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To evaluate the safety and potential therapeutic activity of humanized anti-IL-2 receptor mAb (Daclizumab) therapy in the treatment of patients with severe, sight-threatening, intermediate and posterior noninfectious uveitis, a nonrandomized, open-label, pilot study was performed. Patients with uveitis were treated with a minimum of 20 mg of prednisone, cyclosporine, antimetabolites, or any combination of these agents were eligible. Patients were weaned off their systemic immunosuppressive agents according to a standardized schedule, while ultimately receiving Daclizumab infusions every 4 weeks. Anti-IL-2 receptor antibody therapy, given intravenously with intervals of up to 4 weeks in lieu of standard immunosuppressive therapy, appeared to prevent the expression of severe sight-threatening intraocular inflammatory disease in 8 of 10 patients treated over a 12-month period, with noted improvements in visual acuity. One patient met a primary endpoint with a loss of vision of 10 letters or more from baseline in one eye and another patient discontinued therapy because of evidence of increased ocular inflammation. All patients were able to tolerate the study medications without the need for dose reduction. We report effective long-term use of anti-IL-2 therapy for an autoimmune indication. These initial findings would suggest that anti-IL-2 receptor therapy may be an effective therapeutic approach for uveitis and, by implication, other disorders with a predominant Th1 profile.

Abstract Background To examine the associations between vision-targeted health-related quality of life (VT-HRQ) and ocular surface parameters in patients with Sjögren's syndrome, a systemic autoimmune disease characterized by dry eye and dry mouth. Methods Forty-two patients fulfilling European / American diagnostic criteria for Sjögren's syndrome underwent Schirmer testing without anesthesia, ocular surface vital dye staining; and measurement of tear film breakup time (TBUT). Subjects were administered the Ocular Surface Disease Index (OSDI) and the 25-item National Eye Institute Vision Functioning Questionnaire (NEI-VFQ). Main outcome measures included ocular surface parameters, OSDI subscales describing ocular discomfort (OSDI-symptoms), vision-related function (OSDI-function), and environmental triggers, and NEI-VFQ subscales. Results Participants (aged 31–81 y; 95% female) all had moderate to severe dry eye. Associations of OSDI subscales with the ocular parameters were modest (Spearman r (ρ) < 0.22) and not statistically significant. Associations of NEI-VFQ subscales with the ocular parameters reached borderline significance for the near vision subscale with TBUT (ρ = 0.32, p = .05) and for the distance vision subscale with van Bijsterveld score (ρ = 0.33, p = .04). The strongest associations of the two questionnaires were for: ocular pain and mental function with OSDI-symptoms (ρ = 0.60 and 0.45, respectively); and general vision, ocular pain, mental function, role function, and driving with OSDI-function (ρ = 0.60, 0.50, 0.61, 0.64, 0.57, and 0.67, respectively). Conclusions Associations between conventional objective measures of dry eye and VT-HRQ were modest. The generic NEI-VFQ was similar to the disease-specific OSDI in its ability to measure the impact of Sjögren's syndrome-related dry eye on VT-HRQ.

Background: To examine the associations between vision-targeted health-related quality of life (VT-HRQ) and ocular surface parameters in patients with Sjögren's syndrome, a systemic autoimmune disease characterized by dry eye and dry mouth. Methods: Forty-two patients fulfilling European / American diagnostic criteria for Sjögren's syndrome underwent Schirmer testing without anesthesia, ocular surface vital dye staining; and measurement of tear film breakup time (TBUT). Subjects were administered the Ocular Surface Disease Index (OSDI) and the 25-item National Eye Institute Vision Functioning Questionnaire (NEI-VFQ). Main outcome measures included ocular surface parameters, OSDI subscales describing ocular discomfort (OSDI-symptoms), vision-related function (OSDI-function), and environmental triggers, and NEI-VFQ subscales. Results: Participants (aged 31.81 y; 95% female) all had moderate to severe dry eye. Associations of OSDI subscales with the ocular parameters were modest (Spearman r (ρ) < 0.22) and not statistically significant. Associations of NEI-VFQ subscales with the ocular parameters reached borderline significance for the near vision subscale with TBUT (ρ = 0.32, p = .05) and for the distance vision subscale with van Bijsterveld score (ρ = 0.33, ρ = .04). The strongest associations of the two questionnaires were for: ocular pain and mental function with OSDI-symptoms (ρ = 0.60 and 0.45, respectively); and general vision, ocular pain, mental function, role function, and driving with OSDI-function (ρ = 0.60, 0.50, 0.61, 0.64, 0.57, and 0.67, respectively). Conclusions: Associations between conventional objective measures of dry eye and VT-HRQ were modest. The generic NEI-VFQ was similar to the disease-specific OSDI in its ability to measure the impact of Sjögren's syndrome-related dry eye on VT-HRQ. [ABSTRACT FROM AUTHOR]

Francois-Neetens fleck (mouchetée) corneal dystrophy is an autosomal dominant corneal dystrophy characterized by scattered small white flecks occurring at all levels of the corneal stroma. We report linkage of the CFD locus to D2S2289 (Zmax=4.46, θ=0), D2S325 (Zmax=3.28, θ=0), D2S317 (Zmax=3.1, θ=0), D2S143 (Zmax=3.8, θ=0.03), and D2S2382 (Zmax=5.0, θ=0) on chromosome 2q35. Multipoint analysis confirmed linkage to the region between D2S117 and D2S126 with a maximum multipoint lod score of 5.0 located midway between D2S2289 and D2S325. Analysis of CFD in these same families assuming a 90% penetrance increased the maximum lod score to 6.28 at D2S157. [ABSTRACT FROM AUTHOR]

The article announces several awards given to botanists including 10th annual Margaret Flockton Award for scientific botanical illustration to Rogério Lupo, the Highly Commended Awards to Klei Sousa and Edmundo Saavedra Vidal.

François­Neetens fleck corneal dystrophy (CFD) is a rare, autosomal dominant corneal dystrophy characterized by numerous small white flecks scattered in all layers of the stroma. Linkage analysis localized CFD to a 24-cM (18-Mb) interval of chromosome 2q35 flanked by D2S2289 and D2S126 and containing PIP5K3. PIP5K3 is a member of the phosphoinositide 3-kinase family and regulates the sorting and traffic of peripheral endosomes that contain lysosomally directed fluid phase cargo, by controlling the morphogenesis and function of multivesicular bodies. Sequencing analysis disclosed missense, frameshift, and/or protein-truncating mutations in 8 of 10 families with CFD that were studied, including 2256delA, 2274delCT, 2709C↵T (R851X), 3120C↵T (Q988X), IVS19-1G↵C, 3246G↵T (E1030X), 3270C↵T (R1038X), and 3466A↵G (K1103R). The histological and clinical characteristics of patients with CFD are consistent with biochemical studies of PIP5K3 that indicate a role in endosomal sorting. [ABSTRACT FROM AUTHOR]

Accurate diagnosis for patients living with neurodevelopmental disorders is often met with numerous challenges, related to the ambiguity of findings and lack of specificity in genetic variants leading to pathology. Genome-wide DNA methylation analysis has been used to develop highly sensitive and specific 'episignatures' as biomarkers capable of differentiating and classifying complex neurodevelopmental disorders. In this study we describe distinct episignatures for KAT6A syndrome, caused by pathogenic variants in the lysine acetyltransferase A gene ( KAT6A ), and for the two neurodevelopmental disorders associated with lysine acetyl transferase B ( KAT6B ). We demonstrate the ability of our models to differentiate between highly overlapping episignatures, increasing the ability to effectively identify and diagnose these conditions.

KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.

Purpose: Pterygium is a sunlight-related, ocular-surface lesion that can obscure vision. In order to identify specific genes that may play a role in pterygium pathogenesis, we analyzed the global gene expression profile of pterygium in relation to autologous conjunctiva., Methods: Oligonucleotide microarray hybridization was used to compare the gene expression profile between human whole pterygium and autologous conjunctiva. Selected genes were further characterized by RT-PCR, western blot, and immunohistochemistry, and comparisons were made with limbal and corneal tissues., Results: Thirty-four genes exhibited a 2 fold or greater difference in expression between human whole pterygium and autologous conjunctiva. Twenty-nine transcripts were increased and five transcripts were decreased in pterygium. Fibronectin, macrophage-inflammatory protein-4 (MIP-4), and lipocalin 2 (oncogene 24p3; NGAL) were increased 9, 5, and 2.4 fold, respectively, while Per1 and Ephrin-A1 were decreased 2 fold in pterygium. Western blots showed that fibronectin and MIP-4 were increased in pterygium compared to limbus, cornea, and conjunctiva. Immunohistochemical analysis showed fibronectin in the stroma; lipocalin 2 in the basal epithelial cells, basement membrane, and extracellular stroma; and MIP-4 in all areas of the pterygium., Conclusions: These data show both novel and previously identified extracellular-matrix-related, proinflammatory, angiogenic, fibrogenic, and oncogenic genes expressed in human pterygium. Comparisons of selected genes with limbal and corneal tissues gave results similar to comparisons between pterygium and normal conjunctiva. The increased expression of lipocalin 2, which activates matrix metalloproteinases (MMP), is consistent with our previous findings that MMP-9 and other MMPs are highly expressed in pterygium basal epithelium.

Purpose: To examine the conjunctiva of patients with Sjögren's syndrome keratoconjunctivitis sicca (SS-KCS) and non-Sjögren's keratoconjunctivitis sicca (NS-KCS) for evidence of immune-based inflammation., Methods: Conjunctival biopsy specimens were obtained from 15 patients with SS-KCS and 15 with NS-KCS. Immunohistochemistry was performed on frozen sections to characterize and quantify T-cell subtypes (CD3, CD4, and CD8) and markers of immune activation (major histocompatibility complex [MHC] class II: HLA-DR, HLA-DQ) and inflammation (intercellular adhesion molecule [ICAM]-1). The numbers of cells positive for each marker were counted by two masked observers and averaged., Results: Conjunctival biopsy specimens from patients with SS-KCS or NS-KCS revealed lymphocytic infiltration and increased immunoreactivity for the markers of inflammation and immune activation. The extent of cellular immunoreactivity did not differ significantly between SS-KCS and NS-KCS tissue samples., Conclusions: The authors' findings indicate that patients with SS-KCS or NS-KCS have conjunctival inflammation manifested by inflammatory cell infiltrates and upregulation of expression in markers of immune activation. Clinical symptoms of KCS may be more dependent on T-cell activation and resultant inflammation than previously believed. In addition to tear substitutes, anti-inflammatory therapeutics should be investigated for the treatment of KCS.