ABSTRACT
Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD) is an age-related macular degeneration-like (AMD-like) retinal dystrophy caused by an autosomal dominant R345W mutation in the secreted glycoprotein, fibulin-3 (F3). To identify new small molecules that reduce F3 production in retinal pigmented epithelium (RPE) cells, we knocked-in a luminescent peptide tag (HiBiT) into the endogenous F3 locus that enabled simple, sensitive, and high-throughput detection of the protein. The GSK3 inhibitor, CHIR99021 (CHIR), significantly reduced F3 burden (expression, secretion, and intracellular levels) in immortalized RPE and non-RPE cells. Low-level, long-term CHIR treatment promoted remodeling of the RPE extracellular matrix, reducing sub-RPE deposit-associated proteins (e.g., amelotin, complement component 3, collagen IV, and fibronectin), while increasing RPE differentiation factors (e.g., tyrosinase, and pigment epithelium-derived factor). In vivo, treatment of 8-month-old R345W+/+ knockin mice with CHIR (25 mg/kg i.p., 1 mo) was well tolerated and significantly reduced R345W F3-associated AMD-like basal laminar deposit number and size, thereby preventing the main pathological feature in these mice. This is an important demonstration of small molecule-based prevention of AMD-like pathology in ML/DHRD mice and may herald a rejuvenation of interest in GSK3 inhibition for the treatment of retinal degenerative diseases, including potentially AMD itself.
Subject(s)
Extracellular Matrix Proteins , Extracellular Matrix , Macular Degeneration , Retinal Pigment Epithelium , Animals , Mice , Retinal Pigment Epithelium/pathology , Retinal Pigment Epithelium/metabolism , Retinal Pigment Epithelium/drug effects , Macular Degeneration/pathology , Macular Degeneration/genetics , Macular Degeneration/drug therapy , Macular Degeneration/metabolism , Humans , Extracellular Matrix Proteins/metabolism , Extracellular Matrix Proteins/genetics , Extracellular Matrix/metabolism , Extracellular Matrix/drug effects , Pyridines/pharmacology , Pyrimidines/pharmacology , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3/antagonists & inhibitors , Glycogen Synthase Kinase 3/genetics , Disease Models, Animal , Retinal Dystrophies/metabolism , Retinal Dystrophies/pathology , Retinal Dystrophies/genetics , Optic Disk Drusen/congenitalABSTRACT
OBJECTIVE: To evaluate clinical characteristics impacting surgical outcomes of patients undergoing pars plana vitrectomy (PPV) for complications of proliferative diabetic retinopathy (PDR). DESIGN: Retrospective consecutive observational case series of patients at a large county hospital in Dallas, Texas, from 2014 to 2019. SUBJECTS: Seven hundred thirty-two patients (933 eyes) undergoing PPV for PDR complications. METHODS: Collected data included demographics, surgical indication, adjuvant therapies, intraoperative course, complications, and best corrected visual acuity (BCVA). Patients with < 6 months of follow-up were excluded. Best corrected visual acuity was converted to logarithm of the minimum angle of resolution for analysis. Statistics performed included t test, analysis of variance, and multivariate analyses. MAIN OUTCOME MEASURES: Postoperative BCVA, primary anatomic success rate, and postoperative complications. RESULTS: Three hundred ninety-three patients were male (509 eyes; 54.5%) with an average age of 52 years. Postoperative BCVA at 6 months was significantly different among surgical indications: 0.79 versus 0.77 versus 1.20 (P < 0.0001) for vitreous hemorrhage (VH), vitreomacular interface abnormalities, and tractional retinal detachment (TRD), respectively. Adjuvant preoperative therapy with panretinal photocoagulation (PRP) versus no PRP (0.95 vs. 1.25; P < 0.001) and insulin versus no insulin (0.99 vs. 1.17; P < 0.01) were associated with improved vision. Iatrogenic breaks were associated with decreased postoperative vision (1.40 vs. 0.88; P < 0.001). The primary anatomic success rate for TRD was 85% (495 eyes). Combined TRD/RRD (tractional and rhegmatogenous retinal detachment) was associated with a lower success rate compared with macula-on/macula-off TRD, with odds ratios of 0.36, 0.46, and 0.53, respectively. Patients experiencing recurrent detachment postsurgery had worse preoperative visual acuity (VA) (1.93 vs. 1.63; P < 0.01) and were younger (47.6 vs. 50.0; P = 0.02). Postoperative complications occurred in 699 eyes (75%), with VH (498 eyes, 53%), cataract (465, 50%), and elevated intraocular pressure (149, 16%) being the most common. Two hundred thirty-six eyes (25%) required a second PPV operation. Endophthalmitis (1 eye; <1%) and choroidal detachment (5 eyes; <1%) were rare. CONCLUSIONS: In this retrospective series analyzing surgical outcomes among patients with complications from PDR, vitrectomy led to improved vision on average, with a meaningful proportion of patients receiving additional surgical intervention. Surgical indication, presenting VA, age, and adjuvant therapies appeared to impact outcomes. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Subject(s)
Diabetic Retinopathy , Visual Acuity , Vitrectomy , Humans , Vitrectomy/methods , Male , Retrospective Studies , Female , Middle Aged , Diabetic Retinopathy/surgery , Diabetic Retinopathy/diagnosis , Diabetic Retinopathy/complications , Follow-Up Studies , Treatment Outcome , Aged , Adult , Postoperative Complications , Tomography, Optical Coherence/methodsABSTRACT
Purpose: To evaluate the presentations, clinical course, treatments, and outcomes of endogenous endophthalmitis cases. Methods: Consecutive medical records from 2016 to 2021 of a county hospital and an academic, private hospital in Dallas, Texas were retrospectively reviewed. This study comprised 37 eyes of 31 patients with endogenous endophthalmitis. Collected data included demographic factors, identifiable risk factors, medical history, presenting symptoms, infectious data, complications, and best-corrected visual acuity (VA) throughout the clinical course. Results: Twenty-two eyes had bacterial endophthalmitis, 7 had fungal endophthalmitis, and 8 had infections that could not be classified. Of the bacterial cases, 5 eyes had panophthalmitis with associated cellulitis. The most common organisms were Staphylococcus aureus, Candida albicans, and Pseudomonas aeruginosa. The most common presenting symptoms were decreased vision (70%), eye redness (41%), and eye pain (38%). Among all cases, there was no significant difference in the presenting logMAR VA (1.86) before treatment and the most recent logMAR VA (1.75; P = .70) after treatment. However, fungal infections demonstrated better logMAR VA than bacterial infections 6 months after diagnosis (mean logMAR VA, 0.93 vs 2.54, respectively; P = .016) and at most recent follow-up (mean logMAR VA, 0.76 vs 2.3, respectively; P = .004). There was also a strong correlation between presenting VA and most recent VA (r2 = 0.81; P < .01). Conclusions: Visual outcomes of endogenous endophthalmitis cases were poor. Our study found 2 components to be predictive of final VA: (1) whether the infecting organism was bacterial or fungal and (2) a patient's presenting VA.
ABSTRACT
Malattia Leventinese/Doyne Honeycomb Retinal Dystrophy (ML/DHRD) is an age-related macular degeneration (AMD)-like retinal dystrophy caused by an autosomal dominant R345W mutation in the secreted glycoprotein, fibulin-3 (F3). To identify new small molecules that reduce F3 production from retinal pigmented epithelium (RPE) cells, we knocked-in a luminescent peptide tag (HiBiT) into the endogenous F3 locus which enabled simple, sensitive, and high throughput detection of the protein. The GSK3 inhibitor, CHIR99021 (CHIR), significantly reduced F3 burden (expression, secretion, and intracellular levels) in immortalized RPE and non-RPE cells. Low-level, long-term CHIR treatment promoted remodeling of the RPE extracellular matrix (ECM), reducing sub-RPE deposit-associated proteins (e.g., amelotin, complement component 3, collagen IV, and fibronectin), while increasing RPE differentiation factors (e.g., tyrosinase, and pigment epithelium derived factor). In vivo, treatment of 8 mo R345W+/+ knockin mice with CHIR (25 mg/kg i.p., 1 mo) was well tolerated and significantly reduced R345W F3-associated AMD-like basal laminar deposit number and size, thereby preventing the main pathological feature in these mice. This is the first demonstration of small molecule-based prevention of AMD-like pathology in ML/DHRD mice and may herald a rejuvenation of interest in GSK3 inhibition for the treatment of neurodegenerative diseases, including, potentially AMD itself.
ABSTRACT
Firefighters are intermittently exposed to complex, mixed pollutants in random settings. Of those pollutants, PAHs (polycyclic aromatic hydrocarbons) are the most commonly studied and best understood. PAH exposure can occur via multiple routes; therefore, the levels of hydroxylated metabolites of PAHs in urine have been used as a biomonitoring tool for risk assessment. We performed a systematic review and meta-analysis of the literature to estimate the levels of urinary hydroxylated PAH (OHPAH) among firefighters, determine risk attributions, and, finally, evaluate the scope of preventive efforts and their utility as diagnostic tools. The meta-regression confirmed increases in OHPAH concentrations after fire activities by up to 1.71-times (p-values: <0.0001). Samples collected at a time point of 2−4 h after a fire suppression showed a consistent, statistically significant pattern as compared with baseline samples. The National Fire Protection Association (NFPA) standard 1582 Standard on Comprehensive Occupational Medical Program for Fire Departments lists various health examinations, including a urinalysis for occupational chemical exposure if indicated and medical screening for cancers and cardiovascular diseases. Biomonitoring is a valuable screening tool for assessing occupational exposure and the results of this meta-analysis support their inclusion in regular health screenings for firefighters.
Subject(s)
Air Pollutants, Occupational , Firefighters , Occupational Exposure , Polycyclic Aromatic Hydrocarbons , Air Pollutants, Occupational/analysis , Environmental Monitoring/methods , Humans , Occupational Exposure/analysis , Polycyclic Aromatic Hydrocarbons/analysisABSTRACT
Endotracheal intubation in rabbits can be challenging due to their unusual anatomy. Achieving a patent airway during anesthesia is critical for the avoidance of airway obstruction, prevention of gastric tympany, and to allow ventilatory support. Due to the difficulty of intubation, alternative methods such as the use of laryngeal mask airways or laryngeal tubes have been explored. However, these methods do not result in direct access to the trachea and thus may present a risk for development of complications. In addition, lack of direct intubation of the trachea can result in personnel exposure to waste anesthetic gases. Numerous methods for endotracheal intubation have been described, including blind placement, use of a fiberoptic laryngoscope or endoscope, and cricoid placement. Despite these numerous publications, many still struggle to achieve success. Here we provide a detailed description of an intubation technique that can be taught with minimal training with a short time to proficiency. Briefly, after administration of injectable anesthesia and proper positioning of the rabbit, a polypropylene catheter is placed into the trachea by direct visualization using a laryngoscope. The catheter is then used as a guide to direct the endotracheal tube into the trachea. This method allows for intubation without the need for expensive equipment and can be performed by a single individual without the need for an assistant. In conclusion, this technique can be easily taught and performed at very little cost in any clinical or research setting.