Unveiling biomarkers and therapeutic targets in IgA nephropathy through large-scale blood transcriptome analysis.

INTRODUCTION: IgA nephropathy (IgAN) is the most prevalent form of glomerulonephritis. Unfortunately, molecular biomarkers for IgAN derived from omics studies are still lacking. This research aims to identify critical genes associated with IgAN through large-scale blood transcriptome analysis. METHODS: We constructed novel blood transcriptome profiles from peripheral blood mononuclear cells (PBMCs) of 53 Chinese IgAN patients and 28 healthy individuals. Our analysis included GO, KEGG, and GSEA for biological pathways. We analyzed immune cell profiles with CIBERSORT and constructed PPI networks with STRING, visualized in Cytoscape. Key differentially expressed genes (DEGs) were identified using CytoHubba and MCODE. We assessed the correlation between gene expressions and clinical data to evaluate clinical significance and identified hub genes through machine learning, validated with an open-access dataset. Potential drugs were explored using the CMap database. RESULTS: We identified 333 DEGs between IgAN patients and healthy controls, mainly related to immune response and inflammation. Key pathways included NK cell mediated cytotoxicity, complement and coagulation cascades, antigen processing, and B cell receptor signaling. Cytoscape revealed 16 clinically significant genes (including KIR2DL1, KIR2DL3, VISIG4, C1QB, and C1QC, associated with sub-phenotype and prognosis). Machine learning identified two hub genes (KLRC1 and C1QB) for a diagnostic model of IgAN with 0.92 accuracy, validated at 1.00 against the GSE125818 dataset. Sirolimus, calcifediol, and efaproxiral were suggested as potential therapeutic agents. CONCLUSION: Key DEGs, particularly VISIG4, KLRC1, and C1QB, emerge as potential specific markers for IgAN, paving the way for future targeted personalized treatment options.

Tight adherent feature on optical coherence tomography predict postoperative visual outcome in epiretinal membrane eyes.

BACKGROUND: To identify the predictive parameter among preoperative measurements that best predicts postoperative visual outcome in the epiretinal membrane (ERM). METHODS: Thirty-three consecutive patients with idiopathic unilateral ERM patients between 2015 and 2018 were enrolled. Nineteen healthy normal eyes were selected as an independent age-matched group. Based on preoperative optical coherence tomography (OCT), we further divided the patients with ERM into two groups: type 1, loosely attached ERM, and type 2, tight adherent ERM. We documented the vision and thickness of various retinal layers: nerve fiber layer, ganglion cell layer, inner plexiform layer (GCL + IPL), inner nuclear layer (INL), outer retinal layer (ORL), and retinal pigment epithelium/Bruch complex layer before and after the surgery. The association between postoperative visual acuity and these variables was analyzed using multiple linear regression analysis. RESULTS: All retinal layers of ERM eyes were thicker than the normal eyes (P < 0.05). Among ERMs, we identified 11 eyes with type 1 adhesions and 22 eyes with type 2 adhesions. The preoperative GCL + IPL layers were significantly thicker in type 2 patients than in type 1 patients (93.67 ± 33.03 um vs 167.71 ± 13.77 um; P = 0.023). Greater GCL + IPL thickness was correlated with a worse postoperative visual acuity and multiple linear regression analysis showed that GCL + IPL thickness was an independent predictor of postoperative visual acuity (VA) (beta value = 0.689; P = 0.012). A greater thickness of GCL + IPL layers of type 2 patients had worse postoperative best-corrected visual acuity (BCVA) (P = 0.028). Ectopic inner foveal layers with disappearance of fovea pit were persistently presented in OCT profiles of both groups. CONCLUSION: Idiopathic ERM demonstrated significantly thicker inner retinal layers (GCL + IPL and INL). However, the ORL thickness was similar between the normal eyes and ERM eyes. The preoperative GCL + IPL layers were significantly thicker in patients with type 2 ERM than that in patients with type 1 ERM. The increase in GCL + IPL thickness was significantly correlated with worse postoperative visual outcomes.

Real-life experience of ranibizumab for diabetic macular edema in Taiwan.

PURPOSE: To evaluate the visual and anatomical outcomes of intravitreal ranibizumab for diabetic macular edema (DME) in the healthcare system of Taiwan. METHODS: A total of 39 eyes from 39 patients were retrospectively enrolled in the study. All eyes that fulfilled the key criteria, including a baseline vision between 20 and 70 ETDRS letters and a minimum central macular thickness (CMT) of 300 µm, had at least 3 monthly loading injections of ranibizumab in a year. Macular laser or posterior subtenon injections of triamcinolone acetonide (PSTA) could be performed as supplementary treatments following loading injections. Primary outcomes include best-corrected visual acuity and CMT. RESULTS: Patients' vision improved from 46.5 ± 15.3 letters at baseline to 51.4 ± 16.6 letters at 12 months (p = 0.031). Mean CMT at baseline was 406 ± 105 µm, which decreased to 329 ± 108 µm (p = 0.002). At 12 months, 44.4% of eyes with total injection number < 5 and 42.9% with injection number ≥ 5 achieved a gain in vision that was 10 letters or more. A total of 5 injections or more did not lead to a better visual gain in comparison with only 3-4 injections (p = 0.71), and both had similar number of supplementary treatments (p = 0.43). Monthly reinjections of ranibizumab resulted in a lower likelihood of visual loss of 10 or 15 letters (p = 0.019 and 0.015, respectively, adjusted for age, baseline vision, severity of diabetic retinopathy and the presence of previous treatments); however, supplementary macular lasers, PSTA or ranibizumab without monthly reinjections did not (all p > 0.05). The average number of injections was 4.3 ± 1.0. CONCLUSION: Treatment for DME with at least three monthly ranibizumab loading injections, with or without other supplementary treatments, is effective at 12 months thereafter. Two monthly reinjections of ranibizumab, while not significantly increasing vision, may have a role in preventing visual loss.

Comparison between intravitreal bevacizumab and posterior sub-tenon injection of triamcinolone acetonide in macular edema secondary to retinal vein occlusion.

AIM: To compare the efficacy and safety between posterior sub-tenon injection of triamcinolone acetonide (PSTA) and intravitreal injection of bevacizumab (Avastin) (IVIA) in the treatment of macular edema secondary to retinal vein occlusion. PATIENTS AND METHODS: A total of 45 eyes were retrospectively enrolled (23 eyes with intravitreal bevacizumab and 22 eyes with posterior sub-tenon triamcinolone acetonide). Main endpoints included logMAR of best-corrected visual acuity (BCVA), central macular thickness (CMT), and intraocular pressure (IOP) before and after treatment at 6 months. RESULTS: The mean logMAR improved from 0.78 to 0.56 at 6 months for intravitreal bevacizumab (p=0.001), and from 0.91 to 0.79 and 0.87 at 3 and 6 months (p=0.038 and 0.13), respectively, for sub-tenon triamcinolone acetonide. At 6 months, the BCVA was significantly better in the bevacizumab group (p=0.02). Both groups' mean CMT significantly improved, from 478 µm at baseline to 295 µm at 6 months in IVIA group (p<0.001) and from 419 µm at baseline to 350 µm in PSTA group (p=0.012); however, this was not different between the groups at 6 months (p=0.065). Recurrence of macular edema was not different between the groups either (p=0.08). Poorer final vision was associated with poorer baseline BCVA and diagnosis of central retinal vein occlusion after adjustment for age and sex (p<0.001 and 0.012, respectively). Significant elevation of IOP was noted at 3 months in the PSTA group, but declined at 6 months compared with baseline (p=0.002 and 0.41, respectively). CONCLUSION: Intravitreal bevacizumab seemed to achieve better visual acuity compared with posterior sub-tenon injections of triamcinolone acetonide at 6 months, while CMT was comparable. PSTA still resulted in transient IOP elevation.

Impact of metabolic control on macular thickness in diabetic macular oedema.

PURPOSE: To investigate the impact of metabolic control on macular thickness measured using optical coherence tomography in patients with diabetic retinopathy with or without macular oedema. METHODS: A total of 124 patients with diabetic retinopathy ( n = 70 without macular oedema and n = 54 with macular oedema) were enrolled. Optical coherence tomography parameters measured included central macular thickness and total macular volume. Metabolic factors with correlation to optical coherence tomography parameters were fasting plasma glucose, glycosylated haemoglobin, triglyceride, low-density lipoprotein and estimated glomerular filtration rate. Multiple linear regression models were used to evaluate associations between optical coherence tomography parameters and metabolic factors. RESULTS: Higher glycosylated haemoglobin values were correlated with increased central macular thickness in patients without macular oedema ( R = 0.289, p = 0.015), whereas glycosylated haemoglobin values were inversely associated with central macular thickness in patients with macular oedema ( R = -0.374, p = 0.005). Both were found to be statistically significant after adjusting for age, sex and diabetic retinopathy severity in addition to other metabolic factors ( p = 0.009 and p = 0.002, respectively). CONCLUSION: Strict metabolic control may not be associated with better macular thickness in diabetic patients with co-existing macular oedema.

Systemic Associations with Residual Subretinal Fluid after Ranibizumab in Diabetic Macular Edema.

PURPOSE: To investigate the impact of systemic diseases on the occurrence of subretinal fluid (SRF) in diabetic macular edema (DME) and prognostic factors for residual SRF following three consecutive monthly intravitreal ranibizumab. METHODS: Ninety-seven eyes from 68 patients with DME who completed 3 consecutive monthly injections of ranibizumab were enrolled. Systemic parameters mainly included chronic kidney disease (CKD), hypertension, HbA1c, and insulin dependence. Renal parameters for CKD were serum creatinine, estimated glomerular filtration rate (eGFR), and serum albumin. Ocular factors were baseline central macular thickness (CMT), severity of diabetic retinopathy (DR), and status of panretinal photocoagulation (PRP). RESULTS: Chronic kidney disease had significant correlation with baseline SRF (R = 0.397, p < 0.001 after partial correlation with adjustment for age and DR severity). As for CKD, lower serum albumin, but not eGFR or serum creatinine, was associated with baseline presence of SRF (p = 0.026, p = 0.08 and p = 0.53, resp., after adjustment for age and DR severity). Overall, lower eGFR and lower HbA1c values, contrary to popular belief, predicted the presence of residual SRF following intravitreal injections (p = 0.016 and p < 0.001, resp.). CONCLUSIONS: Tight sugar control and poorer baseline kidney function may slow the resorption of SRF after anti-VEGF injections in patients with DME in the short term.

Biodegradable balloon-expandable self-locking polycaprolactone stents as buckling explants for the treatment of retinal detachment: an in vitro and in vivo study.

The purpose of this report was to develop biodegradable balloon-expandable self-locking poly(ε-caprolactone) (PCL) stents for the treatment of retinal detachment. To create the biodegradable stents, polycaprolactone components were first fabricated by a laboratory-scale microinjection molding machine. The components were then assembled into mesh-like stents of 6 and 8 mm in diameter. A special geometry of the components was designed to self-lock the assembled stents after being expanded by balloons. Characterization of the biodegradable PCL stents was carried out. PCL stents exhibited comparable mechanical properties with that of silicone sponge. Neither significant amount of collapse pressure reduction nor weight loss of the stents was observed after being submerged in phosphate buffered saline for 30 days. In addition, the stents were also implanted in the episcleral space of 10 New Zealand white rabbits. The stents were placed in radial direction and left unsutured after balloon expansion. The stents achieved an efficient buckling effect in echographic and fundus photographic examinations. The ocular pressure was significantly elevated after stent implantation and gradually normalized after the second week. The computed tomography studies verified the hypothesis of minimal migration of the PCL stents. The in vivo result suggests that balloon-expandable biodegradable stents can potentially serve as an ideal indenting biomaterial in retinal detachment surgery.

The application of tissue engineering in reversing mitomycin C-induced ischemic conjunctiva.

The purpose of this study is to evaluate the angiogenic potential of collagen-glycosaminoglycan (CG) matrices in mitomycin C-induced ischemic conjunctival defect, in New Zealand white rabbits. After creating a conjunctival defect at the center of ischemic conjunctiva, a CG matrix was implanted into subconjunctival space to evaluate the conjunctival reepithelialization and angiogenesis during the wound healing process. In the grafted group, the vessel count of the healed conjunctiva was substantially elevated by two fold within the initial 4 weeks and the increased vascular content originated mostly from the fornix site. The rate of conjunctival reepithelialization was not retarded in the grafted group, and the final thickness of healed conjunctiva was similar in both grafted and ungrafted groups. The histological studies revealed that the collagen matrix did not elicit pronounced inflammatory reaction and the regenerated conjunctiva showed loosely arranged collagen deposition without significant scar formation. The α SMA staining positive myofibroblasts were identified in the acute inflammatory stage and were absent, 8 weeks after implantation in both groups. The results indicated that the porous collagen scaffold was able to enhance vascularization and physiological recovery of ischemic conjunctival defect, implying a potential alternative therapy for the ischemic leaking bleb after glaucoma filtrating surgery in ophthalmic practices.

Transcleral posterior chamber paracentesis for angle closure glaucoma secondary to posterior chamber gas entrapment after intravitreal c3f8 injection in a phakic eye.

PURPOSE: The purpose of this study was to describe a new technique for treating a case of angle closure glaucoma secondary to posterior chamber (PC) gas entrapment after intravitreal C3F8 injection. METHODS: Retrospective case report. RESULTS: A 26-year-old woman received intravitreal injection of 0.4 mL of C3F8 after segmental scleral buckling for retinal detachment of her phakic eye. Prone positioning was not maintained postoperatively, and severe eye pain developed within hours of surgery. Intraocular pressure increased to 50 mmHg, and PC was found to be filled with gas accompanying with 360° iridocorneal apposition and angle closure. Transcleral PC paracentesis was performed to evacuate the gas. Anterior chamber angle was reopened inferiorly, and intraocular pressure dropped to 13 mmHg immediately and remained normal. No evidence of lens or iris damage was noted. Postoperatively, the vision improved to 20/25 without major sequelae. CONCLUSION: Posterior chamber gas entrapment with anterior chamber collapse is a rare complication of intravitreal gas injection in phakic eyes. Transcleral PC paracentesis is a safe way to treat angle closure glaucoma secondary to PC gas entrapment.

Steady antibiotic release from biodegradable beads in the pleural cavity: an in vitro and in vivo study.

BACKGROUND: Inadequate localized drug concentrations and systemic adverse effects are among the concerns when regional infections are treated with systemic antibiotics. We designed and fabricated a poly(D,L)-lactide-co-glycolide (PLGA)-based biodegradable drug delivery system and evaluated the release of antibiotics both in vitro and in vivo. METHODS: PLGA copolymer and penicillin G sodium were mixed, compressed, and sintered to fabricate biodegradable antibiotic beads. The beads were placed in phosphate-buffered saline to test the characteristics of in vitro drug release. The beads then were introduced into the pleural cavities through chest tubes of six New Zealand white rabbits. Daily pleural effusion was collected to measure the antibiotic concentration and bacterial inhibitory characteristics. RESULTS: Forty percent of the penicillin was released in the first day in the in vitro study. The rest of the antibiotic was then gradually released in the following 30 days. All six animals survived the experiment. The initial surge of drug release was less significant in the pleural cavity than in the phosphate-buffered saline. The drug concentrations were well above the minimum inhibitory concentration breakpoint for penicillin susceptibility throughout the study period in both in vitro (30 days) and in vivo (14 days) studies. CONCLUSIONS: These preliminary findings demonstrated that the biodegradable PLGA antibiotic beads could achieve a fairly steady antibiotic release in the pleural cavity for at least 2 weeks. This drug delivery system may have the potential to serve as an adjuvant treatment of pleural cavity infection.

Central retinal vein occlusion as the initial manifestation of LHON / MELAS overlap syndrome with mitochondrial DNA G13513A mutation--case report and literature review.

BACKGROUND: The aim of this paper is to describe the clinical features and molecular findings of a unique case of Leber's hereditary optic neuropathy (LHON)/mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) overlap syndrome presenting as nonischemic central retinal vein occlusion (CRVO). METHODS: An 11-year-old Chinese girl presented with sudden onset of bilateral blurred vision. The clinical history, imaging studies, and molecular analysis results were reviewed. The PubMed and OVID databases were used for literature review. RESULTS: Nonischemic CRVO in the subject's right eye and tortuosity of small and medium-sized retinal arterioles in the left eye were found at initial presentation. Bilateral optic disc pallor was then noted with recovery of CRVO. Severe headache and several stroke-like episodes occurred subsequently, with elevated lactate levels in serum and cerebrospinal fluid. LHON/MELAS overlap syndrome was diagnosed, and mitochondrial DNA sequencing revealed G13513A heteroplasmic mutation. Vision was 20/30 in the right eye and 20/800 in the left eye at the last visit. CONCLUSIONS: Mitochondrial DNA G13513A mutation can cause LHON/MELAS overlap syndrome. Nonischemic CRVO is a rare manifestation of LHON/MELAS. Atypical findings in cases of LHON should raise the suspicion of overlap syndrome or other mitochondrial diseases.

Experimental absorbable stent permits airway remodeling.

OBJECTIVE: Despite metallic and silicone stents being effective in treating various airway lesions, many concerns still remain. A bioresorbable stent that scaffolds the airway lumen and dissolves after the remodeling process is completed has advantages over metallic and silicone stents. We designed and fabricated a new mesh-type bioresorbable stent with a backbone of polycaprolactone (PCL), and evaluated its safety and biocompatibility in a rabbit trachea model. METHODS: The PCL stent was fabricated by a laboratory-made microinjection molding machine. In vitro mechanical strength of the PCL stents was tested and compared to that of commercial silicone stents. The bioresorbable stents were surgically implanted into the cervical trachea of New Zealand white rabbits (n=6). Animals received bronchoscopic examination at 1, 2, 4, 8, and 12 weeks after surgery. Histological examination was completed to evaluate the biocompatibility of the stents. RESULTS: No animals died during the period of study. Distal stent migration was noted in 1 rabbit. In-stent secretion accumulation was found in 2 rabbits. Histological examination showed intact ciliated epithelium and marked leukocyte infiltration in the submucosa of the stented area at 10 and 28 weeks. Stent degradation was minimal, and the mechanical strength was well preserved at the end of 33 weeks. CONCLUSIONS: These preliminary findings showed good safety and biocompatibility of the new PCL stent when used in the airway remodeling. PCL could be a promising bioresorbable material for stent design if prolonged degradation time is required.

Solvent-free biodegradable scleral plugs providing sustained release of vancomycin, amikacin, and dexamethasone--an in vivo study.

Delivering effective drugs at sufficiently high concentrations to the area of infection is a standard treatment for infectious disease, such as endophthalmitis. This is currently done by empirical trans pars plana intravitreal injection of both antibiotics directed against gram-positive and gram-negative microorganisms and steroids. However, injections by needles repeatedly may increase the risks of intraocular infection and hemorrhage, as well as retinal detachment. This article explores the alternative of using biodegradable polymers as scleral plugs for a long-term drug release in vivo. To manufacture plugs, poly(lactide-glycolide) copolymers were first mixed with vancomycin, amikacin, and dexamethasone. The mixture was compressed and sintered at 55 degrees C to form scleral plugs 1.4 mm in diameter. Biodegradable scleral plugs released high concentrations of antibiotics (well above the minimum inhibitory concentrations, MIC) and steroids in vivo for the period of time needed to treat intraocular infection. In addition, no major complications such as infectious or sterile endophthalmitis, retinal detachment, ocular phthisis, or uvea protrusion at sclerotomy site were observed throughout the experiment. The sclerotomy wound healed after total degradation of the scleral implants without leakage or local necrosis. Antibiotic/steroid-impregnated biodegradable scleral plugs may have a potential role in the treatment of various intraocular infections.

Sustained release of ganciclovir and foscarnet from biodegradable scleral plugs for the treatment of cytomegalovirus retinitis.

The purpose of this report was to develop solvent-free biodegradable scleral plugs for simultaneous ganciclovir and foscarnet delivery for cytomegalovirus retinitis treatment. To fabricate a biodegradable plug, polylactide-polyglycolide copolymers were pre-mixed with the drugs. The mixture was then compression molded and sintered to form a compact scleral plug. The drug release features were monitored with HPLC assay both in vitro and in vivo. Both drugs showed a biphasic release curvature with an initial burst and followed by a second sustained release phase and maintained at therapeutic level for 3-4 weeks. As compared to ganciclovir, foscarnet was released faster in initial phase, but later, showed extended retention in vitreous humor. For biocompatibility analysis, dark-adapted flash electroretinography was performed, and the a-wave and b-wave amplitudes were statistically equal before and after the scleral plug implantation. Finally, serial microstructure changes of releasing scleral plugs were evaluated with scanning electron microscope. The scleral plug surface showed progressive transformation from granular solid surface to smoothen and cavitated appearance.

In vitro elution of vancomycin/amikacin/steroid from solvent-free biodegradable scleral plugs.

The purpose of this report was to develop solvent-free biodegradable scleral plugs for vancomycin, amikacin and dexamethasone delivery for endophthalmitis treatment. To fabricate a biodegradable plug, polylactide-polyglycolide copolymers were pre-mixed with the drugs. The mixture was then compression molded and sintered to form a scleral plug of 1.4mm in diameter. An elution method was utilized to characterize the in vitro release characteristics of the antibiotics and the steroids over a 14-day period. The HPLC analysis and bacterial inhibition test showed that biodegradable scleral plugs released a high concentration resulting in significant activity of vancomycin and amikacin (well above the minimum inhibition concentrations) and dexamethasone in vitro, for the period of time needed to treat intraocular infection. A bacterial inhibition test was carried out to determine the relative activity of the released antibiotics. The activities of the eluted vancomycin and amikacin ranged from 69% to 89% and from 66% to 88%, respectively. In addition, the experimental result suggests that one will be able to reduce the drug release rate and prolong the total release period of the plugs by adopting a lower antibiotic/steroid to polymer ratio, increasing the sintering temperature, or increasing the compression pressures.