Grey-matter texture abnormalities and reduced hippocampal volume are distinguishing features of schizophrenia

Neurodevelopmental processes are widely believed to underlie schizophrenia. Analysis of brain texture from conventional magnetic resonance imaging (MRI) can detect disturbance in brain cytoarchitecture. We tested the hypothesis that patients with schizophrenia manifest quantitative differences in brain texture that, alongside discrete volumetric changes, may serve as an endophenotypic biomarker. Texture analysis (TA) of grey matter distribution and voxel-based morphometry (VBM) of regional brain volumes were applied to MRI scans of 27 patients with schizophrenia and 24 controls. Texture parameters (uniformity and entropy) were also used as covariates in VBM analyses to test for correspondence with regional brain volume. Linear discriminant analysis tested if texture and volumetric data predicted diagnostic group membership (schizophrenia or control). We found that uniformity and entropy of grey matter differed significantly between individuals with schizophrenia and controls at the fine spatial scale (filter width below 2 mm). Within the schizophrenia group, these texture parameters correlated with volumes of the left hippocampus, right amygdala and cerebellum. The best predictor of diagnostic group membership was the combination of fine texture heterogeneity and left hippocampal size. This study highlights the presence of distributed grey-matter abnormalities in schizophrenia, and their relation to focal structural abnormality of the hippocampus. The conjunction of these features has potential as a neuroimaging endophenotype of schizophrenia

Mycophenolic acid in the treatment of birdshot chorioretinopathy: long-term follow-up

Aim: To assess the long-term efficacy and tolerability of both derivatives of mycophenolic acid, mycophenolate mofetil (MMF) and mycophenolate sodium (MPS), in the therapy of patients with birdshot chorioretinopathy (BSCR). Methods: Retrospective analysis of 24 patients (48 eyes) with BSCR, treated with MMF or MPS with a follow-up of at least 1 year. The main outcome measures included control of inflammation, steroid-sparing potential and side effects. Secondary outcome measure was the development of retinal function during the therapy measured by best-corrected visual acuity (BCVA), visual field and/or electroretinography (ERG). Results: Twelve patients (50%) were treated with MMF and 12 patients (50%) with MPS. Control of intraocular inflammation, defined as complete lack of clinical and angiographic signs of inflammatory activity, was achieved in 16 of 24 patients (67%). The angiographic signs of activity were significantly reduced during the follow-up (p0.05). In 20 out of 21 patients (95%) who received systemic corticosteroids, the corticosteroids could be tapered to a daily dose of ≤10 mg (rate 0.26/patient-year). Drug-related side effects occurred in 12 patients (50%, rate 0.16/patient-year). In four patients (17%), a therapy switch from MMF to MPS was undertaken due to gastrointestinal discomfort. Conclusions: Derivatives of mycophenolic acid are effective and safe drugs for the treatment of BSCR. In cases with gastrointestinal side effects, a therapy switch from MMF to MPS should be considered

DNA resection in eukaryotes: deciding how to fix the break

DNA double-strand breaks are repaired by different mechanisms, including homologous recombination and nonhomologous end-joining. DNA-end resection, the first step in recombination, is a key step that contributes to the choice of DSB repair. Resection, an evolutionarily conserved process that generates single-stranded DNA, is linked to checkpoint activation and is critical for survival. Failure to regulate and execute this process results in defective recombination and can contribute to human disease. Here, I review recent findings on the mechanisms of resection in eukaryotes, from yeast to vertebrates, provide insights into the regulatory strategies that control it, and highlight the consequences of both its impairment and its deregulation

Development of a Core Outcome Set for Clinical Trials in Non-infectious Uveitis of the Posterior Segment

Purpose: To develop an agreed upon set of outcomes known as a “core outcome set” (COS) for noninfectious uveitis of the posterior segment (NIU-PS) clinical trials. Design: Mixed-methods study design comprising a systematic review and qualitative study followed by a 2-round Delphi exercise and face-to-face consensus meeting. Participants: Key stakeholders including patients diagnosed with NIU-PS, their caregivers, and healthcare professionals involved in decision-making for patients with NIU-PS, including ophthalmologists, nurse practitioners, and policymakers/commissioners. Methods: A long list of outcomes was developed based on the results of (1) a systematic review of clinical trials of NIU-PS and (2) a qualitative study of key stakeholders including focus groups and interviews. The long list was used to generate a 2-round Delphi exercise of stakeholders rating the importance of outcomes on a 9-point Likert scale. The proportion of respondents rating each item was calculated, leading to recommendations of “include,” “exclude,” or “for discussion” that were taken to a face-to-face consensus meeting of key stakeholders at which they agreed on the final COS. Main Outcome Measure: Items recommended for inclusion in the COS for NIU-PS. Results: A total of 57 outcomes grouped in 11 outcome domains were presented for evaluation in the Delphi exercise, resulting in 9 outcomes directly qualifying for inclusion and 15 outcomes being carried forward to the consensus meeting, of which 7 of 15 were agreed on for inclusion. The final COS contained 16 outcomes organized into 4 outcome domains comprising visual function, health-related quality of life, treatment side effects, and disease control. Conclusions: This study builds on international work across the clinical trials community and our qualitative research to construct the world's first COS for NIU-PS. The COS provides a list of outcomes that represent the priorities of key stakeholders and provides a minimum set of outcomes for use in all future NIU-PS clinical trials. Adoption of this COS can improve the value of future uveitis clinical trials and reduce noninformative research. Some of the outcomes identified do not yet have internationally agreed upon methods for measurement and should be the subject of future international consensus development

Long-Term Safety and Efficacy of Adalimumab in Patients with Noninfectious Intermediate Uveitis, Posterior Uveitis, or Panuveitis

Purpose: To evaluate long-term efficacy and safety of extended treatment with adalimumab in patients with noninfectious intermediate, posterior, or panuveitis. Design: Open-label, multicenter, phase 3 extension study (VISUAL III). Participants: Adults who had completed a randomized, placebo-controlled phase 3 parent trial (VISUAL I or II) without treatment failure (inactive uveitis) or who discontinued the study after meeting treatment failure criteria (active uveitis). Methods: Patients received subcutaneous adalimumab 40 mg every other week. Data were collected for ≤ 362 weeks. Adverse events (AEs) were recorded until 70 days after the last dose. Main Outcome Measures: Long-term safety and quiescence; other efficacy variables included inflammatory lesions, anterior chamber cell and vitreous haze grade, macular edema, visual acuity, and dose of uveitis-related systemic corticosteroids. Results: At study entry, 67% of patients (283/424) showed active uveitis and 33% (141/424) showed inactive uveitis; 60 patients subsequently met exclusion criteria, and 364 were included in the intention-to-treat analysis. Efficacy variables were analyzed through week 150, when approximately 50% of patients (214/424) remained in the study. Patients showing quiescence increased from 34% (122/364) at week 0 to 85% (153/180) at week 150. Corticosteroid-free quiescence was achieved by 54% (66/123) and 89% (51/57) of patients with active or inactive uveitis at study entry. Mean daily dose of systemic corticosteroids was reduced from 9.4 ± 17.1 mg/day at week 0 (n = 359) to 1.5 ± 3.9 mg/day at week 150 (n = 181). The percentage of patients who achieved other efficacy variables increased over time for those with active uveitis at study entry and was maintained for those with inactive uveitis. The most frequently reported treatment-emergent AEs of special interest were infections (n = 275; 79 events/100 patient-years [PY]); AEs and serious AEs occurred at a rate of 396 events/100 PY and 15 events/100 PY, respectively. Conclusions: Long-term treatment with adalimumab led to quiescence and reduced corticosteroid use for patients who entered VISUAL III with active uveitis and led to maintenance of quiescence for those with inactive uveitis. AEs were comparable with those reported in the parent trials and consistent with the known safety profile of adalimumab

Shelterin-Like Proteins and Yku Inhibit Nucleolytic Processing of Saccharomyces cerevisiae Telomeres

Eukaryotic cells distinguish their chromosome ends from accidental DNA double-strand breaks (DSBs) by packaging them into protective structures called telomeres that prevent DNA repair/recombination activities. Here we investigate the role of key telomeric proteins in protecting budding yeast telomeres from degradation. We show that the Saccharomyces cerevisiae shelterin-like proteins Rif1, Rif2, and Rap1 inhibit nucleolytic processing at both de novo and native telomeres during G1 and G2 cell cycle phases, with Rif2 and Rap1 showing the strongest effects. Also Yku prevents telomere resection in G1, independently of its role in non-homologous end joining. Yku and the shelterin-like proteins have additive effects in inhibiting DNA degradation at G1 de novo telomeres, where Yku plays the major role in preventing initiation, whereas Rif1, Rif2, and Rap1 act primarily by limiting extensive resection. In fact, exonucleolytic degradation of a de novo telomere is more efficient in yku70Δ than in rif2Δ G1 cells, but generation of ssDNA in Yku-lacking cells is limited to DNA regions close to the telomere tip. This limited processing is due to the inhibitory action of Rap1, Rif1, and Rif2, as their inactivation allows extensive telomere resection not only in wild-type but also in yku70Δ G1 cells. Finally, Rap1 and Rif2 prevent telomere degradation by inhibiting MRX access to telomeres, which are also protected from the Exo1 nuclease by Yku. Thus, chromosome end degradation is controlled by telomeric proteins that specifically inhibit the action of different nucleases

Clinical features and outcomes of patients with tubercular uveitis treated with antitubercular therapy in the collaborative ocular tuberculosis study (COTS)-1

IMPORTANCE Eradication of systemic tuberculosis (TB) has been limited by neglected populations and the HIV pandemic. Whereas ocular TB often presents as uveitis without any prior evidence of systemic TB, the existing uncertainty in the diagnosis of TB uveitis may perpetuate missed opportunities to address systemic TB. OBJECTIVE To examine the clinical features of TB uveitis and the associations with response to antitubercular therapy (ATT). DESIGN, SETTING, AND PARTICIPANTS This retrospective multinational cohort study included patients from 25 ophthalmology referral centers diagnosed with TB uveitis and treated with ATT from January 1, 2004, through December 31, 2014, with a minimum follow-up of 1 year. MAIN OUTCOMES AND MEASURES Treatment failure, defined as a persistence or recurrence of inflammation within 6 months of completing ATT, inability to taper oral corticosteroids to less than 10mg/d or topical corticosteroid drops to less than 2 drops daily, and/or recalcitrant inflammation necessitating corticosteroid-sparing immunosuppressive therapy. RESULTS A total of 801 patients (1272 eyes) were studied (mean [SD] age, 40.5 [14.8] years; 413 [51.6%] male and 388 [48.4%] female; 577 [73.6%] Asian). Most patients had no known history (498 of 661 [75.3%]) of systemic TB. Most patients had bilateral involvement (471 of 801 [58.8%]). Common clinical signs reported include vitreous haze (523 of 1153 [45.4%]), retinal vasculitis (374 of 874 [42.8%]), and choroidal involvement (419 of 651 [64.4%]). Treatment failure developed in 102 of the 801 patients (12.7%). On univariate regression analysis, the hazard ratios (HRs) associated with intermediate uveitis (HR, 2.21; 95%CI, 1.07-4.55; P = .03), anterior uveitis (HR, 2.68; 95%CI, 1.32-2.35; P = .006), and panuveitis (HR, 3.28; 95%CI, 1.89-5.67; P < .001) were significantly higher compared with posterior distribution. The presence of vitreous haze had a statistically significant association (HR, 1.95; 95%CI, 1.26-3.02; P = .003) compared with absence of vitreous haze. Bilaterality had an associated HR of 1.50 (95%CI, 0.96-2.35) compared with unilaterality (HR, 1 [reference]), although this finding was not statistically significant (P = .07). On multivariate Cox proportional hazards regression analysis, the presence of vitreous haze had an adjusted HR of 2.98 (95%CI, 1.50-5.94; P = .002), presence of snow banking had an adjusted HR of 3.71 (95%CI, 1.18-11.62; P = .02), and presence of choroidal involvement had an adjusted HR of 2.88 (95%CI, 1.22-6.78; P = .02). CONCLUSIONS AND RELEVANCE A low treatment failure rate occurred in patients with TB uveitis treated with ATT. Phenotypes and test results are studied whereby patients with panuveitis having vitreous and choroidal involvement had a higher risk of treatment failure. These findings are limited by retrospectivemethods. A prospectively derived composite clinical risk score might address this diagnostic uncertainty through holistic and standardized assessment of the combinations of clinical features and investigation results that may warrant diagnosis of TB uveitis and treatment with ATT