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Normal human retinal development involves orderly generation of rods and cones by complex mechanisms. Cell-fate specification involves progenitor cell lineage and external signals such as soluble factors and cell-cell interactions. In most inherited human retinal degenerations, including retinitis pigmentosa, a mutant gene causes loss of visual function, death of mature rods, and eventually death of all cone subtypes. Only one inherited retinal disorder, the enhanced S cone syndrome (ESCS), shows increased visual function, involving the minority S (blue) cones, and decreased rod and L͞M (red͞green) cone function. This autosomal recessive disease is caused by mutations in NR2E3, a photoreceptor nuclear receptor transcription factor, and may result from abnormal cell-fate determination, leading to excess S cones at the expense of other photoreceptor subtypes. In 16 ESCS patients with the most common NR2E3 mutation, R311Q, we documented an abnormal ratio of S to L͞M cone function and progressive retinal degeneration. We studied the postmortem retina of an ESCS patient homozygous for NR2E3 R311Q. No rods were identified, but cones were increased approximately 2-fold, and 92% were S cones. Only 15% of the cones expressed L͞M cone opsin, and some coexpressed S cone opsin. The retina was disorganized, with densely packed cones intermixed with inner retinal neurons. The retina was also degenerate, retaining photoreceptors in only the central and far peripheral regions. These observations suggest a key role for NR2E3 in regulation of human photoreceptor development. Degeneration of the NR2E3 retina may result from defective development, known S cone fragility, or abnormal maintenance of mature photoreceptors. T he molecular events during development of invertebrate and vertebrate retinas are incompletely understood. The specification of rods and cones involves interactions of both intrinsic and extrinsic factors, including cell lineage, soluble factors, and local cell-cell interactions (1-3). These complex signaling pathways involve nuclear receptors, a superfamily of transcription factors that share structural features, including DNA and ligandbinding domains (4, 5). A human photoreceptor-specific nuclear receptor (PNR), NR2E3, is a member of the nuclear receptor subfamily II (6). Coexpression of NR2E3, CRX (cone-rod homeobox; ref. 7), and NRL (nuclear retina leucine zipper; ref. 8) in human Y79 retinoblastoma cells suggests that NR2E3 is a component of a photoreceptor transcription cascade in human retinal development (6).Mutations in NR2E3 (9, 10) cause a unique human retinal disease, the enhanced S cone syndrome (ESCS), initially described using psychophysical and electrophysiological methods (11). ESCS patients lack rod photoreceptor function, like other inherited retinal degenerations such as retinitis pigmentosa (12), but are unique because their S (blue) cones, normally a minority population (13), are more responsive to light than the usually more populous L͞M (red͞green) cones (11, 14-16). The retinal pathology ...

The COPD assessment test (CAT) is a self-administered questionnaire that measures healthrelated quality of life. We aimed to systematically evaluate the literature for reliability, validity, responsiveness and minimum clinically important difference (MCID) of the CAT.Multiple databases were searched for studies analysing the psychometric properties of the CAT in adults with chronic obstructive pulmonary disease. Two reviewers independently screened, selected and extracted data, and assessed methodological quality of relevant studies using the COSMIN checklist.From 792 records identified, 36 studies were included. The number of participants ranged from 45 to 6469, mean age from 56 to 73 years, and mean forced expiratory volume in 1 s from 39% to 98% predicted. Internal consistency (reliability) was 0.85-0.98, and test-retest reliability was 0.80-0.96. Convergent and longitudinal validity using Pearson's correlation coefficient were: SGRQ-C 0.69-0.82 and 0.63, CCQ 0.68-0.78 and 0.60, and mMRC 0.29-0.61 and 0.20, respectively. Scores differed with GOLD stages, exacerbation and mMRC grades. Mean scores decreased with pulmonary rehabilitation (2.2-3 units) and increased at exacerbation onset (4.7 units). Only one study with adequate methodology reported an MCID of 2 units and 3.3-3.8 units using the anchor-based approach and distribution-based approach, respectively. Most studies had fair methodological quality.We conclude that the studies support the reliability and validity of the CAT and that the tool is responsive to interventions, although the MCID remains debatable. @ERSpublications Studies support the reliability, validity and responsiveness of the CAT as a HRQoL tool but its MCID remains unclear