DEXAMETHASONE IMPLANT VERSUS TOPICAL CARBONIC ANHYDRASE INHIBITORS IN PATIENTS WITH BILATERAL RETINITIS PIGMENTOSA-RELATED CYSTOID MACULAR EDEMA: A Prospective, Paired-Eye Pilot Study.

PURPOSE: To compare within-subject efficacy and safety of intravitreal dexamethasone implant and topical carbonic anhydrase inhibitors in the treatment of retinitis pigmentosa-related cystoid macular edema. METHODS: Patients with bilateral retinitis pigmentosa-related cystoid macular edema were treated with intravitreal dexamethasone implant in one eye and topical carbonic anhydrase inhibitors in the contralateral eye. The primary endpoint was a change in central macular thickness. Secondary endpoints were changes in best-corrected visual acuity and microperimetric central retinal sensitivity. Intraocular pressure and other ocular complications were evaluated for safety assessment. RESULTS: Nine patients were recruited for this 12-month follow-up study. Central macular thickness was significantly lower in intravitreal dexamethasone implant-treated eyes than in topical carbonic anhydrase inhibitors-treated eyes at Months 1 and 7, whereas mean best-corrected visual acuity was better in eyes treated with topical carbonic anhydrase inhibitors at Month 12 (borderline significant P = 0.0510). There was no difference in microperimetric sensitivity between the two treatments. Three patients developed ocular hypertension after intravitreal dexamethasone implant. Intravitreal dexamethasone implant showed an effect on the contralateral eye in five of nine patients. CONCLUSION: Intravitreal dexamethasone implant was more effective than topical carbonic anhydrase inhibitors in reducing retinitis pigmentosa-related cystoid macular edema 1 month after treatment. Corticosteroids can play a key role in the management of retinitis pigmentosa-related cystoid macular edema; however, their routes, timing, and modes of administration should be further explored.

Genotypic and Phenotypic Characterization of a Cohort of Patients Affected by Rod Cyclic Nucleotide Channel-Associated Retinitis Pigmentosa.

INTRODUCTION: Retinitis pigmentosa (RP), a heterogeneous inherited retinal disorder causing gradual vision loss, affects over 1 million people worldwide. Pathogenic variants in CNGA1 and CNGB1 genes, respectively, accounting for 1% and 4% of cases, impact the cyclic nucleotide-gated channel in rod photoreceptor cells. The aim of this study was to describe and compare genotypic and clinical characteristics of a cohort of patients with CNGA1- or CNGB1-related RP and to explore potential genotype-phenotype correlations. METHODS: The following data from patients with CNGA1- or CNGB1-related RP, followed in five Italian inherited retinal degenerations services, were retrospectively collected: genetic variants in CNGA1 and CNGB1, best-corrected visual acuity (BCVA), ellipsoid zone (EZ) width, fundus photographs, and short-wavelength fundus autofluorescence (SW-AF) images. Comparisons and correlation analyses were performed by first dividing the cohort in two groups according to the gene responsible for the disease (CNGA1 and CNGB1 groups). In parallel, the whole cohort of RP patients was divided into two other groups, according to the expected impact of the variants at protein level (low and high group). RESULTS: In total, 29 patients were recruited, 11 with CNGA1- and 18 with CNGB1-related RP. In both CNGA1 and CNGB1, 5 novel variants in CNGA1 and 5 in CNGB1 were found. BCVA was comparable between CNGA1 and CNGB1 groups, as well as between low and high groups. CNGA1 group had a larger mean EZ width compared to CNGB1 group, albeit not statistically significant, while EZ width did not differ between low and high groups A statistically significant correlation between EZ width and BCVA as well as between EZ width and age were observed in the whole cohort of RP patients. Fundus photographs of all patients in the cohort showed classic RP pattern, and in SW-AF images an hyperautofluorescent ring was observed in 14/21 patients. CONCLUSION: Rod CNG channel-associated RP was demonstrated to be a slowly progressive disease in both CNGA1- and CNGB1-related forms, making it an ideal candidate for gene augmentation therapies.

Different roles of circulating and intramuscular GDF15 as markers of skeletal muscle health.

Introduction: Growth Differentiation Factor 15 (GDF15) is a mitokine expressed in response to various stresses whose circulating levels increase with age and are associated with numerous pathological conditions, including muscle wasting and sarcopenia. However, the use of circulating GDF15 (c-GDF15) as a biomarker of sarcopenia is still debated. Moreover, the role of GDF15 intracellular precursor, pro-GDF15, in human skeletal muscle (SM-GDF15) is not totally understood. In order to clarify these points, the association of both forms of GDF15 with parameters of muscle strength, body composition, metabolism and inflammation was investigated. Methods: the levels of c-GDF15 and SM-GDF15 were evaluated in plasma and muscle biopsies, respectively, of healthy subjects (HS) and patients with lower limb mobility impairment (LLMI), either young (<40 years-old) or old (>70 years-old). Other parameters included in the analysis were Isometric Quadriceps Strength (IQS), BMI, lean and fat mass percentage, Vastus lateralis thickness, as well as circulating levels of Adiponectin, Leptin, Resistin, IGF-1, Insulin, IL6, IL15 and c-PLIN2. Principal Component Analysis (PCA), Canonical Discriminant Analysis (CDA) and Receiving Operating Characteristics (ROC) analysis were performed. Results: c-GDF15 but not SM-GDF15 levels resulted associated with decreased IQS and IGF-1 levels in both HS and LLMI, while only in LLMI associated with increased levels of Resistin. Moreover, in LLMI both c-GDF15 and SM-GDF15 levels were associated with IL-6 levels, but interestingly SM-GDF15 is lower in LLMI with respect to HS. Furthermore, a discrimination of the four groups of subjects based on these parameters was possible with PCA and CDA. In particular HS, LLMI over 70 years or under 40 years of age were discriminated based on SM-GDF15, c-GDF15 and Insulin levels, respectively. Conclusion: our data support the idea that c-GDF15 level could be used as a biomarker of decreased muscle mass and strength. Moreover, it is suggested that c-GDF15 has a different diagnostic significance with respect to SM-GDF15, which is likely linked to a healthy and active state.

Pigmented paravenous retinochoroidal atrophy and retinitis pigmentosa-like phenotype in the same patient: A case series.

INTRODUCTION: Concomitant manifestation of PPRCA in one eye and RP-like retinopathy in the fellow eye is a rare clinical entity, with limited published descriptions to date. The aim of this study is to describe comprehensive clinical evaluations and long-term follow-up of three patients affected by this clinical picture. METHODS: Three patients with concurrent PPRCA and RP-like retinopathy were prospectively re-evaluated and comprehensive assessments were performed. The progression of disease was assessed by comparing best corrected visual acuity (BCVA) and ellipsoid zone (EZ) width with data available from each patient's medical charts and previous SD-OCT scans. Blood samples were collected and tested to rule out autoimmune or infectious ocular diseases, for testing anti-retinal autoantibodies (ARAs) and for genetic analysis. RESULTS: Reduction in BCVA and a progressive concentric loss of the EZ band over time were detected in the eye with RP-like phenotype in all three patients, while in the eye with PPRCA none of the patients showed significant changes in BCVA and only one patient showed a progressive reduction of the EZ width. No clear etiology has been identified. Two or more ARAs subtypes were detected in two out of three patients. CONCLUSIONS: PPRCA was demonstrated to be a non-progressive or slowly progressive disease, instead the eye with RP-like phenotype showed a progressive visual impairment, highlighting the importance of shedding light on this condition. Its etiology remains unclear: a genetic trait with different phenotype between the two eyes is conceivable, as well as a potential role of ARAs.

24-Hour Evaluation of the Effectiveness and Tolerability of Preservative-Free Tafluprost-Timolol Fixed Combination in Open-Angle Glaucoma or Ocular Hypertensive Patients Previously Treated with Preserved Latanoprost.

Purpose: The effectiveness, safety and tolerability of the preservative-free fixed combination of tafluprost and timolol (PF-TTFC) were evaluated over the 24-h in patients with open-angle glaucoma or ocular hypertension showing signs and symptoms of Ocular Surface Disease (OSD) and uncontrolled intraocular pressure (IOP) on prior benzalkonium chloride (BAK) - Latanoprost monotherapy. Methods: In this multi-center, prospective, interventional, non-comparative clinical trial, patients treated with BAK-Latanoprost underwent 24-h IOP measurements (8 am, 11 am, 2 pm, 5 pm, 8 pm, 11 pm, 2 am, 5 am) at baseline and after 3 months from switch to PF-TTFC. Mean 24-h IOP and daytime (8 am-8 pm) vs nighttime (11 pm - 5 am) IOP were compared. Changes in OSD signs and symptoms, quality of life (QoL) and in-vivo corneal confocal microscopy (IVCM) were also evaluated. Results: Thirty-eight patients were analyzed. The mean 24-h IOP significantly decreased after 3 months from 17.8 mmHg (95% CI: 17.1-18.6) to 15.3 mmHg (95% CI: 14.6-16.1, p < 0.001). IOP was significantly reduced both at daytime (p < 0.001) and nighttime (p < 0.001), with better IOP control at night [-2.9 (95% CI: -3.5 to -2.1) mmHg vs -2.3 (95% CI: -2.9 to -1.6) mmHg]. In 20 patients (52.6%), corneal fluorescein staining improved, whereas in 4 patients (10.5%) it worsened. Hyperemia has improved in 24 (63.3%) patients and worsened in 2 (5.3%). Breakup time, Schirmer test and QoL scores showed no changes. At IVCM, the mean corneal wing-cell size was found significantly decreased (p < 0.005). Conclusion: The switch from BAK-Latanoprost to PF-TTFC significantly reduced IOP over the 24-h and improved OSD signs and symptoms.

Comparison Between 24-2 ZEST and 24-2 ZEST FAST Strategies in Glaucoma and Ocular Hypertension Using a Fundus Perimeter.

PRCIS: Using a Compass (CMP) (CMP, Centervue, Padova, Italy) fundus perimeter, Zippy Estimation by Sequential Testing (ZEST) FAST strategy showed a significant reduction in examination time compared with ZEST, with good agreement in the quantification of perimetric damage. PURPOSE: The aim of this study was to compare the test duration of ZEST strategy with ZEST FAST and to evaluate the test-retest variability of ZEST FAST strategy on patients with glaucoma and ocular hypertension. PATIENTS AND METHODS: This was a multicenter retrospective study. We analyzed 1 eye of 60 subjects: 30 glaucoma patients and 30 patients with ocular hypertension. For each eye we analyzed, 3 visual field examinations were performed with Compass 24-2 grid: 1 test performed with ZEST strategy and 2 tests performed with ZEST FAST. Mean examination time and mean sensitivity between the 2 strategies were computed. ZEST FAST test-retest variability was examined. RESULTS: In the ocular hypertension cohort, test time was 223±29 seconds with ZEST FAST and 362±48 seconds with ZEST (38% reduction, P <0.001). In glaucoma patients, it was respectively 265±62 and 386±78 seconds (31% reduction using ZEST FAST, P <0.001). The difference in mean sensitivity between the 2 strategies was -0.24±1.30 dB for ocular hypertension and -0.14±1.08 dB for glaucoma. The mean difference in mean sensitivity between the first and the second test with ZEST FAST strategy was 0.2±0.8 dB for patients with ocular hypertension and 0.24±0.96 dB for glaucoma patients. CONCLUSIONS: ZEST FAST thresholding provides similar results to ZEST with a significantly reduced examination time.

Downregulation of PLIN2 in human dermal fibroblasts impairs mitochondrial function in an age-dependent fashion and induces cell senescence via GDF15.

Perilipin 2 (PLIN2) is a lipid droplet (LD)-coating protein playing important roles in lipid homeostasis and suppression of lipotoxicity in different tissues and cell types. Recently, a role for PLIN2 in supporting mitochondrial function has emerged. PLIN2 dysregulation is involved in many metabolic disorders and age-related diseases. However, the exact consequences of PLIN2 dysregulation are not yet completely understood. In this study, we knocked down (KD) PLIN2 in primary human dermal fibroblasts (hDFs) from young (mean age 29 years) and old (mean age 71 years) healthy donors. We have found that PLIN2 KD caused a decline of mitochondrial function only in hDFs from young donors, while mitochondria of hDFs from old donors (that are already partially impaired) did not significantly worsen upon PLIN2 KD. This mitochondrial impairment is associated with the increased expression of the stress-related mitokine growth differentiation factor 15 (GDF15) and the induction of cell senescence. Interestingly, the simultaneous KD of PLIN2 and GDF15 abrogated the induction of cell senescence, suggesting that the increase in GDF15 is the mediator of this phenomenon. Moreover, GDF15 KD caused a profound alteration of gene expression, as observed by RNA-Seq analysis. After a more stringent analysis, this alteration remained statistically significant only in hDFs from young subjects, further supporting the idea that cells from old and young donors react differently when undergoing manipulation of either PLIN2 or GDF15 genes, with the latter being likely a downstream mediator of the former.