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Transcriptomes and proteomes can be normalized with a handful of RNAs or proteins (or their peptides), such as GAPDH, β-actin, RPBMS, and/or GAP43. Even with hundreds of standards, normalization cannot be achieved across different molecular mass ranges for small molecules, such as lipids and metabolites, due to the non-linearity of mass by charge ratio for even the smallest part of the spectrum. We define the amount (or range of amounts) of metabolites and/or lipids per a defined amount of a protein, consistently identified in all samples of a multiple-model organism comparison, as the normative level of that metabolite or lipid. The defined protein amount (or range) is a normalized value for one cohort of complete samples for which intrasample relative protein quantification is available. For example, the amount of citrate (a metabolite) per µg of aconitate hydratase (normalized protein amount) identified in the proteome is the normative level of citrate with aconitase. We define normativity as the amount of metabolites (or amount range) detected when compared to normalized protein levels. We use axon regeneration as an example to illustrate the need for advanced approaches to the normalization of proteins. Comparison across different pharmacologically induced axon regeneration mouse models entails the comparison of axon regeneration, studied at different time points in several models designed using different agents. For the normalization of the proteins across different pharmacologically induced models, we perform peptide doping (fixed amounts of known peptides) in each sample to normalize the proteome across the samples. We develop Regen V peptides, divided into Regen III (SEB, LLO, CFP) and II (HH4B, A1315), for pre- and post-extraction comparisons, performed with the addition of defined, digested peptides (bovine serum albumin tryptic digest) for protein abundance normalization beyond commercial labeled relative quantification (for example, 18-plex tandem mass tags). We also illustrate the concept of normativity by using this normalization technique on regenerative metabolome/lipidome profiles. As normalized protein amounts are different in different biological states (control versus axon regeneration), normative metabolite or lipid amounts are expected to be different for specific biological states. These concepts and standardization approaches are important for the integration of different datasets across different models of axon regeneration.

Abstract Objectives The objective of this study is to determine the optimal timing for device‐based infant circumcision under topical anaesthesia. Subjects/patients We include infants aged 1–60 days who were enrolled in a field study of the no‐flip ShangRing device at four hospitals in the Rakai region of south‐central Uganda, between 5 February 2020 and 27 October 2020. Methods Two hundred infants, aged 0–60 days, were enrolled, and EMLA cream was applied on the foreskin and entire penile shaft. The anaesthetic effect was assessed every 5 min by gentle application of artery forceps at the tip of the foreskin, starting at 10 min post‐application until 60 min, the recommended time to start circumcision. The response was measured using the Neonatal Infant Pain Scale (NIPS). We determined the onset and duration of anaesthesia (defined as 4) and maximum anaesthesia (defined as 2). Results Overall, NIPS scores decreased to a minimum and reversed before the recommended 60 min. Baseline response varied with age, with minimal response among infants aged 40 days. Overall, anaesthesia was achieved after at least 25 min and lasted 20–30 min. Maximum anaesthesia was achieved after at least 30 min (except among those aged >45 days where it was not achieved) and lasted up to 10 min. Conclusion The optimal timing for maximum topical anaesthesia occurred before the recommended 60 min of waiting time. A shorter waiting time and speed may be efficient for mass device‐based circumcision.

AIM: To analyze and calculate the relative cost of various childhood glaucoma surgical interventions per mm Hg intraocular pressure (IOP) reduction ($/mm Hg). METHODS: Representative index studies were reviewed to quantitate the reduction of mean IOP and glaucoma medications for each surgical intervention in childhood glaucoma. A US perspective was adopted, using Medicare allowable costs to calculate cost/mm Hg IOP reduction ($/mm Hg) at 1y postoperatively. RESULTS: At 1y postoperatively, the cost/mm Hg IOP reduction was $226/mm Hg for microcatheter-assisted circumferential trabeculotomy, $284/mm Hg for cyclophotocoagulation, $288/mm Hg for conventional ab-externo trabeculotomy, $338/mm Hg for Ahmed glaucoma valve, $350/mm Hg for Baerveldt glaucoma implant, $351/mm Hg for goniotomy, and $400/mm Hg for trabeculectomy. CONCLUSION: Microcatheter-assisted circumferential trabeculotomy is the most cost-efficient surgical method to lower IOP in childhood glaucoma, while trabeculectomy is the least cost-efficient surgical method.

BackgroundGlaucoma is one of the main causes of irreversible visual field loss and blindness worldwide. Vision loss in this multifactorial neurodegenerative disease results from progressive degeneration of retinal ganglion cells (RGCs) and their axons. Identifying molecular markers that can be measured objectively and quantitatively may provide essential insights into glaucoma diagnosis and enhance pathophysiology understanding.MethodsThe chronic, progressive DBA/2J glaucomatous mouse model of glaucoma and C57BL6/J optic nerve crush (ONC) mouse model were used in this study. Changes in PVALB expression with RGC and optic nerve degeneration were assessed via gene expression microarray analysis, quantitative real-time polymerase chain reaction (qRT-PCR), Western blot and immunohistochemistry.ResultsMicroarray analysis of the retinal gene expression in the DBA/2J mice at different ages showed that the expression of PVALB was downregulated as the mice aged and developed glaucoma with retinal ganglion cell loss. Analysis of qRT-PCR results demonstrated PVALB at the mRNA level was reduced in the retinas and optic nerves of old DBA/2J mice and in those after ONC compared to baseline young DBA2/J mice. PVALB protein expression measured by Western blot was also significantly reduced signal in the retinas and optic nerves of old DBA/2J mice and those eyes with crushed nerves. Immunohistochemical staining results demonstrated that there were fewer PVALB-positive cells in the ganglion cell layer (GCL) of the retina and staining pattern changed in the optic nerve from old DBA/2J mice as well as in mice eyes following ONC.ConclusionPVALB is abundantly expressed both by RGCs’ soma in the retinas and RGCs’ axons in the optic nerves of C57BL/6J. Furthermore, the expression level of PVALB decreases with RGC degeneration in the glaucomatous DBA/2J mice and after ONC injury of C57BL6/6J, indicating that PVALB is a reliable RGC molecular marker that can be used to study retinal and optic nerve degeneration.

Male circumcision (MC) is one of the oldest surgical procedures still completed today. Medical indications for MC include phimosis, recurrent balanitis, cosmesis, and infection prevention. In this review, we mainly focus on the role of MC in the prevention of human immunodeficiency virus, human papillomavirus, herpes simplex virus, gonorrhea, chlamydia, chancroid, and syphilis, and the subsequent impact of these genitourinary infections on male fertility. Overall, many compelling data support that MC may play an essential role in both genitourinary infection prevention and male fertility.

This metabolite dataset was collected from transgenic murine retinal ganglion cells (RGC) expressing bacterial channelrhodopsin labeled with fluorescent protein. Mice were subjected to optic nerve crush (ONC) with subsequent RGC stimulation of channelrhodopsin with blue light (promoting regeneration) or non-stimulation (control). ONC induces retinal ganglion cell degeneration over time with progressive loss of axons. In transgenic bacterial channelrhodopsin expressing RGC cells, light stimulation promotes regeneration of ONC axons. Genetically matched wild-type uninjured optic nerves were analyzed as controls for comparison.Metabolites were carefully extracted from finely minced optic nerve tissue using a solvent system (initial separation using 1:1 methanol and H2O and second extraction using 8:1:1 of acetonitrile:acetone:methanol). Untargeted liquid chromatography-mass spectrometry profiling was performed using fractionation on a Vanquish Horizon Binary UHPLC. Subsequent analyses were performed on an inline coupled Q-Exactive Orbitrap instrument. Metabolites were identified using Compound DiscovererTM software. Statistical analysis was performed using MetaboAnalyst 5.0. This data is available on Metabolomics Workbench, Study ID ST002111.

This labeled quantitative proteomics dataset was collected from a transgenic channel rhodopsin mouse model (Chr2) subjected to light stimulation after traumatic optic nerve crush (ONC). Protein extraction was performed by careful mincing of the tissue in extraction buffer (TEAB, NaCl and SDS). Protein amounts were normalized across samples using dot blot densitometry and ImageJ software. Samples were labeled for quantification using a modified TMTpro™ 16plex Label Reagent Set (Thermo Scientific™) after performing an overnight trypsin digestion. Untargeted liquid chromatography-mass spectrometry was performed on an Easy-nLC 1000 liquid chromatograph coupled to a Q Exactive mass spectrometer (LC-MS/MS). Data analysis was performed using Proteome Discoverer™ 2.5 (Thermo Scientific™). This data has been deposited to the ProteomeXchange (PX) and is available through PRIDE with the identifier PXD032788.

Purpose: To report a unique case of metastatic paraganglioma presenting as a junctional scotoma. Observations: A 38-year-old Caucasian man with a history of abdominal paraganglioma presented with minimally blurred vision 20/25 visual acuity in the left eye. The patient was found to have a junctional scotoma upon visual field testing. Cranial MRI revealed a large peri-clival mass compressing the pre-chiasmal optic nerves and other loci of metastatic disease. Intracranial masses, including metastases, can present with a relatively intact central acuity and nonspecific visual symptoms. Conclusions and Importance: To the best of our knowledge, this is the first report of metastatic paraganglioma causing a junctional scotoma. In cases with junctional scotoma, careful neuro-ophthalmic assessment and imaging are of paramount importance, even in patients with excellent visual acuity.

Abstract Background To investigate the distribution of peripheral anterior chamber depth (ACD) and the relationship between peripheral ACD and gonioscopy compared to other ocular parameters for primary angle closure disease (PACD) screening. We performed a population-based survey in Pudong New District of Shanghai, China, in 2011. Methods Cross-sectional study. Adults 50 and older were enrolled from a population-based study using cluster random sampling in Pudong New District, Shanghai. Remote ocular screening was performed with digital anterior eye structure photography. Van Herrick measurements were used to evaluate the peripheral ACD, the depth of the peripheral anterior chamber, and corneal thickness (CT), and the ACD to CT ratio was calculated. Subjects with peripheral ACD less than 0.5 CT were made follow-up appointments for clinical examination with gonioscopy. Receiver operating characteristic curves (ROC) were generated to show the performance of different tests in screening for primary angle closure disease (PACD). Results Two thousand five hundred twenty-eight adults participated in the study with 91 patients diagnosed with PACD. Two thousand four hundred sixty-three subjects had valid data in the right eye available for analysis. The mean peripheral ACD values for men and women were significantly different: 1.04 ± 0.46 (range 0.11–2.93) CT and 0.87 ± 0.41 (range 0.12–2.96) CT respectively (t = − 4.18; P

AIM: To report outcomes of patients after intraocular lens (IOL) repositioning or exchange for the version of the uveitis-glaucoma-hyphema (UGH) syndrome that does not include closed loop anterior chamber IOL (nUGH). METHODS: Chart review of patients with nUGH who underwent IOL repositioning or exchange by one surgeon were reviewed. The main outcome measures were best corrected visual acuity (BCVA) as a decimal fraction preoperatively and postoperatively after IOL repositioning or exchange. Clinical findings evaluated included the presence of uveitis, hyphema, elevated intraocular pressure (IOP), and other complications such as pigment dispersion or vitreous hemorrhage. The number of anti-inflammatory and glaucoma medications were assessed before and after IOL repositioning or exchange. RESULTS: The study included 14 pseudophakic eyes. The median time at the onset of contemporary UGH after cataract extraction and IOL implantation (CE/IOL) was 7.5y. IOL repositioning or exchange was performed at a mean duration of 8.1±4.7mo (median: 4mo) after onset of UGH. The mean BCVA was improved from 0.45±0.26 preoperatively after onset of UGH syndrome to 0.76±0.22 (P=0.016) after IOL repositioning or exchange. Among the 14 eyes, uveitis, elevated IOP, and hyphema were present preoperatively in 13, 13, and 6 eyes, respectively. Uveitis and hyphema resolved in all cases after IOL surgery. The mean IOP was reduced from 26.4±4.5 mm Hg preoperatively to 14.7±4.9 postoperatively (P=0.01). The mean number of glaucoma medications used was reduced from 1.7±1.1 medications preoperatively to 0.8±1.08 (P=0.04) postoperatively. CONCLUSION: IOL repositioning or exchange is an effective treatment in many cases for medically resistant contemporary UGH syndrome.

Purpose. This study investigated the effect of interview format changes (in-person to virtual, one-to-one to multiple-to-one) necessitated by the COVID-19 travel restrictions on preliminary fellowship candidate ranking variabilities. Design. Cross-sectional observational study. Method. In 2018 and 2019, the glaucoma fellowship interviews were conducted in-person in a one-to-one format, whereas in 2020, interviews were virtual and in a multiple (interviewers)-to-one (candidate) format. We compared ranking ranges of interviewers within the same virtual room (WSR) and not within the same virtual room (NWSR) to assess the effect of WSR versus NWSR on ranking variabilities. We also compared ranking categories (“accept,” “alternate,” and “pass”) agreements between 2018, 2019, and 2020 to assess the effect of virtual versus in-person interviews on ranking variabilities. Results. NWSR and WSR mean rankings differed by 1.33 (95% confidence interval difference 0.61 to 2.04, p = 0.0003), with WSR interviewers having less variability than NWSR pairs. The variability between 2018/2019 (in-person interviews) and 2020 (virtual interviews) showed no differences between in-person and virtual interviews (weighted Kappa statistic 0.086 for 2018, 0.158 for 2019, and 0.101 for 2020; p

Purpose: To describe a unique incidence of inadvertent filtering bleb creation after intravitreal injections. Observations: An 84-year-old woman with a history of wet age-related macular degeneration requiring intravitreal injections presented with a Seidel-positive conjunctival cyst. The cyst was in an area where she had received multiple injections and was suspected to be an inadvertent filtering bleb secondary to a full-thickness scleral hole created by these injections. She underwent surgical closure of the fistula and repair of the bleb. Conclusions and Importance: This case emphasizes the importance of recognizing this potential complication of intraocular injections and outlines steps that should be taken to prevent poor outcomes and vision loss.

The optic nerve transfers visual information from the retina to the brain through the axons of retinal ganglion cells (RGCs). In adult mammals, optic nerve injuries and progressive degenerative diseases lead to the irreversible loss of RGCs, resulting in vision loss and blindness. Optogenetic models have proved useful in manipulating the growth of RGCs through expression and stimulation of channelrhodopsins (Chr2) in RGCs using the RGC-specific thy-1 promoter. Using transgenic Chr2 mouse (Thy1-ChR2-EYFP) as a model of regeneration, we profile the lipid changes which occur after traumatic optic nerve crush, light stimulation and forced RGC axonal growth. Thy1-ChR2-EYFP and control (C57BL/6) mice were divided in four groups each – 1) no crush and no stimulation, 2) no crush with stimulation, 3) crush and without stimulation, and 4) crush with stimulation. After euthanasia, the optic nerves were collected for lipidomic analysis. The Bligh and Dyer method was used for lipid extraction, followed by mass spectrometry lipid profiling with a Q-Exactive Orbitrap Liquid Chromatography-Mass Spectrometer (LC MS-MS). The raw scans were analysed with LipidSearch 4.1.3 and the statistical analysis was conducted through Metaboanalyst 4.0. This data is available at Metabolomics Workbench, study ID ST001381: [https://www.metabolomicsworkbench.org/data/DRCCMetadata.php?Mode=Study&StudyID=ST001381&StudyType=MS&ResultType=5].

A 42-year-old Hispanic female underwent intravitreal autologous adipose-tissue derived stem cell injection to her left eye in the Dominican Republic for treatment of retinitis pigmentosa associated with Usher Syndrome. Prior to intravitreal injection, the patient's best-corrected-visual-acuity (BCVA) was 1/200. The patient experienced decreased vision gradually over a 3-month period. The patient presented with no light perception (NLP) vision with a total funnel retinal detachment, as well as hyphema, iris neovascularization, and nearly 360 posterior synechiae of the iris to the lens capsule. The patient suffered from ocular pain with an intraocular pressure (IOP) of 37 mm Hg. Transcleral cyclophotocoagulation was performed. The IOP was 6 mm Hg six weeks after treatment and the patient was pain free.

There have been significant advancements in male infertility microsurgery over time, and there continues to be significant promise for new and emerging techniques, technologies, and methodologies. In this review, we discuss the history of male infertility and the evolution of microsurgery, the essential role of education and training in male infertility microsurgery, and new technologies in this space. We also review the potentially important role of artificial intelligence (AI) in male infertility and microsurgery.

The conventional approach of initially treating glaucoma medically and holding surgical intervention as a reserve option was endorsed by the findings of the Collaborative Initial Glaucoma Treatment Study (CIGTS) study.1 This study reported that patients had similar visual field outcomes at five years from either medical treatment or immediate filtration surgery and supported the status quo of glaucoma management. The market for medical treatments has since increased and polypharmacy is now an accepted norm for glaucoma treatment. Surgical remedies for glaucoma have existed in a less pressured environment such that trabeculectomy, after four decades of slow evolution and complications, remains the most commonly performed type of glaucoma surgery worldwide. This ecosystem has begun to change in recent years. New surgical alternatives have arrived, reached a sizeable number and gained considerable traction as viable competitors to conventional glaucoma medical and surgical treatments. This raises important questions as to how these advances in glaucoma surgical options may affect the future landscape of glaucoma treatment. Has trabeculectomy already yielded some of its high ground? Why has trabeculectomy not been able to evolve more rapidly in response to new competitive pressures? If trabeculectomy has reached its evolutionary zenith are the newer alternatives any better? And, is it time to re-examine the conventional ‘medical before surgical’ approach to glaucoma? This article reviews the evidence for current surgical techniques available to patients with glaucoma.

Purpose. Although most urethral diverticula in women are benign, there is a subset of patients who develop malignant changes. Limited studies report the pathologic findings associated with this relatively rare entity. We describe the clinicopathologic findings of women who underwent urethral diverticulectomy. Methods. A consecutive series of 29 women who underwent surgical resection of a urethral diverticulum were identified between 1992 and 2013. Clinical and radiographic data was collected by retrospective review of patient medical records. All pathological slides were rereviewed by a single urologic pathologist. Results. Of the 14 women with clinical data, 9 (64%) presented with urgency, 7 (50%) with urinary frequency, 3 (21%) with urinary incontinence, and 3 (21%) with dysuria. Mean diverticular size was 2.3 (±1.4) cm. Although one patient (3%) had invasive adenocarcinoma on final pathology, the remaining 28 cases (97%) demonstrated benign features. The most common findings were inflammation (55%) and nephrogenic adenoma (21%). Conclusions. Although most urethral diverticula in women are benign, there is a subset of patients who develop malignancy in association with the diverticulum. In this series, 97% of cases had a benign histology. These findings are important when counseling patients regarding treatment options.

Summary: Background: Use of medical devices represents a unique opportunity to facilitate scale-up of early infant male circumcision (EIMC) across sub-Saharan Africa. The ShangRing, a circumcision device prequalified by WHO, is approved for use in adults and adolescents and requires topical anaesthesia only. We aimed to investigate the safety and efficacy of the ShangRing versus the Mogen clamp for EIMC in infants across eastern sub-Saharan Africa. Methods: In this multicentre, non-inferiority, open-label, randomised controlled trial, we enrolled healthy male infants (aged

The mammalian retina displays incomplete intrinsic regenerative capacities; therefore, retina degeneration is a major cause of irreversible blindness such as glaucoma, age-related macular degeneration and diabetic retinopathy. These diseases lead to the loss of retinal cells and serious vision loss in the late stage. Stem cell transplantation is a great promising novel treatment for these incurable retinal degenerative diseases and represents an exciting area of regenerative neurotherapy. Several suitable stem cell sources for transplantation including human embryonic stem cells, induced pluripotent stem cells and adult stem cells have been identified as promising target populations. However, the retina is an elegant neuronal complex composed of various types of cells with different functions. The replacement of these different types of cells by transplantation should be addressed separately. So far, retinal pigment epithelium transplantation has achieved the most advanced stage of clinical trials, while transplantation of retinal neurons such as retinal ganglion cells and photoreceptors has been mostly studied in pre-clinical animal models. In this review, we opine on the key problems that need to be addressed before stem cells transplantation, especially for replacing injured retinal ganglion cells, may be used practically for treatment. A key problem we have called the Switchboard Dilemma is a major block to have functional retinal ganglion cell replacement. We use the public switchboard telephone network as an example to illustrate different difficulties for replacing damaged components in the retina that allow for visual signaling. Retinal ganglion cell transplantation is confronted by significant hurdles, because retinal ganglion cells receive signals from different interneurons, integrate and send signals to the correct targets of the visual system, which functions similar to the switchboard in a telephone network – therefore the Switchboard Dilemma.

To assess safety of the no-flip ShangRing male circumcision technique and to determine clinical course and safety of spontaneous detachment (i.e., allowing the device to fall off), we conducted a case series of no-flip ShangRing circumcision combined with a randomized controlled trial of removal 7 days postcircumcision versus spontaneous detachment at two health facilities in Kenya. The primary outcome was the safety of the no-flip technique based on moderate and severe adverse events (AEs) during the procedure and through 42-day follow-up. A main secondary outcome was clinical course and safety of spontaneous detachment. Two hundred and thirty males 10 years and older underwent no-flip circumcision; 114 randomized to 7-day removal and 116 to spontaneous detachment. All circumcisions were successfully completed. Overall 5.3% (6/114) of participants in the 7-day group and 1.7% (2/116) in the spontaneous group had an AE; with no differences when compared to the 3% AE rate in historical data from African studies using the original flip technique (P = 0.07 and P = 0.79, respectively). Overall 72.4% (84/116) of participants in the spontaneous group wore the ShangRing until it detached. Among the remaining (27.6%; 32/116), the ring was removed, primarily at the participants' request, due to pain or discomfort. There was no difference in AE rates (P = 0.169), visit day declared healed (P = 0.324), or satisfaction (P = 0.371) between randomization groups. The median time to detachment was 14.0 (IQR: 7–21, range: 5–35) days. The no-flip technique and spontaneous detachment are safe, effective, and acceptable to boys and men 10 years and older. Phimosis and penile adhesions do not limit successful ShangRing circumcision with the no-flip technique.

BACKGROUND:Attention has recently turned toward the use of device-assisted male circumcision to help scale up male circumcision services in sub-Saharan Africa, with increasing emphasis on younger age groups. We assessed the use of the ShangRing for circumcising the subset of boys aged 10 to 12 years who were enrolled in two randomized clinical trials in Kenya. METHODS:We performed a sub-analysis of outcomes in 197 boys aged 10 to 12 years; a subset who were enrolled in two randomized clinical trials to assess the use of the no-flip ShangRing circumcision technique in men and boys. One trial assessed spontaneous detachment vs. planned removal of the ShangRing 7 days post-circumcision. The second trial compared the use of topical vs. injectable anesthesia with ShangRing circumcision. Aside from baseline characteristics, data was collected and analyzed for each trial separately. RESULTS:All participants were successfully circumcised. Duration of circumcision, participants requiring a dorsal slit, rate of adverse events, time to complete wound healing, and participant satisfaction were similar between the two groups in each trial. Mean time required for spontaneous ShangRing detachment was 14.82±3.76 days. Topical anesthesia showed a significantly lower mean pain score at the time of application (0.64±1.71 vs. 1.55± 2.21, p = 0.03) as well as postoperatively (0.54±0.88 vs. 1.72±1.56, p

BackgroundThe ShangRing is a disposable, collar clamp circumcision device pre-qualified for use in men and boys 13 years and above. It has been shown to be faster than conventional circumcision with comparable adverse event (AE) rates and high client satisfaction. Voluntary medical male circumcision (VMMC) has been shown to dramatically reduce the risk of HIV acquisition in males. However, the fear of pain during circumcision is an important barrier to uptake. Use of topical anesthesia thus presents an opportunity to address this.ObjectivesWe sought to evaluate the safety, effectiveness and acceptability of the use of topical anaesthesia with ShangRing circumcision of men and boys 10 years of age and above.MethodsParticipants were randomised 2:1 to receive topical or injectable anaesthesia. All participants underwent no-flip ShangRing circumcision. The primary outcome measure was pain. Secondary outcomes included ease of use of topical versus injectable anaesthesia, AEs and participant satisfaction.ResultsCompared to the topical group, participants in the injectable group reported significantly more pain on administration of the anesthesia and at approximately 20 minutes after the procedure. In the topical group, sufficient anaesthesia with topical cream was not achieved in 21 (9.3%) cases before the start of the procedure; in another 6 (2.6%), supplementary injectable anaesthesia was required as the circumcision was being carried out. The AE rate was significantly lower (pConclusionsOur results demonstrate the safety, improved clinical experience, effectiveness, and acceptability of the use of topical anaesthesia in ShangRing circumcision using the no-flip technique. Topical anaesthesia effectively eliminates needlestick pain from the clients' VMMC experience and thus has the potential to increase demand for the service.Trial registrationClinicalTrials.gov NCT02390310.

Neurodegenerative eye diseases, such as glaucoma, cause irreversible vision loss in millions of patients worldwide, creating serious medical, economic and social issues. Like other mammalian central nervous system tracts, optic nerve intrinsically lacks the capacity for axonal growth and its surrounding environment is also non-permissive to regeneration. Any axonal damage also triggers a vicious cycle of retinal ganglion cell (RGC) death. Exploring methods that can enhance RGCs survival and promote axonal regeneration will not only enable vision restoration for millions of patients, but also shed light on the treatment of other neurodegenerative diseases. In this review article, we will go through three current approaches to cure neurodegenerative eye diseases, including cell based therapy, neuro-regeneration and neuro-rejuvenation.

Retinal ganglion cells (RGCs) are the output neuron of the eye, transmitting visual information from the retina through the optic nerve to the brain. The importance of RGCs for vision is demonstrated in blinding diseases where RGCs are lost, such as in glaucoma or after optic nerve injury. In the present study, we hypothesize that normal RGC function is transcriptionally regulated. To test our hypothesis, we examine large retinal expression microarray datasets from recombinant inbred mouse strains in GeneNetwork and define transcriptional networks of RGCs and their subtypes. Two major and functionally distinct transcriptional networks centering around Thy1 and Tubb3 (Class III beta-tubulin) were identified. Each network is independently regulated and modulated by unique genomic loci. Meta-analysis of publically available data confirms that RGC subtypes are differentially susceptible to death, with alpha-RGCs and intrinsically photosensitive RGCs (ipRGCs) being less sensitive to cell death than other RGC subtypes in a mouse model of glaucoma.

To evaluate the presence of clinical signs consistent with suspected glaucoma in Haitian Afro-Caribbean individuals residing in South Florida who do not receive regular eye examinations.Retrospective, cross-sectional study.Community health center in the Little Haiti district of Miami, Florida.We reviewed medical records and screening forms from five health screenings between October 2011 to October 2013 of 939 Afro-Caribbean individuals older than 18 years, who were never diagnosed with glaucoma or had an eye examination within the last ten years.Measurements of distance visual acuity (VA), intraocular eye pressure (IOP), central corneal thickness (CCT), cup-to-disc ratio (CDR), frequency doubling technology (FDT) perimeter visual field (VF).Proportion of glaucoma suspects, based on IOP greater than or equal to 24 mm Hg or CDR greater than or equal to 0.7 in either eye, and determinants of CDR and IOP.One hundred ninety-one (25.5%) of 750 patients were identified as glaucoma suspects. Glaucoma suspects were common in both the youngest and oldest age groups (70 years, 25.0%; 95% CI, 21.8-28.2) and higher in men than women less than 70 years; the reverse was true after 70 years. Among all patients, mean IOP was 19.2±4.5 mmHg, mean CDR was 0.37±0.17, and mean CCT was 532±37.1 µm. In multiple linear stepwise regression analysis, determinates of increased CDR included increasing age (P = 0.004), lack of insurance (P = 0.019), and higher IOP (P

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10⁻¹⁸), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10⁻¹¹). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10⁻¹²) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10⁻¹⁰). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

Fluid shear modulates many biological properties. How shear mechanosensing occurs in the extracellular matrix (ECM) and is transduced into cytoskeletal change remains unknown. Cochlin is an ECM protein of unknown function. Our investigation using a comprehensive spectrum of cutting-edge techniques has resulted in following major findings: (1) over-expression and down-regulation of cochlin increase and decrease intraocular pressure (IOP), respectively. The overexpression was achieved in DBA/2J-Gpnmb(+)/SjJ using lentiviral vectors, down-regulation was achieved in glaucomatous DBA/2J mice using targeted disruption (cochlin-null mice) and also using lentiviral vector mediated shRNA against cochlin coding region; (2) reintroduction of cochlin in cochlin-null mice increases IOP; (3) injection of exogenous cochlin also increased IOP; (4) increasing perfusion rates increased cochlin multimerization, which reduced the rate of cochlin proteolysis by trypsin and proteinase K; The cochlin multimerization in response to shear stress suggests its potential mechanosensing. Taken together with previous studies, we show cochlin is involved in regulation of intraocular pressure in DBA/2J potentially through mechanosensing of the shear stress.

Fluid flow through large interstitial spaces is sensed at the cellular level, and mechanistic responses to flow changes enables expansion or contraction of the cells modulating the surrounding area and brings about changes in fluid flow. In the anterior eye chamber, aqueous humor, a clear fluid, flows through trabecular meshwork (TM), a filter like region. Cochlin, a secreted protein in the extracellular matrix, was identified in the TM of glaucomatous patients but not controls by mass spectrometry. Cochlin undergoes shear induced multimerization and plays a role in mechanosensing of fluid shear. Cytoskeletal changes in response to mechanosensing in the ECM by cochlin will necessitate transduction of mechanosensing. TREK-1, a stretch activated outward rectifying potassium channel protein known to act as mechanotransducer was found to be expressed in TM. Cochlin expression results in co-expression of TREK-1 and filopodia formation. Prolonged cochlin expression results in expression and subsequent secretion of annexin A2, a protein known to play a role in cytoskeletal remodeling. Cochlin interacts with TREK-1 and annexin A2. Cochlin-TREK-1 interaction has functional consequences and results in changes in cell shape and motility. Annexin A2 expression and secretion follows cochlin-TREK-1 syn-expression and correlates with cell elongation. Thus cytoskeleton changes in response to fluid shear sensed by cochlin are further mediated by TREK-1 and annexin A2.