Pediatric ophthalmology and strabismus: something for everyone.

This issue of Current Opinion in Ophthalmology highlights the uniquely broad range of pediatric ophthalmology and strabismus. Perhaps, unlike any other area of ophthalmology, our specialty covers virtually every part of the eye and a multitude of systemic disorders. Pediatric ophthalmology offers the practitioner the opportunity to impact a patient’s visual life for many decades giving them a lifetime of good vision. This issue of the journal highlights the many ways that this is so

Spontaneous disconnection of glaucoma tube shunt extenders.

Glaucoma drainage implants are frequently used in children with severe forms of glaucoma, and tube extenders are sometimes required to compensate for ocular growth or when the intraocular portion of the tube is thought to be too short. We report 2 cases of spontaneous disconnection of a tube extender, occurring 8 months after insertion in one case and 3 years later in the other. In both cases the tube was removed and the patient treated with endoscopic diode laser photocoagulation

Inclusive gluon production in the dipole approach: AGK cutting rules

We consider single gluon production in the dipole model and reproduce the result of Kovchegov and Tuchin for the adjoint (gluonic) dipole structure of the inclusive cross section. We show the validity of the adjoint dipole structure to any order of evolution deriving and solving the non-linear evolution for the non-diagonal cross section of a dipole scattering off the target. The form of the solution to this equation restores the dipole interpretation for non-diagonal cross sections, that appear in gluon production. Using this formalism, we analyse the single inclusive production cross section in terms of the contributions of different multiplicities, and we derive the Abramovskii-Gribov-Kancheli(AGK) cutting rules for two Pomeron exchange. The cutting rules, which were found in this formalism, fully reproduce the original AGK rules for the total cross section. However, for the case of gluon production, the AGK rules are violated already for one gluon emission from the vertex.Comment: 32 pages, 16 figure

The formal and informal surgical ethics curriculum: views of resident and staff surgeons in Toronto.

BACKGROUND: Understanding what staff surgeons think surgical trainees should learn and the ethical issues that trainees need to manage can strengthen surgical ethics education. METHODS: Participants were recruited from the 15 surgical specialty and subspecialty programs at the University of Toronto. Semistructured interviews and focus groups were conducted with 13 ethics coordinators from the surgical staff and 64 resident trainees. Data were analyzed qualitatively using modified thematic analysis. RESULTS: All coordinators and trainees felt that ethics education was an important component of surgical training. Real cases, varying teaching methods, and teachers with applicable clinical experience were valued. Trainees identified intraprofessional and interprofessional conflict, staff behavior perceived to be unethical, and their own lack of experience as challenging issues rarely addressed in the formal ethics curriculum. CONCLUSIONS: Ethics education is highly valued by trainees and teachers. Some ethical issues important to trainees are underrepresented in the formal curriculum. Staff surgeons and senior residents are practicing ethicists and role models whose impact on the moral development of residents is profound. Their participation in the formal curriculum helps less experienced junior residents realize its value

Resident immune cells of the avascular lens: Mediators of the injury and fibrotic response of the lens.

Tissues typically harbor subpopulations of resident immune cells that function as rapid responders to injury and whose activation leads to induction of an adaptive immune response, playing important roles in repair and protection. Since the lens is an avascular tissue, it was presumed that it was absent of resident immune cells. Our studies now show that resident immune cells are a shared feature of the human, mouse, and chicken lens epithelium. These resident immune cells function as immediate responders to injury and rapidly populate the wound edge following mock cataract surgery to function as leader cells. Many of these resident immune cells also express MHCII providing them with antigen presenting ability to engage an adaptive immune response. We provide evidence that during development immune cells migrate on the ciliary zonules and localize among the equatorial epithelial cells of the lens adjacent to where the ciliary zonules associate with the lens capsule. These findings suggest that the vasculature-rich ciliary body is a source of lens resident immune cells. We identified a major role for these cells as rapid responders to wounding, quickly populating each wound were they can function as leaders of lens tissue repair. Our findings also show that lens resident immune cells are progenitors of myofibroblasts, which characteristically appear in response to lens cataract surgery injury, and therefore, are likely agents of lens pathologies to impair vision like fibrosis

Comparison and relative utility of inequality measurements: as applied to Scotland’s child dental health

This study compared and assessed the utility of tests of inequality on a series of very large population caries datasets. National cross-sectional caries datasets for Scotland’s 5-year-olds in 1993/94 (n = 5,078); 1995/96 (n = 6,240); 1997/98 (n = 6,584); 1999/00 (n = 6,781); 2002/03 (n = 9,747); 2003/04 (n = 10,956); 2005/06 (n = 10,945) and 2007/08 (n = 12,067) were obtained. Outcomes were based on the d3mft metric (i.e. the number of decayed, missing and filled teeth). An area-based deprivation category (DepCat) measured the subjects’ socioeconomic status (SES). Simple absolute and relative inequality, Odds Ratios and the Significant Caries Index (SIC) as advocated by the World Health Organization were calculated. The measures of complex inequality applied to data were: the Slope Index of Inequality (absolute) and a variety of relative inequality tests i.e. Gini coefficient; Relative Index of Inequality; concentration curve; Koolman and Doorslaer’s transformed Concentration Index; Receiver Operator Curve and Population Attributable Risk (PAR). Additional tests used were plots of SIC deciles (SIC10) and a Scottish Caries Inequality Metric (SCIM10). Over the period, mean d3mft improved from 3.1(95%CI 3.0–3.2) to 1.9(95%CI 1.8–1.9) and d3mft = 0% from 41.1(95%CI 39.8–42.3) to 58.3(95%CI 57.8–59.7). Absolute simple and complex inequality decreased. Relative simple and complex inequality remained comparatively stable. Our results support the use of the SII and RII to measure complex absolute and relative SES inequalities alongside additional tests of complex relative inequality such as PAR and Koolman and Doorslaer’s transformed CI. The latter two have clear interpretations which may influence policy makers. Specialised dental metrics (i.e. SIC, SIC10 and SCIM10) permit the exploration of other important inequalities not determined by SES, and could be applied to many other types of disease where ranking of morbidity is possible e.g. obesity. More generally, the approaches described may be applied to study patterns of health inequality affecting worldwide populations

Changes in Nascent Chromatin Structure Regulate Activation of the Pro-fibrotic Transcriptome and Myofibroblast Emergence in Organ Fibrosis

Cell reprogramming to a myofibroblast responsible for the pathological accumulation of extracellular matrix is fundamental to the onset of fibrosis. Here, we explored how condensed chromatin structure marked by H3K72me3 becomes modified to allow for activation of repressed genes to drive emergence of myofibroblasts. In the early stages of myofibroblast precursor cell differentiation, we discovered that H3K27me3 demethylase enzymes UTX/KDM6B creates a delay in the accumulation of H3K27me3 on nascent DNA revealing a period of decondensed chromatin structure. This period of decondensed nascent chromatin structure allows for binding of pro-fibrotic transcription factor, Myocardin-related transcription factor A (MRTF-A) to nascent DNA. Inhibition of UTX/KDM6B enzymatic activity condenses chromatin structure, prevents MRTF-A binding, blocks activation of the pro-fibrotic transcriptome, and results in an inhibition of fibrosis in lens and lung fibrosis models. Our work reveals UTX/KDM6B as central coordinators of fibrosis, highlighting the potential to target its demethylase activity to prevent organ fibrosis

Wear Compliance and Activity in Children Wearing Wrist and Hip-Mounted Accelerometers.

PURPOSE: This study aimed to (i) explore children's compliance to wearing wrist and hip-mounted accelerometers, (ii) compare children's physical activity (PA) derived from wrist and hip raw accelerations, and (iii) examine differences in raw and counts PA measured by hip-worn accelerometry. METHODS: One hundred and twenty nine 9-10 y old children wore a wrist-mounted GENEActiv accelerometer (GAwrist) and a hip-mounted ActiGraph GT3X+ accelerometer (AGhip) for 7 d. Both devices measured raw accelerations and the AGhip also provided counts-based data. RESULTS: More children wore the GAwrist than the AGhip regardless of wear time criteria applied (p<.001 - .035). Raw data signal vector magnitude (SVM; r = .68), moderate PA (MPA; r = .81), vigorous PA (VPA; r = .85), and moderate-to-vigorous PA (MVPA; r = .83) were strongly associated between devices (p<.001). GAwrist SVM (p = .001), MPA (p = .037), VPA (p = .002), and MVPA (p = .016) were significantly greater than AGhip. According to GAwrist raw data, 86.9% of children engaged in at least 60 min MVPA[BULLET OPERATOR]d, compared to 19% for AGhip. ActiGraph MPA (raw) was 42.00 ± 1.61 min[BULLET OPERATOR]d compared to 35.05 ± 0.99 min[BULLET OPERATOR]d (counts) (p=.02). Actigraph VPA was 7.59 ± 0.46 min[BULLET OPERATOR]d (raw) and 37.06 ± 1.85 min[BULLET OPERATOR]d (counts; p=.19). CONCLUSION: In children accelerometer wrist placement promotes superior compliance than the hip. Raw accelerations were significantly higher for GAwrist compared to AGhip, possibly due to placement location and technical differences between devices. AGhip PA calculated from raw accelerations and counts differed substantially, demonstrating that PA outcomes derived from cutpoints for raw output and counts cannot be directly compared

Patients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approach.

Retinitis pigmentosa (RP) is a major cause of blindness that affects 1.5 million people worldwide. Mutations in cyclic nucleotide-gated channel β 1 (CNGB1) cause approximately 4% of autosomal recessive RP. Gene augmentation therapy shows promise for treating inherited retinal degenerations; however, relevant animal models and biomarkers of progression in patients with RP are needed to assess therapeutic outcomes. Here, we evaluated RP patients with CNGB1 mutations for potential biomarkers of progression and compared human phenotypes with those of mouse and dog models of the disease. Additionally, we used gene augmentation therapy in a CNGβ1-deficient dog model to evaluate potential translation to patients. CNGB1-deficient RP patients and mouse and dog models had a similar phenotype characterized by early loss of rod function and slow rod photoreceptor loss with a secondary decline in cone function. Advanced imaging showed promise for evaluating RP progression in human patients, and gene augmentation using adeno-associated virus vectors robustly sustained the rescue of rod function and preserved retinal structure in the dog model. Together, our results reveal an early loss of rod function in CNGB1-deficient patients and a wide window for therapeutic intervention. Moreover, the identification of potential biomarkers of outcome measures, availability of relevant animal models, and robust functional rescue from gene augmentation therapy support future work to move CNGB1-RP therapies toward clinical trials

Eight previously unidentified mutations found in the OA1 ocular albinism gene

BACKGROUND: Ocular albinism type 1 (OA1) is an X-linked ocular disorder characterized by a severe reduction in visual acuity, nystagmus, hypopigmentation of the retinal pigmented epithelium, foveal hypoplasia, macromelanosomes in pigmented skin and eye cells, and misrouting of the optical tracts. This disease is primarily caused by mutations in the OA1 gene. METHODS: The ophthalmologic phenotype of the patients and their family members was characterized. We screened for mutations in the OA1 gene by direct sequencing of the nine PCR-amplified exons, and for genomic deletions by PCR-amplification of large DNA fragments. RESULTS: We sequenced the nine exons of the OA1 gene in 72 individuals and found ten different mutations in seven unrelated families and three sporadic cases. The ten mutations include an amino acid substitution and a premature stop codon previously reported by our team, and eight previously unidentified mutations: three amino acid substitutions, a duplication, a deletion, an insertion and two splice-site mutations. The use of a novel Taq polymerase enabled us to amplify large genomic fragments covering the OA1 gene. and to detect very likely six distinct large deletions. Furthermore, we were able to confirm that there was no deletion in twenty one patients where no mutation had been found. CONCLUSION: The identified mutations affect highly conserved amino acids, cause frameshifts or alternative splicing, thus affecting folding of the OA1 G protein coupled receptor, interactions of OA1 with its G protein and/or binding with its ligand