Recessive mutations in SLC38A8 cause foveal hypoplasia and optic nerve misrouting without albinism.

Foveal hypoplasia and optic nerve misrouting are developmental defects of the visual pathway and only co-occur in connection with albinism; to date, they have only been associated with defects in the melanin-biosynthesis pathway. Here, we report that these defects can occur independently of albinism in people with recessive mutations in the putative glutamine transporter gene SLC38A8. Nine different mutations were identified in seven Asian and European families. Using morpholino-mediated ablation of Slc38a8 in medaka fish, we confirmed that pigmentation is unaffected by loss of SLC38A8. Furthermore, by undertaking an association study with SNPs at the SLC38A8 locus, we showed that common variants within this gene modestly affect foveal thickness in the general population. This study reveals a melanin-independent component underpinning the development of the visual pathway that requires a functional role for SLC38A8.

A new recessively inherited disorder composed of foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis maps to chromosome 16q23.3-24.1.

PURPOSE: We have previously described two families with unique phenotypes involving foveal hypoplasia. The first family (F1) presented with foveal hypoplasia and anterior segment dysgenesis, and the second family (F2) presented with foveal hypoplasia and chiasmal misrouting in the absence of albinism. A genome-wide linkage search in family F1 identified a 6.5 Mb locus for this disorder on chromosome 16q23.2-24.1. The aim of this study was to determine if both families have the same disorder and to see if family F2 is also linked to the 16q locus. METHODS: Family members underwent routine clinical examination. Linkage was determined by genotyping microsatellite makers and calculating logarithm of the odds (LOD) scores. Locus refinement was undertaken with single nucleotide polymorphism (SNP) microarray analysis. RESULTS: The identification of chiasmal misrouting in family F1 and anterior segment abnormalities in family F2 suggested that the families have the same clinical phenotype. This was confirmed when linkage analysis showed that family F2 also mapped to the 16q locus. The single nucleotide polymorphism microarray analysis excluded a shared founder haplotype between the families and refined the locus to 3.1 Mb. CONCLUSIONS: We report a new recessively inherited syndrome consisting of foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis, which we have abbreviated to FHONDA syndrome. The gene mutated in this disorder lies within a 3.1 Mb interval containing 33 genes on chromosome 16q23.3-24.1 (chr16:83639061 - 86716445, hg19).

Bilateral changes in foveal structure in individuals with amblyopia.

PURPOSE: To examine foveal structure in amblyopia using spectral-domain optical coherence tomography (SD-OCT). DESIGN: Prospective, cross-sectional study. PARTICIPANTS AND CONTROLS: Two subject groups were recruited to the study: 85 amblyopes (34 adults, 51 children) and 110 visually normal controls (44 adults, 66 children). METHODS: A detailed eye examination, including an SD-OCT scan, was performed in all participants. A total of 390 eyes of 195 subjects were imaged using a 3-dimensional (3D) macula scan covering a nominal 6 × 6-mm area with a resolution of 256 × 256 (65,536 axial scans). Data from the B-scans bisecting the fovea both horizontally and vertically were fitted with a mathematical model of the fovea to determine a range of foveal parameters. MAIN OUTCOME MEASURES: Foveal thickness, foveal pit depth, and foveal pit slope. RESULTS: Bilateral differences between the eyes of amblyopes compared with visually normal controls were found. The difference between foveal structure in amblyopic participants relative to structure in subjects with normal vision persisted even when variables such as age, ethnicity, axial length, and sex were taken into account. Amblyopes showed increased foveal thickness (+8.31 µm; P = 0.006) and a reduction in pit depth in the horizontal meridian (-10.06 µm; P = 0.005) but not in the vertical meridian (P = 0.082) when compared with subjects with normal vision. Foveal pit slopes were found to be approximately 1 degree flatter in the nasal (P = 0.033) and temporal (P = 0.014) meridians in amblyopes, but differences between amblyopes and controls in the superior (P = 0.061) and inferior (P = 0.087) meridians did not reach statistical significance. No statistically significant interocular differences were found in the foveal structure between amblyopic and fellow eyes. CONCLUSIONS: Differences were found in the foveal structure in both eyes of amblyopes compared with subjects with normal vision. These differences consisted of increased foveal thickness, reduced pit depth when measured along the horizontal meridian, and flattening of the nasal and temporal sides of the foveal pit.

The impact of pitch counts and days of rest on performance among major-league baseball pitchers.

Although the belief that overuse can harm pitchers is widespread, there exists little evidence to show that the number of pitches thrown and the days of rest affect future performance and injury among adults. The purpose of this study is to quantify the effects of pitches thrown and the days of rest on pitcher performance. We examined performances of major-league baseball starting pitchers from 1988 to 2009 using fractional polynomial multiple regression to estimate the immediate and cumulative impact of pitches thrown and the days of rest on performance, while controlling for other factors that likely affect pitcher effectiveness. Estimates indicate each pitch thrown in the preceding game increased earned run average (ERA) by 0.007 in the following game. Each pitch averaged in the preceding 5 and 10 games increased the ERA by 0.014 and 0.022, respectively. Older pitchers were more sensitive to cumulative pitching loads than younger pitchers were, but they were less affected by pitches thrown in the preceding game. Rest days were weakly associated with performance. In summary, we found that there is a negative relationship between past pitches thrown and future performance that is virtually linear. The impact of the cumulative pitching load is larger than the impact of a single game. Rest days do not appear to have a large impact on performance. This study supports the popular notion that high pitching loads can dampen future performance; however, because the effect is small, pitch-count benchmarks have limited use for maintaining performance and possibly preventing injury.

Familial exudative vitreoretinopathy and DiGeorge syndrome: a new locus for familial exudative vitreoretinopathy on chromosome 22q11.2?

PURPOSE: To describe a patient with DiGeorge syndrome in association with familial exudative vitreoretinopathy (FEVR). DESIGN: Observational case report. PARTICIPANTS: A newborn female and her parents. METHODS: Family members were examined by slit-lamp biomicroscopy and indirect ophthalmoscopy. Deletion mapping was performed by fluorescent in situ hybridization and genotyping. Mutation screening was undertaken by direct sequencing. MAIN OUTCOME MEASURES: The presence or absence of a microdeletion on chromosome 22q11.2 in the patient and her parents and mutation screening of FZD4 and LRP5 in the patient. RESULTS: The patient had classical features of DiGeorge syndrome and FEVR. A de novo microdeletion on chromosome 22q11.2 was found in the patient, confirming the diagnosis of DiGeorge syndrome. No mutations were identified in the known FEVR genes. CONCLUSIONS: Patients with DiGeorge syndrome should have a dilated retinal examination to look for signs of FEVR. Chromosome 22q11.2 may represent a novel locus for FEVR.

The effect of adherence to spectacle wear on early developing literacy: a longitudinal study based in a large multiethnic city, Bradford, UK.

OBJECTIVES: To determine the impact of adherence to spectacle wear on visual acuity (VA) and developing literacy following vision screening at age 4-5 years. DESIGN: Longitudinal study nested within the Born in Bradford birth cohort. SETTING AND PARTICIPANTS: Observation of 944 children: 432 had failed vision screening and were referred (treatment group) and 512 randomly selected (comparison group) who had passed (<0.20 logarithm of the minimum angle of resolution (logMAR) in both eyes). Spectacle wear was observed in school for 2 years following screening and classified as adherent (wearing spectacles at each assessment) or non-adherent. MAIN OUTCOME MEASURES: Annual measures of VA using a crowded logMAR test. Literacy was measured by Woodcock Reading Mastery Tests-Revised subtest: letter identification. RESULTS: The VA of all children improved with increasing age, -0.009 log units per month (95% CI -0.011 to -0.007) (worse eye). The VA of the adherent group improved significantly more than the comparison group, by an additional -0.008 log units per month (95% CI -0.009 to -0.007) (worse eye) and -0.004 log units per month (95% CI -0.005 to -0.003) in the better eye.Literacy was associated with the VA, letter identification (ID) reduced by -0.9 (95% CI -1.15 to -0.64) for every one line (0.10 logMAR) fall in VA (better eye). This association remained after adjustment for socioeconomic and demographic factors (-0.33, 95% CI -0.54 to -0.12). The adherent group consistently demonstrated higher letter-ID scores compared with the non-adherent group, with the greatest effect size (0.11) in year 3. CONCLUSIONS: Early literacy is associated with the level of VA; children who adhere to spectacle wear improve their VA and also have the potential to improve literacy. Our results suggest failure to adhere to spectacle wear has implications for the child's vision and education.

Prevalence of, and risk factors for, presenting visual impairment: findings from a vision screening programme based on UK NSC guidance in a multi-ethnic population.

PURPOSE: To determine presenting visual acuity levels and explore the factors associated with failing vision screening in a multi-ethnic population of UK children aged 4-5 years. METHODS: Visual acuity (VA) using the logMAR Crowded Test was measured in 16,541 children in a population-based vision screening programme. Referral for cycloplegic examination was based on national recommendations (>0.20logMAR in one or both eyes). Presenting visual impairment (PVI) was defined as VA >0.3logMAR in the better eye. Multivariable logistic regression was used to assess the association of ethnicity, maternal, and early-life factors with failing vision screening and PVI in participants of the Born in Bradford birth cohort. RESULTS: In total, 2467/16,541 (15%) failed vision screening, 732 (4.4%) had PVI. Children of Pakistani (OR: 2.49; 95% CI: 1.74-3.60) and other ethnicities (OR: 2.00; 95% CI: 1.28-3.12) showed increased odds of PVI compared to white children. Children born to older mothers (OR: 1.63; 95% CI: 1.19-2.24) and of low birth weight (OR: 1.52; 95% CI: 1.00-2.34) also showed increased odds. Follow-up results were available for 1068 (43.3%) children, 993 (93%) were true positives; 932 (94%) of these had significant refractive error. Astigmatism (>1DC) (44%) was more common in children of Pakistani ethnicity and hypermetropia (>3.0DS) (27%) in white children (Fisher's exact, p < 0.001). CONCLUSIONS: A high prevalence of PVI is reported. Failing vision screening and PVI were highly associated with ethnicity. The positive predictive value of the vision screening programme was good, with only 7% of children followed up confirmed as false positives.

Myectomy versus anterior transposition for inferior oblique overaction.

BACKGROUND: Inferior oblique overaction can be either secondary (as a sequela of ipsilateral superior oblique palsy) or primary (commonly associated with horizontal strabismus). Superior oblique underaction often coexists with both primary and secondary inferior oblique overaction. This retrospective case series compares the efficacy of inferior oblique myectomy versus anterior transposition in improving inferior oblique overaction and superior oblique underaction in eyes with either primary or secondary inferior oblique overaction. METHODS: One hundred twenty eyes of 81 patients were included in this retrospective case series, of which 20 had anterior transposition of the inferior oblique and 100 eyes underwent myectomy. Inferior oblique myectomy was compared with inferior oblique anterior transposition in improving inferior oblique overaction and superior oblique underaction in each diagnostic subgroup. Postoperative outcome was qualitatively and quantitatively assessed. Fisher's exact test was used to compare the outcomes. The quantitative improvement of function in terms of inferior oblique overaction and superior oblique underaction was analyzed by regression analysis. RESULTS: When postoperative inferior oblique overaction was considered, there was no statistically significant difference between myectomy and anterior transposition in both primary and secondary inferior oblique overaction. Myectomy was superior to anterior transposition in improving superior oblique underaction in both primary inferior oblique overaction (OR = 0.14; 95% CI, 0.015-1.45; p = 0.056) and secondary inferior oblique overaction (OR = 0; 95% CI, 0-0.027; p < 0.001). The quantitative improvement of function showed a significant difference between procedures for superior oblique underaction (t-test; p = 0.005; 95% CI, 0.25-1.3) but not inferior oblique overaction (t-test; p = 0.8; 95% CI, -0.67-0.54). CONCLUSIONS: This study demonstrates both inferior oblique myectomy and inferior oblique anterior transposition to be effective in correcting primary and secondary inferior oblique overaction. Myectomy is more effective in improving superior oblique underaction associated with both primary and secondary inferior oblique overaction. On this basis, we feel that inferior oblique myectomy has some advantage over anterior transposition in treating combined inferior oblique overaction and superior oblique underaction and can be considered the procedure of choice.

Comparison of modified anchored "hang-back technique (HBT)" with conventional HBT in bimedial rectus recession.

PURPOSE: We conducted a retrospective study to establish whether bimedial rectus recession (BMR) using a modified "hang-back technique" (HBT) is comparable with conventional HBT. METHODS: Consecutive patients younger than the age of 16 underwent BMR during 1999 and 2000 with at least a 6-month postoperative follow-up period were included. In 1999, all patients had operations performed with conventional HBT, whereas those in 2000 were conducted with modified HBT. Angles of strabismus were measured preoperatively and at 2 weeks, 2 months, and 6 months postoperatively. RESULTS: Thirty-nine and 43 patients underwent BMR using conventional and modified HBT respectively. Preoperative angles for near and distance were 43.6 (PD) versus 43.5 PD and 36.4 PD versus 36.8 PD. At 6 months' postop, the mean angles for near and distance were 6.4 PD Eso (range, 35 PD Eso - 40 PD Exo) and 5.4 PD Eso (range, 35 PD Eso - 35 PD Exo) in the conventional group: 8.1 PD Eso (range, 35 PD Eso - 20 PD Exo) and 6.3 PD Eso (range, 35 PD Eso - 25 PD Exo) in the modified group. The overall success rate (alignment to within 10 PD of orthotropia for distance and near) was similar between the two groups (conventional HBT:69.2% vs. modified HBT: 67.4%, P = 0.352). However, modified HBT was found to be associated with significantly lower consecutive exotropia rate postoperatively at 6 months (4.7% vs. 20.5%, P = 0.031). CONCLUSION: BMR using modified HBT is as effective as conventional HBT but with a significantly lower consecutive exotropia rate.

Severe complications of strabismus surgery.

PURPOSE: To determine the type, incidence, and clinical outcomes of severe complications from strabismus surgery in the United Kingdom. METHODS: Cases were identified prospectively through a national surveillance unit between September 1, 2008, and August 31, 2010. Questionnaire data were requested at the time of the complication recognition and at 6 months' follow-up. Outcome was graded I to V, with a poor or very poor outcome meaning either loss of corrected visual acuity or primary position double vision. RESULTS: A total of 60 completed reports of adverse events and complications were received during the study period. During the same time approximately 24,000 strabismus surgeries were performed in the United Kingdom, yielding an overall incidence of 1 in 400 operations (95% binomial confidence, 1 per 333-500 operations). The most common reported complication was perforation of the globe (19 [0.08%]), followed by a suspected slipped muscle (16 [0.067%]), severe infection (14 [0.06%]), scleritis (6 [0.02%]), and lost muscle (5 [0.02%]). Overall, complications were reported in adults and children in equal numbers; however, scleritis was significantly more common in adults. A poor or very poor clinical outcome was recorded as 1 operation per 2,400. CONCLUSIONS: This study provides an assessment of the overall risks associated with strabismus surgery in the United Kingdom. Complications with the potential for a poor outcome are relatively common, but the final clinical outcome is good in the majority of cases.

Strabismus surgical skills assessment tool: development of a surgical assessment tool for strabismus surgery training.

PURPOSE: To develop a structured tool to assess strabismus surgical skills and to determine the face and content validity of this tool. DESIGN: Development of a surgical assessment tool and its validation by an expert panel. METHODS: A structured subjective evaluation form was developed to evaluate a trainee's technique and skill in strabismus surgery. The tool consists of strabismus surgery-specific components, such as conjunctival incision, muscle exposure, and suture placement, and global indices, such as hemostasis, tissue control, and knowledge of instruments. Each of these components was evaluated on a 5-point Likert scale. A survey of experienced strabismus surgeons was performed to establish the face and content validity of the tool. The results of the survey were used to amend the tool. RESULTS: The final tool comprises 10 strabismus surgery-specific competencies and 7 global indices. The final version of the tool was deemed to address the vital aspects of a strabismus surgical procedure (face validity), and the components of the assessment tool were deemed to assess appropriate competencies and skills associated with the procedure (content validity). CONCLUSIONS: The strabismus surgery skill assessment tool is a structured quantitative instrument designed to aid surgical evaluation and training of ophthalmic surgical trainees. The Strabismus Surgical Skill Assessment Tool is a paper-based tool that is easy to use, provides the trainee with detailed feedback and a measure of progression of their surgical skills, and stimulates discussion between trainee and trainer to direct further training.

Peak athletic performance and ageing: evidence from baseball.

Baseball players exhibit a pattern of improvement and decline in performance; however, differing lengths of careers and changes in rules and characteristics of the game complicate assessments of age-related effects on performance. This study attempts to isolate the impact of age on several player skills while controlling for relevant outside factors using longitudinal data from 86 seasons of Major League Baseball. The results indicate that players age in different skills in accord with studies of ageing in other athletic contests. For overall performance, multiple-regression estimates indicate that hitters and pitchers peak around the age of 29 - later than previous estimates. Athletic skills such as hitting and running peak earlier than skills that rely heavily on experience and knowledge, such as issuing and drawing walks.

Nurse specialist treatment of eye emergencies: five year follow up study of quality and effectiveness.

The role of specialist nurses in triage, diagnosis and management of emergency eye conditions is well established, and encouraging reports of the safety and effectiveness of such services have been published. Specialist nurses in an emergency eye clinic in the UK seeing >7000 patients per year had been found at initial evaluation to treat 22% of the 1976 patients seen over a three month period without referring on to an ophthalmologist. A repeat of this evaluation five years later found this proportion had dropped to 17% (chi(2) = 16.7, p<0.01). In addition, the initial evaluation had found no incident of any patient having been treated and discharged by the specialist nurses returning to the department due to incorrect diagnosis or mismanagement. By contrast, from the sample 5 years later, 3 patients were identified who returned to the department due to possible misdiagnosis or sub-optimal management. We suggest that provision must be made for continuing professional development of nurses in this type of extended role, and the commitment to ongoing education should be backed up by a system of monitoring and critical incident reporting to facilitate skill maintenance and the life long learning process for specialist nurses.

Variable expression of neurological phenotype in autosomal recessive oculodentodigital dysplasia of two sibs and review of the literature.

Individuals with oculodentodigital dysplasia (ODDD) have a characteristic facial appearance and variable involvement of the eyes, teeth and fingers. Gutmann et al. (Am J Med Genet 41:18, 1990) drew attention to neurological symptoms as a feature in a proportion of individuals with ODDD and demonstrated white matter changes on cranial magnetic resonance imaging. The majority of cases described previously have family histories compatible with autosomal dominant inheritance. Until now, five families have been reported where autosomal recessive inheritance is more likely. Neurological symptoms were described in only one of these families but cerebral imaging was not performed. We describe clinical, including neurological and radiological findings, in two sisters with autosomal recessive ODDD.

Subterranean archipelago in the Australian arid zone: mitochondrial DNA phylogeography of amphipods from central Western Australia.

In 1998, a unique subterranean ecosystem was discovered in numerous isolated calcrete (carbonate) aquifers in the arid Yilgarn region of Western Australia. Previous morphological and genetic analyses of a subterranean water beetle fauna suggest that calcrete aquifers are equivalent to closed island habitats that have been isolated for millions of years. We tested this hypothesis further by phylogeographic analyses of subterranean amphipods (Crangonyctoidea: Paramelitidae and Hyalidae) using mitochondrial DNA sequence data derived from the cytochrome oxidase I gene. Phylogenetic analyses and population genetic analyses (samova) provided strong evidence for the existence of at least 16 crangonyctoid and six hyalid divergent mitochondrial lineages, each restricted in their distribution to a single calcrete aquifer, in support of the 'subterranean island (archipelago) hypothesis' and extending its scope to include entirely water respiring invertebrates. Sequence divergence estimates between proximate calcrete populations suggest that calcretes have been isolated at least since the Pliocene, coinciding with a major aridity phase that led to the intermittent drying of surface water. The distribution of calcretes along palaeodrainage channels and on either side of drainage divides, have had less influence on the overall phylogeographic structure of populations, with evidence that ancestral crangonyctoid and hyalid species moved between catchments multiple times prior to their isolation within calcretes. At least two potential modes of evolution may account for the diversity of subterranean amphipod populations: dispersal/vicariance of stygobitic species or colonization of calcretes by surface species and independent evolution of stygobitic characteristics.

A homozygous diploid subset of commercial wine yeast strains.

Genetic analysis was performed on 45 commercial yeasts which are used in winemaking because of their superior fermentation properties. Genome sizes were estimated by propidium iodide fluorescence and flow cytometry. Forty strains had genome sizes consistent with their being diploid, while five had a range of aneuploid genome sizes that ranged from 1.2 to 1.8 times larger. The diploid strains are all Saccharomyces cerevisiae, based on genetic analysis of microsatellite and minisatellite markers and on DNA sequence analysis of the internal transcribed spacer (ITS) region of nuclear ribosomal DNA of four strains. Four of the five aneuploid strains appeared to be interspecific hybrids between Saccharomyces kudriavzevii and Saccharomyces cerevisiae, with the fifth a hybrid between two S. cerevisiae strains. An identification fingerprint was constructed for the commercial yeast strains using 17 molecular markers. These included six published trinucleotide microsatellites, seven new dinucleotide microsatellites, and four published minisatellite markers. The markers provided unambiguous identification of the majority of strains; however, several had identical or similar patterns, and likely represent the same strain or mutants derived from it. The combined use of all 17 polymorphic loci allowed us to identify a set of eleven commercial wine yeast strains that appear to be genetically homozygous. These strains are presumed to have undergone inbreeding to maintain their homozygosity, a process referred to previously as 'genome renewal'.

Reading speed test for potential central vision measurement.

This study examines the validity and reliability of a reading speed test as a measure of potential central vision. Reading speed was calculated in words per minute (wpm) from the time taken to read 30 words of 1.20 logMAR size text. Scores were obtained from subjects with cataract (n = 48), macular disease(n = 35), peripheral vision loss(n = 14) and normal eyes (n = 10). Subjects with macular disease (27.0 +/- 13.2 wpm) read much slower than subjects with cataract (91.9 +/- 13.6 wpm). Little difference was found between subjects with cataract, peripheral vision loss (91.5 +/- 14.7 wpm)and normal eyes (103.8 +/- 15.5 wpm). Repeat testing gave values within +/- 16% of reading speed. These results suggest that a reading speed test using large text could be useful as a potential central vision test in cataract patients.