Diagnostic accuracy of nonmydriatic fundus photography for the detection of glaucoma in diabetic patients.

Purpose. To determine the diagnostic accuracy for glaucoma of a set of criteria with nonmydriatic monoscopic fundus photography (NMFP) in diabetics. Methods. Diabetics recruited from a screening program for diabetic retinopathy and diabetic glaucoma patients recruited from our glaucoma unit were included. Any patient with evidence of diabetic retinopathy was excluded. Diabetic patients had to have no visual field defects to be included as controls. Glaucoma patients had to have a glaucomatous field defect in at least one eye to be included. One NMFP was taken per eye for all subjects. These photographs were evaluated by two masked glaucoma specialists for the presence of the following: bilateral cup to disc (C/D) ratio ≥0.6, notching or thinning of the neuroretinal rim, disc hemorrhages, and asymmetry in the C/D ratio between both eyes ≥0.2.This evaluation led to a dichotomous classification: if any of the above criteria was present, the patient was classified as glaucoma. If none were present, the patient was classified as normal. Results. 72 control subjects and 72 glaucoma patients were included. Evaluation of NMFP had a sensitivity of 79.17% and a specificity of 80.56% for specialist 1 and a sensitivity of 72.22% and a specificity of 88.88% for specialist 2 for the detection of glaucoma. The overall accuracy was 79.83% and 80.55%, respectively. Discussion. NMFP evaluation by a glaucoma specialist may be useful for the detection of glaucoma in diabetics.Ministerio de Economía y Competitivida

Safety of lenadogene nolparvovec gene therapy over 5 years in 189 patients with Leber hereditary optic neuropathy

Purpose: Evaluate the safety profile of lenadogene nolparvovec (Lumevoq®) in patients with Leber hereditary optic neuropathy. Design: Pooled analysis of safety data from 5 clinical studies. Methods: A total of 189 patients received single unilateral or bilateral intravitreal injections of a recombinant adeno-associated virus 2 (rAAV2/2) vector encoding the human wild-type ND4 gene. Adverse events (AEs) were collected throughout the studies, up to 5 years. Intraocular inflammation and increased intraocular pressure (IOP) were ocular AEs of special interest. Other assessments included ocular examinations, vector bio-dissemination and systemic immune responses against rAAV2/2. Results: Almost all patients (95.2%) received 9 × 1010 viral genomes and 87.8% had at least 2 years of follow-up. Most patients (75.1%) experienced at least one systemic AE, but systemic treatment-related AEs occurred in 3 patients, none was serious. Intraocular inflammation was reported in 75.6% of lenadogene nolparvovec-treated eyes. Almost all intraocular inflammations occurred in the anterior chamber (58.8%) or in the vitreous (40.3%) and was of mild (90.3%) or moderate (8.8%) intensity; most resolved with topical corticosteroids alone. All IOP increases were mild to moderate in intensity. No AE led to study discontinuation. Bio-dissemination of lenadogene nolparvovec and systemic immune response were limited. The safety profile was comparable for patients treated bilaterally and unilaterally. Conclusions: Lenadogene nolparvovec has a good overall safety profile with excellent systemic tolerability, consistent with limited bio-dissemination. The product is well tolerated, with mostly mild ocular side effects responsive to conventional ophthalmologic treatments

Indirect Comparison of Lenadogene Nolparvovec Gene Therapy Versus Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G\u3eA MT-ND4 Mutation

INTRODUCTION: Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G\u3eA ND4 mutation (MT-ND4). A previous pooled analysis of phase 3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to natural history. Here, we report updated results by incorporating data from the latest phase 3 trial REFLECT in the pool, increasing the number of treated patients from 76 to 174. METHODS: The visual acuity of 174 MT-ND4-carrying patients with LHON injected in one or both eyes with lenadogene nolparvovec from four pooled phase 3 studies (REVERSE, RESCUE and their long-term extension trial RESTORE; and REFLECT trial) was compared to the spontaneous evolution of an external control group of 208 matched patients from 11 natural history studies. RESULTS: Treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared to natural history. Mean improvement versus natural history was - 0.30 logMAR (+ 15 ETDRS letters equivalent) at last observation (P \u3c 0.01) with a maximal follow-up of 3.9 years after injection. Most treated eyes were on-chart as compared to less than half of natural history eyes at 48 months after vision loss (89.6% versus 48.1%; P \u3c 0.01) and at last observation (76.1% versus 44.4%; P \u3c 0.01). When we adjusted for covariates of interest (gender, age of onset, ethnicity, and duration of follow-up), the estimated mean gain was - 0.43 logMAR (+ 21.5 ETDRS letters equivalent) versus natural history at last observation (P \u3c 0.0001). Treatment effect was consistent across all phase 3 clinical trials. Analyses from REFLECT suggest a larger treatment effect in patients receiving bilateral injection compared to unilateral injection. CONCLUSION: The efficacy of lenadogene nolparvovec in improving visual acuity in MT-ND4 LHON was confirmed in a large cohort of patients, compared to the spontaneous natural history decline. Bilateral injection of gene therapy may offer added benefits over unilateral injection. TRIAL REGISTRATION NUMBERS: NCT02652780 (REVERSE); NCT02652767 (RESCUE); NCT03406104 (RESTORE); NCT03293524 (REFLECT); NCT03295071 (REALITY)

Current Approach in the diagnosis and management of uveitic glaucoma.

Uveitic glaucoma (UG) typically is associated with very high intraocular pressure (IOP) and more intense optic nerve damage than other glaucoma types.This secondary glaucoma requires an early diagnosis and adequate management of both uveitis and glaucoma. It is mandatory to identify the mechanisms of IOP elevation that in many eyes have multiple combined mechanisms. Management of these patients commonly requires an interdisciplinary approach that includes a glaucoma specialist and rheumatologist to control the inflammation and IOP. Glaucoma surgery is required early in these patients due to the high IOP usually present and is less successful than in primary open-angle glaucoma. Recurrent uveitic episodes, multiple mechanism, and the complications associated with uveitis make surgical management of UG challenging. In this review, the management and treatment of UG are updated to clarify the pathogenesis and prevent optic nerve damageMinisterio de Economía y Competitivida

Diagnostic accuracy of nonmydriatic fundus photography for the detection of glaucoma in diabetic patients.

Purpose. To determine the diagnostic accuracy for glaucoma of a set of criteria with nonmydriatic monoscopic fundus photography (NMFP) in diabetics. Methods. Diabetics recruited from a screening program for diabetic retinopathy and diabetic glaucoma patients recruited from our glaucoma unit were included. Any patient with evidence of diabetic retinopathy was excluded. Diabetic patients had to have no visual field defects to be included as controls. Glaucoma patients had to have a glaucomatous field defect in at least one eye to be included. One NMFP was taken per eye for all subjects. These photographs were evaluated by two masked glaucoma specialists for the presence of the following: bilateral cup to disc (C/D) ratio ��.6, notching or thinning of the neuroretinal rim, disc hemorrhages, and asymmetry in the C/D ratio between both eyes ��.2.This evaluation led to a dichotomous classification: if any of the above criteria was present, the patient was classified as glaucoma. If none were present, the patient was classified as normal. Results. 72 control subjects and 72 glaucoma patients were included. Evaluation of NMFP had a sensitivity of 79.17% and a specificity of 80.56% for specialist 1 and a sensitivity of 72.22% and a specificity of 88.88% for specialist 2 for the detection of glaucoma. The overall accuracy was 79.83% and 80.55%, respectively. Discussion. NMFP evaluation by a glaucoma specialist may be useful for the detection of glaucoma in diabetics.Ministerio de Economía y Competitivida

Prognostic irrelevance of HLA-G in B-cell chronic lymphocytic leukemia

In the last few years, it has been suggested that the involvement of human leukocyte antigen-G (HLA-G) in several tumoral processes and its likely participation as a factor of immune tolerance in malignant cells. Recently, positive HLA-G surface expression has been associated with a poor prognosis in a small group of patients with B-cell chronic lymphocytic leukemia (B-CLL), a lymphoproliferative disorder characterized by a heterogeneous clinical course. In the present work, 169 patients suffering from B-CLL were analyzed for the expression of HLA-G by flow cytometry in order to verify its prognostic value in a larger cohort. We observed a low expression of this molecule on leukemic B cells and no significant relation to clinical data or progression-free survival time, indicating that this molecule is not as good immunologic prognostic marker for B-CLL as suggested.This study was supported by Fundacion LAIR

CD5 provides viability signals to B cells from a subset of B-CLL patients by a mechanism that involves PKC

B-chronic lymphocytic leukaemia (B-CLL) is a heterogeneous disease characterized by an accumulation of B lymphocytes expressing CD5. To date, the biological significance of this molecule in B-CLL B cells remains to be elucidated. In this study, we have analysed the functional consequences of the binding of an anti-CD5 antibody on B-CLL B cells. To this purpose, we have measured the percentage of viability of B-CLL B cells in the presence or in the absence of anti-CD5 antibodies and also examined some of the biochemical events downstream the CD5-signalling. We demonstrate that anti-CD5 induces phosphorylation of protein tyrosine kinases and protein kinase C (PKC), while no activation of Akt/PKB and MAPKs is detected. This signalling cascade results in viability in a group of patients in which we observe an increase of Mcl-1 levels, whereas the levels of bcl-2, bcl-xL and XIAP do not change. We also report that this pathway leads to IL-10 production, an immunoregulatory cytokine that might act as an autocrine growth factor for leukaemic B cells. Inhibition of PKC prevents the induction of Mcl-1 and IL-10, suggesting that the activation of PKC plays an important role in the CD5-mediated survival signals in B cells from a subset of B-CLL patients.This study was supported by Fundacion LAIR and Ministerio de Ciencia y Tecnologia (SAF2002-04329). G. Perez-Chacon is the recipient of a fellowship from Fundacion LAIR

Utility of Bruch membrane opening-based optic nerve head parameters in myopic subjects

Purpose: To evaluate whether the new rim analysis software with spectral-domain optical coherence tomography (SD-OCT) shows advantages over the retinal nerve fiber layer (RNFL) thickness in patients with moderate myopia. Methods: In this prospective cross-sectional study, we studied 65 healthy subjects, 37 with spherical refractive errors in the range of -3 to -6 D (moderate, G1) and 28 with less than -3 D (low/non-myopic, G0). All patients were examined with Heidelberg Spectralis SD-OCT, including Glaucoma Premium Module Edition (GPME) software. With GPME, we analyzed the neuroretinal rim (Bruch membrane opening-minimum rim width [BMO-MRW]) and RNFL. Results: The average age of subjects was 30.2 ± 9.3 years for G0 and 29.9 ± 7.1 years for G1 (p = 0.903). Mean sphere was −0.5 ± 0.3 D (-1.25 to 0 D) G0 and -3.9 ± 0.3 D (-6.00 to -3 D) G1 (p<0.001). The RNFL thickness comparison between G0 and G1 showed a significantly lower thickness in G1 (p = 0.018). The BMO-MRW measurements were similar in both groups (p = 0.331). With the BMO-MRW examination, the number of sectors classified as pathologic per subject in G1 were significantly lower compared to RNFL analysis (p = 0.023). Conclusions: Ring analysis based on BMO-MRW measurements shows a lower rate of false-positives compared to RNFL thickness when studying healthy moderate myopic eyes and it would be advisable to take this into consideration when analyzing these patients

CD5 does not regulate the signaling triggered through BCR in B cells from a subset of B-CLL patients

CD5 is a transmembrane protein expressed on all T lineage cells and a subset of B cells. It is known that CD5 is physically associated with the T-cell receptor and B-cell receptor (BCR), inhibiting the signaling triggered by both of them. CD5 is also characteristic of B-chronic lymphocytic leukemia (B-CLL) B cells, although its implication in the development of this lymphoproliferative disorder has not been studied. In the present study, we examined the effect of CD5 in apoptosis, cell viability and global protein tyrosine phosphorylation mediated by BCR in B cells from B-CLL patients. As opposed to tonsil B cells, we did not observe an increase in the apoptotic or viability signals induced by anti-immunoglobulin M or SAC/interleukin-2 when CD5 was dissociated from BCR in leukemic cells of the majority of patients. We also observed that CD5 did not regulate the BCR-induced phosphotyrosine pattern in B-CLL B cells. These findings suggest that CD5 does not inhibit properly the BCR-mediated signaling in leukemic cells. This defect in inhibiting the BCR might contribute to the enhanced survival of B-CLL B cells

Expression of human leukocyte antigen-G in systemic lupus erythematosus

The purpose of this study was to examine the expression of human leukocyte antigen-G (HLA-G) in patients with systemic lupus erythematosus (SLE) and its relation with interleukin-10 (IL-10) production. The study included 50 female SLE patients and 59 healthy female donors. HLA-G expression in peripheral blood and cutaneous biopsies was determined by flow cytometry and immunohistochemistry, respectively. Soluble HLA-G (sHLA-G) and IL-10 were quantified in serum samples by enzyme-linked immunosorbent assay. SLE patients presented with serum sHLA-G and IL-10 levels significantly higher than that observed in controls (median [interquartile range (IQR)] = 43.6 U/ml [23.2–150.2] vs 26.84 U/ml [6.0–45.2], p = 0.004; and 1.4 pg/ml [0–2.3] vs 0 pg/ml [0–1.5], p = 0.01, respectively). But no correlation was observed between sHLA-G and both IL-10 levels and the disease activity index for SLE patients. The expression of membrane HLA-G in peripheral lymphocytes from SLE patients was low, but higher than in controls (median [IQR] = 1.5% [0.6–1.8] and 0.3% [0.2–0.8], respectively; p = 0.02). Finally, these findings were in accordance with the weak expression of HLA-G in skin biopsies. Despite the fact that patients present higher levels of HLA-G than healthy controls, which suggests a possible relevance of this molecule in SLE, it seems not to be related to IL-10 production or disease activity.This study was supported by Fundacion LAIR (8108) and by the Ministerio de Educacion y Cultura (AP2000-2160).Peer reviewe