LncRNA VEAL2 regulates PRKCB2 to modulate endothelial permeability in diabetic retinopathy.

Long non-coding RNAs (lncRNAs) are emerging as key regulators of endothelial cell function. Here, we investigated the role of a novel vascular endothelial-associated lncRNA (VEAL2) in regulating endothelial permeability. Precise editing of veal2 loci in zebrafish (veal2gib005Δ8/+ ) induced cranial hemorrhage. In vitro and in vivo studies revealed that veal2 competes with diacylglycerol for interaction with protein kinase C beta-b (Prkcbb) and regulates its kinase activity. Using PRKCB2 as bait, we identified functional ortholog of veal2 in humans from HUVECs and named it as VEAL2. Overexpression and knockdown of VEAL2 affected tubulogenesis and permeability in HUVECs. VEAL2 was differentially expressed in choroid tissue in eye and blood from patients with diabetic retinopathy, a disease where PRKCB2 is known to be hyperactivated. Further, VEAL2 could rescue the effects of PRKCB2-mediated turnover of endothelial junctional proteins thus reducing hyperpermeability in hyperglycemic HUVEC model of diabetic retinopathy. Based on evidence from zebrafish and hyperglycemic HUVEC models and diabetic retinopathy patients, we report a hitherto unknown VEAL2 lncRNA-mediated regulation of PRKCB2, for modulating junctional dynamics and maintenance of endothelial permeability.

Distinct NOD2 mutations reported in three families with Blau syndrome (BS) from a single center in India - Case series and review of literature.

OBJECTIVE: Blau syndrome (BS), considered a rare pediatric autoinflammatory disease, is characterised by a triad of granulomatous arthritis, dermatitis and uveitis. Here we present a tale of three families visited in our outpatient department in the last two years (2020-2022) where more than one member was affected with either skin, ophthalmological and joint involvement with either biopsy-proven granuloma or genetic mutation at NOD2 gene suggesting the diagnosis of BS. CASE SERIES: The first family had three affected members where the mother and her two children had skin changes, polyarthritis and a pathogenic mutation in NOD2 gene (exon 4, c.1000C > T, p.Arg334Trp) suggesting BS. The second family had two affected members where both mother and her son had uveitis, skin changes with NOD2 mutation at exon 4 with c.1147G > A (p Glu 383 Lys) variant. The son also had polyarthritis and his skin biopsy was suggestive of granulomatous inflammation. In the third family with two affected members, we found a mutation in NOD2 on exon 4 (c 1324C > T, p.Lys 442 Phe) which was described as pathogenic with only one report published till date. CONCLUSION: These three cases presented to us within the last two years and led to a diagnosis of BS in three other family members with discrete mutations (commonest to rarest) on the NOD2 gene in the three families.

GIANT RETINAL TEAR DETACHMENT: Clinical Presentation and Treatment Outcomes in 396 Patients.

PURPOSE: To study etiology, clinical presentation, anatomical, and functional outcomes of patients with giant retinal tear detachment at a tertiary eye institute. METHODS: Retrospective, consecutive case series of 396 patients (396 eyes) who underwent surgery were reviewed. Factors affecting the final anatomical and functional success were determined. RESULTS: Mean age was 37 years (range; 1-79 years), and 86% (n = 339) of the subjects were men. Trauma (21%) and high myopia (11%) were predisposing risk factors. Two hundred and seventy-seven eyes (70%) had giant retinal tear configuration of >180° and <270°, associated with partial retinal detachment in 282 (71%) eyes and macular detachment in 262 (66%) eyes. Primary surgery included pars plana vitrectomy (n = 240, 61%), pars plana vitrectomy with encirclage band (n = 152, 38%), or scleral buckle (n = 4, 1%). The mean follow-up duration was 15 months (median, 8.4 months; range, 3-83 months). Anatomical success after initial surgery was 64% (255 eyes), which improved to 78% (308 eyes) after undergoing a second vitreoretinal procedure for recurrent retinal detachment (53 eyes). Median visual acuity improved from 20/1,500 preoperatively to 20/400 at final follow-up ( P = 0.01), and 15% of eyes achieved postoperative visual acuity of 20/60 or better. Factors associated with poor anatomical success included age <16 years ( P = 0.005) and presenting visual acuity 20/400 or less ( P = 0.001). CONCLUSION: Trauma and myopia constituted the major risk factors for giant retinal tear detachment in our series. Surgery for giant retinal tear detachment managed with pars plana vitrectomy with or without encirclage band and silicone oil tamponade had good anatomical and favorable visual outcomes at last follow-up.

CLINICAL PREDICTORS OF TUBERCULAR RETINAL VASCULITIS IN A HIGH-ENDEMIC COUNTRY.

PURPOSE: To determine clinical signs suggestive of tubercular etiology in retinal vasculitis. METHODS: A retrospective comparative study of patients who presented with retinal vasculitis at three tertiary care centers in India. All patients underwent detailed clinical evaluation and tailored laboratory investigations for etiological diagnosis. Tubercular etiology was diagnosed on basis on the presence of retinal periphlebitis in association with ancillary evidence of systemic tuberculosis and exclusion of nontuberculosis entities. Patients with tubercular (Group A) and nontubercular (Group B) etiology were compared for demographic characteristics, supportive diagnostic evidence, and specific ocular signs. Statistical analysis was performed at 5% confidence levels. RESULTS: Of the 114 patients diagnosed with retinal vasculitis, Group A had 69 patients (100 eyes) and Group B had 45 patients (75 eyes). Active or healed subvascular lesions (P ≤ 0.0001), focal vascular tortuosity (P ≤ 0.0001), and occlusive vasculitis (P = 0.002) were significantly more common in Group A patients than in Group B patients. All three were independent predictors of tubercular etiology on multivariate regression analysis. CONCLUSION: The presence of healed or active subvascular lesions, focal vascular tortuosity, and occlusive vasculitis could be predictive of tubercular etiology in retinal vasculitis.

Topiramate induced bilateral hypopyon uveitis and choroidal detachment: a report of two cases and review of literature.

BACKGROUND: Topiramate (TPM) is a drug commonly used by neurophysicians and psychiatrists for a plethora of indications. Topiramate has been reported to induce acute angle closure glaucoma as an adverse effect. However, there is limited literature on Topiramate causing hypopyon uveitis and intense ocular inflammation. It is imperative for ophthalmologists as well as physicians to be aware of the potential sight threatening ocular adverse effects of Topiramate. We report 2 rare consecutive cases of severe hypopyon uveitis and choroidal detachments after using Topiramate. CASE PRESENTATION: Two patients presented with sudden onset of angle closure, bilateral hypopyon uveitis and choroidal detachments. On reassessing a detailed treatment history, it was found that both patient were taking oral Topiramate which had been started 2 weeks before the onset of ocular symptoms. The bilateral hypopyon and angle closure were considered to be induced by Topiramate and the drug was discontinued. The patients were started on oral and topical steroids which led to resolution of hypopyon uveitis and choroidal detachments. The visual acuity improved and the intraocular pressure also got normalised in both the cases. CONCLUSIONS: Topiramate can lead to a bilateral hypopyon uveitis and severe ocular inflammation. An urgent cessation of topiramate along with topical and systemic steroids is required to prevent serious complications.

Combinatorial Use of Both Epigenetic and Non-Epigenetic Mechanisms to Efficiently Reactivate HIV Latency.

The persistence of latent HIV provirus pools in different resting CD4+ cell subsets remains the greatest obstacle in the current efforts to treat and cure HIV infection. Recent efforts to purge out latently infected memory CD4+ T-cells using latency-reversing agents have failed in clinical trials. This review discusses the epigenetic and non-epigenetic mechanisms of HIV latency control, major limitations of the current approaches of using latency-reversing agents to reactivate HIV latency in resting CD4+ T-cells, and potential solutions to these limitations.

ENTEROCOCCUS ENDOPHTHALMITIS: Clinical Settings, Antimicrobial Susceptibility, and Management Outcomes.

PURPOSE: To report the clinical presentation and management outcome of patients with endophthalmitis caused by Enterococcus species and to report the susceptibility profile of the isolates. METHODS: Twenty-nine cases with culture-proven Enterococcus endophthalmitis from January 2005 to May 2018 underwent vitrectomy/vitreous biopsy, intravitreal antibiotic with or without additional procedures. The undiluted vitreous was subjected to microbiologic evaluation. A favorable anatomical outcome was defined as preservation of the globe, absence of hypotony, attached retina, and absence of active inflammation at the last visit. Favorable visual outcome was final visual acuity ≥20/400. RESULTS: There were 24 men (82.8%). Mean age at presentation was 32.89 ± 25.25 years (median 24 years). Inciting event was open globe injury in 18 (62%), endogenous in 5 (17.24%), postcataract surgery in 3 (10.34%), postscleral buckling in 2 (6.89%), and postkeratoplasty in 1 (3.44%). Enterococcus casseliflavus was the commonest species isolated (14/29, 48.27%) followed by E. faecalis (9/29, 31%). Susceptibility to vancomycin was seen in 27/29 isolates (93%). Visual acuity was ≤20/400 in all eyes at presentation and ≥20/400 in 10/29 cases (34.48%) at final visit. Anatomical success was seen in 18/29 eyes (62%). Corneal involvement was high at 24/29 eyes (82.75%). CONCLUSION: Enterococcus is not an uncommon organism in the setting of endophthalmitis after open globe injury. Resistance to vancomycin is rare. Multidrug resistance pattern is restricted to E. faecalis. Visual outcome is poor despite early and appropriate therapy due to inherent organism virulence.

SURGICAL OUTCOMES AFTER INVERTED INTERNAL LIMITING MEMBRANE FLAP VERSUS CONVENTIONAL PEELING FOR VERY LARGE MACULAR HOLES.

PURPOSE: To evaluate the anatomical and visual outcomes of inverted flap technique of peeling of internal limiting membrane (ILM) versus standard peeling of ILM for macular holes of basal diameter more than 800 µm. METHODS: Patients with very large idiopathic macular holes more than 800 µm in basal diameter (ranging from 243 µm to 840 µm in minimum diameter) were retrospectively included in the study. In Group A, 18 eyes of 18 patients underwent ILM peeling using the inverted flap technique. In Group B, 18 eyes of 18 patients underwent conventional ILM peeling. The primary endpoint was the rate of hole closure at 6 months after surgery. The secondary outcome measure was the change in best-corrected visual acuity at 6 months after surgery. RESULTS: There were no significant differences in ocular characteristics of the study groups at baseline except for the age distribution. Mean macular hole diameter was 1,162.8 ± 206.0 µm and 1,229.6 ± 228.1 µm in Group A and Group B, respectively. The hole closure rate was 88.9% (16/18) in Group A and 77.8% (14/18) in Group B (P = 0.66). The mean gain in best-corrected visual acuity was higher in Group A than in Group B (P = 0.12) at 6 months, but this was not statistically significant. There were no severe ocular adverse events in either group. CONCLUSION: In this multicenter series, inverted ILM flap technique did not lead to significantly higher anatomical closure rates than conventional ILM peeling in large macular holes more than 800 µm in diameter.

CLINICAL PRESENTATION, MICROBIOLOGIC PROFILE AND FACTORS PREDICTING OUTCOMES IN BACILLUS ENDOPHTHALMITIS.

PURPOSE: To describe the clinical presentation, microbiologic profile, and factors predicting outcomes in Bacillus endophthalmitis. METHODS: Retrospective interventional case series. Eighty-six patients with culture-proven Bacillus endophthalmitis, from January 2001 to December 2015, underwent vitrectomy/vitreous biopsy and intravitreal antibiotic with or without steroid as appropriate. The undiluted vitreous biopsy was subjected to microbiologic evaluation. The duration of symptoms, presenting visual acuity, organisms isolated, influence of intravitreal dexamethasone with intravitreal antibiotics, and type of initial intervention were examined for any clinical and statistical correlation in terms of odds ratio with the final visual outcome. RESULTS: Trauma was the commonest etiology (n = 75; 87.2%). Mixed infection with other bacteria was seen in 11 patients. All Bacillus species were sensitive to gentamicin followed by ciprofloxacin (n = 85; 98.83%) and vancomycin (n = 81; 94.18%). Odds in favor of a favorable visual outcome were seen with clinical treatment within 48 hours of the symptoms (OR 25.47, 95% CI 2.45-254.16, P = 0.006), better presenting vision (OR 31.21, 95% CI 2.96-323.64, P = 0.004), and absence of polymicrobial infection (OR 18.03, 95% CI 0.9-344.4, P = 0.05). Only 20% of all treated patients regained ambulatory vision, and one fifth of all of them developed phthisis. CONCLUSION: Patients diagnosed with Bacillus endophthalmitis merit aggressive vitreous intervention guided by the culture-sensitivity report. Despite early and appropriate treat ment, the outcomes are generally poor.

Dysbiosis in the Gut Bacterial Microbiome of Patients with Uveitis, an Inflammatory Disease of the Eye.

Uveitis (UVT), an inflammatory disease of the eye significantly contributes to vision impairment and blindness. Uveitis is associated with systemic infectious and autoimmune diseases, but in most cases, the aetiology remains unidentified. Dysbiosis in the gut microbiome has been implicated in autoimmune diseases, inflammatory diseases, cancers and mental disorders. In a mice model of autoimmune UVT, it was observed that manipulating the gut microbiome reduces the inflammation and disease severity. Further, alterations in the bacterial gut microbiome and their metabolites were reported in UVT patients from a Chinese cohort. Hence, it is worth comparing the bacterial gut microbiome of UVT patients with that of healthy controls (HC) to ascertain whether dysbiosis of the gut microbiome has implications in UVT. Our analyses showed reduced diversity of several anti-inflammatory organisms including Faecalibacterium, Bacteroides, Lachnospira, Ruminococcus and members of Lachnospiraceae and Ruminococcaceae families, and enrichment of Prevotella (proinflammatory) and Streptococcus (pathogenic) OTUs in UVT microbiomes compared to HC. In addition, decrease in probiotic and antibacterial organisms was observed in UVT compared to HC microbiomes. Heatmap and PCoA plots also indicated significant variations in the microbiomes of UVT versus HC. This is the first study demonstrating dysbiosis in the gut bacterial communities of UVT patients in an Indian cohort and suggests a role of the gut microbiome in the pathophysiology of UVT.

The effects of cocaine on HIV transcription.

Illicit drug users are a high-risk population for infection with the human immunodeficiency virus (HIV). A strong correlation exists between prohibited drug use and an increased rate of HIV transmission. Cocaine stands out as one of the most frequently abused illicit drugs, and its use is correlated with HIV infection and disease progression. The central nervous system (CNS) is a common target for both drugs of abuse and HIV, and cocaine intake further accelerates neuronal injury in HIV patients. Although the high incidence of HIV infection in illicit drug abusers is primarily due to high-risk activities such as needle sharing and unprotected sex, several studies have demonstrated that cocaine enhances the rate of HIV gene expression and replication by activating various signal transduction pathways and downstream transcription factors. In order to generate mature HIV genomic transcript, HIV gene expression has to pass through both the initiation and elongation phases of transcription, which requires discrete transcription factors. In this review, we will provide a detailed analysis of the molecular mechanisms that regulate HIV transcription and discuss how cocaine modulates those mechanisms to upregulate HIV transcription and eventually HIV replication.

SCLERAL BUCKLING WITH WIDE-ANGLED ENDOILLUMINATION AS A SURGICAL EDUCATIONAL TOOL.

PURPOSE: To describe a technique of wide-angle viewing as an educational tool in scleral buckling for rhegmatogenous retinal detachment. METHODS: Retrospective comparative study of the reported technique was performed. Fourteen consecutive patients each who underwent Chandelier-assisted scleral buckling (CSB) or standard scleral buckling (SSB) using indirect ophthalmoscope were included. The primary outcome measure was the proportion of eyes that had successful reattachment of retina. RESULTS: Mean study eye baseline visual acuity was 20/160 in the CSB group and 20/320 in SSB group. The primary reattachment rate was similar, with 13 of 14 eyes (92.85%) successfully attached in the CSB group and 12 of 14 eyes (85.71%) in the SSB group. The mean visual acuity improved from 20 of 160 to 20 of 80 in the CSB group, and 20 of 320 to 20 of 160 in the SSB group. The surgical time was significantly less in the CSB group (77.85 ± 16.37 minutes) compared with the SSB group (95.71 ± 26.59 minutes, P = 0.037). CONCLUSION: Chandelier-assisted buckling had similar outcomes compared with standard buckling. It could be used as a valuable educational tool for teaching fellows by allowing them to simultaneously view the operative steps along with the surgeon.

Reactivation of latent HIV-1 provirus via targeting protein phosphatase-1.

BACKGROUND: HIV-1 escapes antiretroviral drugs by integrating into the host DNA and forming a latent transcriptionally silent HIV-1 provirus. This provirus presents the major hurdle in HIV-1 eradication and cure. Transcriptional activation, which is prerequisite for reactivation and the eradication of latent proviruses, is impaired in latently infected T cells due to the lack of host transcription factors, primarily NF-κB and P-TEFb (CDK9/cyclin T1). We and others previously showed that protein phosphatase-1 (PP1) regulates HIV-1 transcription by modulating CDK9 phosphorylation. Recently we have developed a panel of small molecular compounds targeting a non-catalytic site of PP1. RESULTS: Here we generated a new class of sulfonamide-containing compounds that activated HIV-1 in acute and latently infected cells. Among the tested molecules, a small molecule activator of PP1 (SMAPP1) induced both HIV-1 replication and reactivation of latent HIV-1 in chronically infected cultured and primary cells. In vitro, SMAPP1 interacted with PP1 and increased PP1 activity toward a recombinant substrate. Treatment with SMAPP1 increased phosphorylation of CDK9's Ser90 and Thr186 residues, but not Ser175. Proteomic analysis showed upregulation of P-TEFb and PP1 related proteins, including PP1 regulatory subunit Sds22 in SMAPP1-treated T cells. Docking analysis identified a PP1 binding site for SMAPP1 located within the C-terminal binding pocket of PP1. CONCLUSION: We identified a novel class of PP1-targeting compounds that reactivate latent HIV-1 provirus by targeting PP1, increasing CDK9 phosphorylation and enhancing HIV transcription. This compound represents a novel candidate for anti-HIV-1 therapeutics aiming at eradication of latent HIV-1 reservoirs.

Update on non-infectious uveitis treatment: anti-TNF-alpha and beyond.

Non-infectious uveitis (NIU) encompasses a range of conditions marked by inflammation within various layers of the eye. NIU is a significant contributor to irreversible vision loss among the working-age population in developed countries. The aim of treating uveitis is to manage inflammation, prevent its recurrences and to restore or salvage vision. Presently, the standard treatment protocol for NIU involves initiating corticosteroids as the primary therapeutic agents, although more aggressive approaches and steroid sparing agent may be necessary in certain cases. These advanced treatments option include synthetic immunosuppressants like antimetabolites, calcineurin inhibitors and alkylating agents. For patients who exhibit an intolerance or resistance to corticosteroids and conventional immunosuppressive therapies, biologic agents have emerged as a promising alternative. Notably, among the biologic treatments evaluated, TNF-α inhibitors, anti-CD20 therapy and alkylating agents have shown considerable efficacy. In this review, we delve into the latest evidence surrounding the effectiveness of biologic therapy and introduce novel therapeutic strategies targeting immune components as potential avenues for advancing treatment of NIU.

Intraocular Bioadhesives in Vitreoretinal Surgeries: A Systematic Review.

BACKGROUND: Bioadhesion is the ability of materials to adhere to biological surfaces. Bioadhesives are substances which induce or promote bioadhesion. The internal application of bioadhesives is gaining popularity in recent years and is being increasingly utilized in vitreoretinal surgeries. The aim of this review is to discuss the various bioadhesives and their applications in vitreoretinal surgeries. METHODS: PubMed, Google Scholar, ePub and Cochrane library database were used for literature selection. Keywords such as vitreoretinal surgery, bioadhesives, intraocular bioadhesives, glue, fibrin glue, cyanoacrylate glue and transforming growth factor were used individually and in differing combinations to perform a comprehensive systematic literature search. RESULTS: A total of 47 papers were retrieved and included in this review. Cyanoacrylate glue was the first bioadhesive to be utilized for vitreoretinal surgery in human eyes in 1976. The most common indications for the use of bioadhesives were in optic disc pit maculopathy, macular holes and rhegmatogenous retinal detachments. CONCLUSION: The use of intraocular bioadhesives in vitreoretinal surgery represents a significant and evolving area of interest within ophthalmic research. While the pioneering use of cyanoacrylate glue, fibrin glue and transforming growth factor beta demonstrated the possible use of intraocular adhesives, fibrin glue is the most widely used intraocular bioadhesive in vitreoretinal surgery.

Suspected Retinal Toxicity After Multiple Intravitreal Ganciclovir Injections in a Patient of CMV Retinitis.

PURPOSE: Intravitreal Ganciclovir has been one of the treatments of choice for cytomegalovirus (CMV) retinitis and has been used extensively for its treatment since 1987. It has not been shown to have any major adverse effects. There are no reports on any retinal toxicity even after multiple, repeated injections. Herein, we report a rare case of retinal toxicity after multiple intravitreal injections in a patient of CMV retinitis. CASE REPORT: A 69-year-old one eyed male, who was on oral corticosteroids and systemic immunosuppression for Granulomatosis with Polyangiitis, presented with CMV retinitis in both eyes. His visual acuity was 20/60 in his right eye and no perception of light in his left eye. He was treated with multiple injections of intravitreal Ganciclovir in his right eye. The left eye was not treated since it had no vision potential. The right eye of the patient which had received multiple injections went on to developed a progressive diffuse atrophy of Retinal Pigment Epithelium (RPE). No such changes were noted in the left eye of the patient. CONCLUSION AND IMPORTANCE: We present a case of progressive diffuse RPE atrophy as a result of toxicity of intravitreal ganciclovir injections. It is important to be aware of this rare potential toxicity of intravitreal Ganciclovir.

Fibrin-Glue-Assisted Surgery for Idiopathic Macular Holes.

METHODS: This pilot clinical trial included 10 eyes of 10 patients with idiopathic MH, where PPV along with ILMP was done. Fibrin glue was used as a tamponade, and no postoperative positioning was given to any patient. The primary outcome measure was successful anatomical closure of the MH. The secondary outcome measures were postoperative improvement in best-corrected visual acuity (BCVA) and any complications of the procedure. RESULTS: The median age of patients was 62.5 years. Eight eyes were pseudophakic and two were phakic. The mean basal diameter of the MH was 1193 microns. The mean minimal linear diameter was 652 microns. Successful anatomic closure of MH was achieved in eight cases. The median BCVA improved from a Snellen equivalent of 20/100 preoperatively to 20/60 at 1 month postoperatively. The median follow-up period was 4 months. CONCLUSION: The findings of this study suggest that the use of fibrin glue can be useful in patients where postoperative positioning is difficult.