypes in 6-month- and 12-month-old mice with targeted replacement for the human ApoE2, ApoE3, or ApoE4 genes. Odor investigation and habituation were assessed, along with, olfactory bulb and piriform cortical local field potential activity. The results demonstrate that while initial odor investigation was unaffected by ApoE genotype, odor habituation was impaired in E4 relative to E2 mice, with E3 mice intermediate in function. There was also significant deterioration of odor habituation from 6 to 12 months of age regardless of the ApoE genotype. Olfactory system excitability and odor responsiveness were similarly determined by ApoE genotype, with an ApoE4 > ApoE3 > ApoE2 excitability ranking. Although motivated behavior is influenced by many processes, hyper-excitability of ApoE4 mice may contribute to impaired odor habituation, while hypo-excitability of ApoE2 mice may contribute to its protective effects. Given that these ApoE mice do not have AD pathology, our results demonstrate how ApoE affects the olfactory system at early stages, prior to the development of AD., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

Zeolites are commonly used as adsorbents for metal removal in most applications e.g. in wastewater. However, the ubiquity of iron in such systems may, in the long-term, distort the true interactions and mechanisms of contaminant removal as a result of modification of the zeolite surface. In this study, this potential phenomenon was assessed for the removal of uranium(VI) from aqueous solution by hydrous ferric oxide-modified zeolite (HFOMZ). This was prepared by precipitating iron hydroxide (the common precipitate of iron in aqueous systems) onto zeolite. The prepared HFOMZ was characterised by the scanning electron microscope (SEM), and Fourier transform infrared spectroscopy (FTIR). Batch adsorption experiments were performed to assess the effect of: pH, initial uranium(VI) concentration, adsorbent dosage, contact time, temperature, presence of cations (Pb 2+ , Cr 3+ , Cu 2+ , Mn 2+ and Co 2+ ) and anions ( [Formula: see text] , [Formula: see text] and [Formula: see text] ) on the adsorption of uranium(VI). Kinetic studies under these conditions indicated that the pseudo second-order kinetic model (R 2  > 0.99) best described the adsorption behaviour, implying that this could be proceeding through a chemisorption process. The experimental data was best described by the Freundlich isotherm model (R 2  > 0.93), an implication that the adsorption surface was heterogeneous. The thermodynamic parameters calculated from the experimental data suggested that the adsorption of U(VI) onto HFOMZ was spontaneous and exothermic in nature. The adsorption of U(VI) onto HFOMZ was dominated by complexation with strong ionizable hydroxyl sites on the hydrous ferric oxide surfaces and the edge sites of the zeolite. At pH values from 2 to 6, increased adsorption was observed and this decreased at higher pH values (above 6). This corresponded with the changes in speciation as determined by the PHREEQC modelling code. The presence of the cations (Pb 2+ , Cr 3+ , Cu 2+ , Mn 2+ and Co 2+ ) and anions ( [Formula: see text] and [Formula: see text] ) resulted in a significant decrease in the adsorption capacity of U(VI) by HFOMZ, implying that in a system where these anions and cations are present in high concentrations over time, U(VI) will adsorb less onto the material., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Possession of the ε4 allele of apolipoprotein E ( APOE ) is the major genetic risk factor for late-onset Alzheimer's disease (AD). Although numerous hypotheses have been proposed, the precise cause of this increased AD risk is not yet known. In order to gain a more comprehensive understanding of APOE4 's role in AD, we performed RNA-sequencing on an AD-vulnerable vs. an AD-resistant brain region from aged APOE targeted replacement mice. This transcriptomics analysis revealed a significant enrichment of genes involved in endosomal-lysosomal processing, suggesting an APOE4 -specific endosomal-lysosomal pathway dysregulation in the brains of APOE4 mice. Further analysis revealed clear differences in the morphology of endosomal-lysosomal compartments, including an age-dependent increase in the number and size of early endosomes in APOE4 mice. These findings directly link the APOE4 genotype to endosomal-lysosomal dysregulation in an in vivo , AD pathology-free setting, which may play a causative role in the increased incidence of AD among APOE4 carriers.

Purpose: To analyze the distribution of tear film osmolarity in patients with dry eye and its association with other ocular surface parameters., Methods: Tear osmolarity and other quantitative dry eye parameters were obtained from patients with 1) clinically significant dry eye (significant symptoms and ocular surface staining, n = 131), 2) symptoms-only dry eye (significant symptoms but no significant ocular surface staining, n = 52), and 3) controls (no significant symptoms or staining, n = 42)., Results: Tear osmolarity varied significantly across groups (P = 0.01), with patients with clinically significant dry eye having the highest tear osmolarity (312.0 ± 16.9 mOsm/L), control patients having the lowest tear osmolarity (305.6 ± 9.7 mOsm/L), and patients with symptoms-only dry eye falling in between (307.4 ± 5.6 mOsm/L). Patients with clinically significant dry eye also tended to have a greater intereye difference in osmolarity (12.0 ± 13.4) than did the individuals with symptoms-only dry eye (9.1 ± 12.4) and controls (9.0 ± 7.4) (P = 0.06). In multivariable regression models, higher tear osmolarity was associated with higher Ocular Surface Disease Index, discomfort subscore (P = 0.02), and higher corneal and conjunctival staining scores (P < 0.01 for both). Worse eye tear osmolarity was not correlated with the corresponding tear film breakup time or Schirmer test (P > 0.05 for both)., Conclusions: Individuals with symptomatic dry eye that is not yet clinically significant seem to have higher and more variable osmolarity measurements than controls, potentially indicating that changes in osmolarity precede clinical findings.

Purpose: To determine whether cataract surgery accelerates disease progression in retinitis pigmentosa (RP)., Design: Retrospective cohort study., Methods: Seventy eyes of 40 patients with RP were categorized as having had phacoemulsification with intraocular lens implantation vs no cataract surgery at a single tertiary-level institution. Spectral-domain optical coherence tomography (SDOCT) was used to measure the ellipsoid zone (EZ) width, which has been demonstrated to be a reliable marker of RP severity, at baseline and throughout follow-up (median 768 days). RP progression was calculated as the loss of EZ width over time for all patients. Additional postoperative data were collected for the cataract surgery group, including preoperative and postoperative best-corrected visual acuity, incidence of macular edema, posterior capsular opacification, epiretinal membrane, and intraocular lens subluxation., Results: Multivariable analysis including age, baseline EZ width, mode of inheritance, and cataract surgery status showed that there was no significant difference in RP progression between the cataract surgery and control groups (P = .23). Mode of inheritance was associated with RP progression, with autosomal recessive RP progressing at 148 μm/year and autosomal dominant RP progressing at 91 μm/year (P = .003). Visual acuity improved in almost all eyes that underwent surgery (17/19, 89%) and remained stable in remaining eyes (2/19, 11%). There was a high incidence of postsurgical posterior capsular opacification (18/19, 95%). There were no serious complications, such as lens subluxation or endophthalmitis., Conclusions: Our findings suggest that cataract surgery is a safe and effective means of improving visual acuity in RP patients and that it does not seem to be associated with faster disease progression as measured using SDOCT., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In this work, the synthesis of iron (hydr) oxide modified zeolite was achieved through precipitation of iron on the zeolite. The structure and surface morphology of iron (hydr) oxide modified zeolite (IHOMZ) was studied by scanning electron microscopy (SEM), coupled with an energy-dispersive X-ray spectroscopy (EDX), and Fourier transform infrared (FT-IR) spectra. The efficiency of IHOMZ was then investigated through batch technique for the extraction of As(V) from mine waste water. The optimum parameters for maximum As(V) adsorption were: an initial As(V) concentration (10 mg L -1 ), adsorbent dosage (3.0 g), contact time (90 min) and temperature (53 °C). The initial pH of the solution had no compelling effect on As(V) adsorption by IHOMZ. However, adsorption capacity was significantly affected by the solution temperature with 53 °C registering the maximum removal efficiency. The thermodynamic parameters: Entropy (ΔS° = 0.00815 kJ (K mol) -1 ), variation of the Gibbs free energy (ΔG°) and enthalpy (ΔH° = 9.392 kJ mol -1 ) of As(V) adsorption onto IHOMZ system signified a non-spontaneous and endothermic process. It was noted that Freundlich isotherm model exhibited a better fit to the equilibrium experimental data, implying that the adsorption process occurred on a heterogeneous surface. The kinetic data from As(V) adsorption experiments was depicted by the pseudo-second-order kinetic model (R 2  > 0.999), suggesting a chemisorption adsorption process. The experimental batch equilibrium results indicated that IHOMZ could be used as an effective sorbent for As(V) ion extraction from acid mine drainage., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background/aims: To evaluate the impact of dry eye on reading performance., Methods: Out-loud and silent reading in patients with clinically significant dry eye (n=41) and controls (n=50) was evaluated using standardised texts. Dry eye measures included tear film break-up time, Schirmer's test and corneal epithelial staining. Symptoms were assessed by the Ocular Surface Disease Index (OSDI)., Results: The dry eye group had a greater proportion of women as compared with the control group but did not differ in age, race, education level or visual acuity (p≥0.05 for all). Out-loud reading speed averaged 148 words per minute (wpm) in dry eye subjects and 163 wpm in controls (p=0.006). Prolonged silent reading speed averaged 199 wpm in dry eye subjects versus 226 wpm in controls (p=0.03). In multivariable regression models, out-loud and sustained silent reading speeds were 10 wpm (95% CI -20 to -1 wpm, p=0.039) and 14% (95% CI -25% to -2%, p=0.032) slower, respectively, in dry eye subjects as compared with controls. Greater corneal staining was associated with slower out-loud (-2 wpm/1 unit increase in staining score, 95% CI =-3 to -0.3 wpm) and silent (-2%, 95% CI -4 to -0.6 wpm) reading speeds (p<0.02 for both). Significant interactions were found between OSDI score and word-specific features (longer and less commonly used words) on out-loud reading speed (p<0.05 for both)., Conclusions: Dry eye is associated with slower out-loud and silent reading speeds, providing direct evidence regarding the functional impact of dry eye. Reading speed represents a measurable clinical finding that correlates directly with dry eye severity., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

While apolipoprotein (Apo) E4 is linked to increased incidence of Alzheimer's disease (AD), there is growing evidence that it plays a role in functional brain irregularities that are independent of AD pathology. However, ApoE4-driven functional differences within olfactory processing regions have yet to be examined. Utilizing knock-in mice humanized to ApoE4 versus the more common ApoE3, we examined a simple olfactory perceptual memory that relies on the transfer of information from the olfactory bulb (OB) to the piriform cortex (PCX), the primary cortical region involved in higher order olfaction. In addition, we have recorded in vivo resting and odor-evoked local field potentials (LPF) from both brain regions and measured corresponding odor response magnitudes in anesthetized young (6-month-old) and middle-aged (12-month-old) ApoE mice. Young ApoE4 compared to ApoE3 mice exhibited a behavioral olfactory deficit coinciding with hyperactive odor-evoked response magnitudes within the OB that were not observed in older ApoE4 mice. Meanwhile, middle-aged ApoE4 compared to ApoE3 mice exhibited heightened response magnitudes in the PCX without a corresponding olfactory deficit, suggesting a shift with aging in ApoE4-driven effects from OB to PCX. Interestingly, the increased ApoE4-specific response in the PCX at middle-age was primarily due to a dampening of baseline spontaneous activity rather than an increase in evoked response power. Our findings indicate that early ApoE4-driven olfactory memory impairments and OB network abnormalities may be a precursor to later network dysfunction in the PCX, a region that not only is targeted early in AD, but may be selectively vulnerable to ApoE4 genotype., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

Under normal conditions, the function of catalytically active proteases is regulated, in part, by their endogenous inhibitors, and any change in the synthesis and/or function of a protease or its endogenous inhibitors may result in inappropriate protease activity. Altered proteolysis as a result of an imbalance between active proteases and their endogenous inhibitors can occur during normal aging, and such changes have also been associated with multiple neuronal diseases, including Amyotrophic Lateral Sclerosis (ALS), rare heritable neurodegenerative disorders, ischemia, some forms of epilepsy, and Alzheimer's disease (AD). One of the most extensively studied endogenous inhibitor is the cysteine-protease inhibitor cystatin C (CysC). Changes in the expression and secretion of CysC in the brain have been described in various neurological disorders and in animal models of neurodegeneration, underscoring a role for CysC in these conditions. In the brain, multiple in vitro and in vivo findings have demonstrated that CysC plays protective roles via pathways that depend upon the inhibition of endosomal-lysosomal pathway cysteine proteases, such as cathepsin B (Cat B), via the induction of cellular autophagy, via the induction of cell proliferation, or via the inhibition of amyloid-β (Aβ) aggregation. We review the data demonstrating the protective roles of CysC under conditions of neuronal challenge and the protective pathways induced by CysC under various conditions. Beyond highlighting the essential role that balanced proteolytic activity plays in supporting normal brain aging, these findings suggest that CysC is a therapeutic candidate that can potentially prevent brain damage and neurodegeneration., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Placental changes associated with SCNT have been described in several species, but little information is available in this area in the horse. We evaluated the ultrasonographic, gross, and histopathological characteristics of placentas from three successful and five unsuccessful equine SCNT pregnancies, established using cells from a single donor horse. Starting at approximately 6-month gestation, the pregnancies were monitored periodically using transrectal (TR) and transabdominal (TA) ultrasonography (US) to examine the placentas, fetal fluids, and fetuses. Of the five mares that aborted, one mare did so suddenly without any abnormal signs detected by US and four had enlarged umbilical vessels visible on TA-US before abortion. Placental edema (TR-US) and intravascular thrombi in the umbilical cords were seen (TA-US) in two of these four mares; one mare aborted shortly after acute placental separation was identified on TA-US. In three mares that delivered live foals, TA-US showed engorged allantoic vessels and enlarged umbilical vessels. Two of these mares had placental thickening visible on TR-US, interpreted as a sign of placentitis, that subsided after aggressive medical treatment. Seven of the eight placentas were submitted for gross and histopathological examinations after delivery. All placentas had some degree of edema, abnormally engorged allantoic vessels, and enlarged umbilical vessels. Placentitis, large allantoic vesicles, cystic pouches in the fetal part of the cord, and hemorrhages and thrombi in the umbilical vessels were detected only in placentas from mares that aborted. Equine pregnancies resulting from SCNT may be associated with placental pathologies that can be detected using ultrasonography. However, interpreting their severity is difficult. Although placental abnormalities have been observed in SCNT pregnancies in other species, to the best of our knowledge, placentitis has not been previously reported and may be an important complication of equine SCNT pregnancies, leading to pregnancy loss., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Epidemiological findings suggest that diabetic individuals are at a greater risk for developing Alzheimer's disease (AD). To examine the mechanisms by which diabetes mellitus (DM) may contribute to AD pathology in humans, we examined brain tissue from streptozotocin-treated type 1 diabetic adult male vervet monkeys receiving twice-daily exogenous insulin injections for 8-20 weeks. We found greater inhibitory phosphorylation of insulin receptor substrate 1 in each brain region examined of the diabetic monkeys when compared with controls, consistent with a pattern of brain insulin resistance that is similar to that reported in the human AD brain. Additionally, a widespread increase in phosphorylated tau was seen, including brain areas vulnerable in AD, as well as relatively spared structures, such as the cerebellum. An increase in active ERK1/2 was also detected, consistent with DM leading to changes in tau-kinase activity broadly within the brain. In contrast to these widespread changes, we found an increase in soluble amyloid-β (Aβ) levels that was restricted to the temporal lobe, with the greatest increase seen in the hippocampus. Consistent with this localized Aβ increase, a hippocampus-restricted decrease in the protein and mRNA for the Aβ-degrading enzyme neprilysin (NEP) was found, whereas various Aβ-clearing and -degrading proteins were unchanged. Thus, we document multiple biochemical changes in the insulin-controlled DM monkey brain that can link DM with the risk of developing AD, including dysregulation of the insulin-signaling pathway, changes in tau phosphorylation, and a decrease in NEP expression in the hippocampus that is coupled with a localized increase in Aβ., Significance Statement: Given that diabetes mellitus (DM) appears to increase the risk of developing Alzheimer's disease (AD), understanding the mechanisms by which DM promotes AD is important. We report that DM in a nonhuman primate brain leads to changes in the levels or posttranslational processing of proteins central to AD pathobiology, including tau, amyloid-β (Aβ), and the Aβ-degrading protease neprilysin. Additional evidence from this model suggests that alterations in brain insulin signaling occurred that are reminiscent of insulin signaling pathway changes seen in human AD. Thus, in an in vivo model highly relevant to humans, we show multiple alterations in the brain resulting from DM that are mechanistically linked to AD risk., (Copyright © 2016 the authors 0270-6474/16/364248-11$15.00/0.)

β-amyloid precursor protein (APP) and amyloid beta peptide (Aβ) are strongly implicated in Alzheimer's disease (AD) pathogenesis, although recent evidence has linked APP-βCTF generated by BACE1 (β-APP cleaving enzyme 1) to the development of endocytic abnormalities and cholinergic neurodegeneration in early AD. We show that partial BACE1 genetic reduction prevents these AD-related pathological features in the Ts2 mouse model of Down syndrome. Partially reducing BACE1 by deleting one BACE1 allele blocked development of age-related endosome enlargement in the medial septal nucleus, cerebral cortex, and hippocampus and loss of choline acetyltransferase (ChAT)-positive medial septal nucleus neurons. BACE1 reduction normalized APP-βCTF elevation but did not alter Aβ40 and Aβ42 peptide levels in brain, supporting a critical role in vivo for APP-βCTF in the development of these abnormalities. Although ameliorative effects of BACE1 inhibition on β-amyloidosis and synaptic proteins levels have been previously noted in AD mouse models, our results highlight the additional potential value of BACE1 modulation in therapeutic targeting of endocytic dysfunction and cholinergic neurodegeneration in Down syndrome and AD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To compare repeat penetrating keratoplasty (PK) with Boston type I keratoprosthesis (KPro) implantation for full-thickness donor corneal graft failure., Design: Previous donor graft failure is a common indication for both PK and KPro implantation. Selection of the surgical procedure is entirely dependent on the surgeon because there are no studies available for guidance. Therefore, a systematic review was undertaken to examine vision, device retention, graft clarity, and postoperative glaucoma and infection outcomes after repeat PK versus KPro implantation., Methods: Articles with data regarding repeat PK published between 1990 and 2014 were identified in PubMed, EMBASE, the Latin American and Caribbean Health Sciences Literature Database, and the Cochrane Central Register of Controlled Trials and were reviewed. Results were compared with a retrospective review of consecutive, nonrandomized, longitudinal case series of KPro implantations performed at 5 tertiary care centers in the United States. Visual acuity at 2 years was the primary outcome measure. The proportion of clear grafts in the repeat PK group, device retention in the KPro group, and the development of postoperative glaucoma and infection were secondary outcome measures., Results: The search strategy identified 17 128 articles in the PK analysis. After screening, 26 studies (21 case series and 5 cohort studies) were included in the review. Pooled analysis of the 26 unique studies demonstrated a 42% (95% confidence interval [CI], 30%-56%) likelihood of maintaining 20/200 or better at 2 years after repeat PK, compared with an 80% (95% CI, 68%-88%) probability with KPro implantation. The probability of maintaining a clear graft at 5 years was 47% (95% CI, 40%-54%) after repeat PK, whereas the probability of retention of the KPro at 5 years was 75% (95% CI, 64%-84%). The rate of progression of glaucoma at 3 years was 25% (95% CI, 10%-44%) after repeat PK and 30% in the KPro cohort., Conclusions: These results demonstrate favorable outcomes of KPro surgery for donor corneal graft failure with a greater likelihood of maintaining visual improvement without higher risk of postoperative glaucoma compared with repeat donor PK., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To describe the outcomes and prognostic characteristics of patients who had a repeat Boston type 1 keratoprosthesis (KPro) implantation., Design: Retrospective case series., Methods: setting: Data regarding preoperative clinical and demographic characteristics and postoperative course during initial and repeat KPro placement were collected at multiple centers across the country., Patients: Forty-eight eyes underwent explantation of KPro owing to complications between September 2003 and August 2014 at 5 participating tertiary eye care centers in the United States. Of those, 36 eyes that received a subsequent replacement device were included., Main Outcome Measures: Visual acuity (VA) outcomes and postoperative complications., Results: Ocular surface disease was significantly more common in eyes that required a device explantation, compared to those that retained the device (P < .001). Sixty-seven percent of eyes (24/36) achieved VA ≥ 20/200 vision after the repeat KPro. The probability of these 24 eyes maintaining VA ≥ 20/200 after the repeat KPro was 87% at 1 year and 75% at 2 years. Predictors of the ability to maintain vision ≥ 20/200 following surgery were a better last-recorded vision before explantation (P = .0002) and better vision immediately after repeat KPro (P < .001)., Conclusion: Ocular surface disease and its complications were associated with more frequent device removal. In these patients, repeat KPro resulted in restoration of vision. A reasonable visual acuity prior to device removal was associated with favorable long-term postoperative visual acuity and retention., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The presenilin 1 (PSEN1) L271V mutation causes early-onset familial Alzheimer's disease by disrupting the alternative splicing of the PSEN1 gene, producing some transcripts harboring the L271V point mutation and other transcripts lacking exon 8 (PS1(∆exon8)). We previously reported that PS1 L271V increased amyloid beta (Aβ) 42/40 ratios, while PS1(∆exon8) reduced Aβ42/40 ratios, indicating that the former and not the exon 8 deletion transcript is amyloidogenic. Also, PS1(∆exon8) did not rescue Aβ generation in PS1/2 double knockout cells indicating its identity as a severe loss-of-function splice form. PS1(∆exon8) is generated physiologically raising the possibility that we had identified the first physiological inactive PS1 isoform. We studied PS1(∆exon8) in vivo by crossing PS1(∆exon8) transgenics with either PS1-null or Dutch APP(E693Q) mice. As a control, we crossed APP(E693Q) with mice expressing a deletion in an adjacent exon (PS1(∆exon9)). PS1(∆exon8) did not rescue embryonic lethality or Notch-deficient phenotypes of PS1-null mice displaying severe loss of function in vivo. We also demonstrate that this splice form can interact with wildtype PS1 using cultured cells and co-immunoprecipitation (co-IP)/bimolecular fluorescence complementation. Further co-IP demonstrates that PS1(∆exon8) interacts with nicastrin, participating in the γ-secretase complex formation. These data support that catalytically inactive PS1(∆exon8) is generated physiologically and participates in protein-protein interactions.

Purpose: To report the ocular complications of primary Sjögren syndrome (SS) in men., Design: Retrospective cohort study., Methods: setting: Tertiary-care SS center., Patient Population: Total of 163 consecutive primary Sjögren syndrome patients evaluated between January 2007 and March 2013., Main Outcome Measure: Frequency of extraglandular ocular and systemic manifestations and serologic results in men compared to women., Results: Fourteen of the 163 primary SS patients (9%) were men. On initial presentation, men were a decade older (61 vs 50 years, P < .01) and less likely than women to have a prior diagnosis of SS (43% vs 65%, P = .09). A majority of men reported dry eye on presentation (92%), albeit less chronic compared to women (5.9 vs 10.8 years, P = .07). Men were more likely to present with serious ocular complications than women (43% vs 11%, P = .001). Extraglandular systemic complications of SS (ie, vasculitis, interstitial nephritis) were also more common in men (64% vs 40%, P = .07). Further, men were more likely to be negative for anti-SSA/Ro, anti-SSB/La, and antinuclear antibodies than women (36% men vs 11% women, P = .01)., Conclusion: Men with primary SS have a higher frequency of serious ocular and systemic manifestations. Although primary Sjögren syndrome is typically considered a disease of middle-aged women, it may be underdiagnosed and consequentially more severe in men. Physicians should have a lower threshold to test for SS in men with dry eye., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Endogenous murine amyloid-β peptide (Aβ) is expressed in most Aβ precursor protein (APP) transgenic mouse models of Alzheimer's disease but its contribution to β-amyloidosis remains unclear. We demonstrate ∼ 35% increased cerebral Aβ load in APP23 transgenic mice compared with age-matched APP23 mice on an App-null background. No such difference was found for the much faster Aβ-depositing APPPS1 transgenic mouse model between animals with or without the murine App gene. Nevertheless, both APP23 and APPPS1 mice codeposited murine Aβ, and immunoelectron microscopy revealed a tight association of murine Aβ with human Aβ fibrils. Deposition of murine Aβ was considerably less efficient compared with the deposition of human Aβ indicating a lower amyloidogenic potential of murine Aβ in vivo. The amyloid dyes Pittsburgh Compound-B and pentamer formyl thiophene acetic acid did not differentiate between amyloid deposits consisting of human Aβ and deposits of mixed human-murine Aβ. Our data demonstrate a differential effect of murine Aβ on human Aβ deposition in different APP transgenic mice. The mechanistically complex interaction of human and mouse Aβ may affect pathogenesis of the models and should be considered when models are used for translational preclinical studies., (Copyright © 2015 Elsevier Inc. All rights reserved.)