The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.
This statement revises a previous statement on screening of preterm infants for retinopathy of prematurity (ROP) that was published in 2006. ROP is a pathologic process that occurs only in immature retinal tissue and can progress to a tractional retinal detachment, which can result in functional or complete blindness. Use of peripheral retinal ablative therapy by using laser photocoagulation for nearly 2 decades has resulted in a high probability of markedly decreasing the incidence of this poor visual outcome, but the sequential nature of ROP creates a requirement that at-risk preterm infants be examined at proper times and intervals to detect the changes of ROP before they become permanently destructive. This statement presents the attributes on which an effective program for detecting and treating ROP could be based, including the timing of initial examination and subsequent reexamination intervals. Pediatrics 2013;131:189-195
The repair and regeneration of tissues using endogenous stem cells represents an ultimate goal in regenerative medicine. To our knowledge, human lens regeneration has not yet been demonstrated. Currently, the only treatment for cataracts, the leading cause of blindness worldwide, is to extract the cataractous lens and implant an artificial intraocular lens. However, this procedure poses notable risks of complications. Here we isolate lens epithelial stem/progenitor cells (LECs) in mammals and show that Pax6 and Bmi1 are required for LEC renewal. We design a surgical method of cataract removal that preserves endogenous LECs and achieves functional lens regeneration in rabbits and macaques, as well as in human infants with cataracts. Our method differs conceptually from current practice, as it preserves endogenous LECs and their natural environment maximally, and regenerates lenses with visual function. Our approach demonstrates a novel treatment strategy for cataracts and provides a new paradigm for tissue regeneration using endogenous stem cells.
Purpose The objectives of the present study were to evaluate whether investigator bias influenced the Convergence Insufficiency Symptom Survey (CISS) scores of children with normal binocular vision (NBV) in our original validation study, reevaluate the usefulness of the cut-off score of 16, and reexamine the validity of the CISS. Methods Six clinical sites participating in the Convergence Insufficiency Treatment Trial (CITT) enrolled 46 children 9 - <18 years with NBV. Examiners masked to the child’s binocular vision status administered the CISS. The mean CISS score was compared to that from the children with NBV in the original, unmasked CISS study and also to that of the 221 symptomatic CI children enrolled in the CITT. Results The mean (±SD) CISS score for 46 subjects with NBV was 10.4 (±8.1). This was comparable to that from our prior unmasked NBV study (mean = 8.1(± 6.2); p = 0.11), but was significantly different from that of the CITT CI group (mean = 29.8 ± 9.0; p < 0.001). Eighty-three percent of these NBV subjects scored less than 16 on the CISS, which is not statistically different from the 87.5% found in the original unmasked study (p = 0.49). Conclusions Examiner bias did not affect the CISS scores for subjects with NBV in our prior study. The CISS continues to be a valid instrument for quantifying symptoms in 9 to <18 year-old children and these results confirm the validity of a cut-point of ≥ 16 in distinguishing children with symptomatic CI from those with NBV.
Objective-To compare home-based pencil push-ups (HBPP), home-based computer vergence/ accommodative therapy and pencil push-ups (HBCVAT+), office-based vergence/accommodative therapy with home reinforcement (OBVAT), and office-based placebo therapy with home reinforcement (OBPT) as treatments for symptomatic convergence insufficiency (CI).Methods-In a randomized clinical trial, 221 children 9 to 17 years with symptomatic CI were assigned to one of four treatments.Main Outcome Measures-Convergence Insufficiency Symptom Survey (CISS) score after 12 weeks of treatment. Secondary outcomes were near point of convergence (NPC) and positive fusional vergence at near (PFV).Results-After 12 weeks of treatment the OBVAT group's CISS score (15.1) was statistically significantly lower than the HBCVAT+, HBPP, and OBPT groups' scores of 21.3, 24.7, and 21.9, respectively (P < 0.001). The OBVAT group also demonstrated a significantly improved NPC and PFV compared with the other groups (P <= 0.005). A successful or improved outcome for the OBVAT, HBPP, HBCVAT+, and OBPT groups was found in 73%, 43%, 33%, and 35%, respectively.Conclusion-Twelve weeks of OBVAT results in a significantly greater improvement in symptoms and clinical measures of NPC and PFV and a greater percentage of patients reaching predetermined criteria of success when compared with HBPP, HBCVAT+, or OBPT.
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