Genetic testing for inherited eye conditions in over 6,000 individuals through the eyeGENE network

Genetic testing in a multisite clinical trial network for inherited eye conditions is described in this retrospective review of data collected through eyeGENE®, the National Ophthalmic Disease Genotyping and Phenotyping Network. Participants in eyeGENE were enrolled through a network of clinical providers throughout the United States and Canada. Blood samples and clinical data were collected to establish a phenotype:genotype database, biorepository, and patient registry. Data and samples are available for research use, and participants are provided results of clinical genetic testing. eyeGENE utilized a unique, distributed clinical trial design to enroll 6,403 participants from 5,385 families diagnosed with over 30 different inherited eye conditions. The most common diagnoses given for participants were retinitis pigmentosa (RP), Stargardt disease, and choroideremia. Pathogenic variants were most frequently reported in ABCA4 (37%), USH2A (7%), RPGR (6%), CHM (5%), and PRPH2 (3%). Among the 5,552 participants with genetic testing, at least one pathogenic or likely pathogenic variant was observed in 3,448 participants (62.1%), and variants of uncertain significance in 1,712 participants (30.8%). Ten genes represent 68% of all pathogenic and likely pathogenic variants in eyeGENE. Cross‐referencing current gene therapy clinical trials, over a thousand participants may be eligible, based on pathogenic variants in genes targeted by those therapies. This article is the first summary of genetic testing from thousands of participants tested through eyeGENE, including reports from 5,552 individuals. eyeGENE provides a launching point for inherited eye research, connects researchers with potential future study participants, and provides a valuable resource to the vision community.     

148例新生儿眼结膜炎与产妇阴道病原感染相关性的分析

目的了解自然分娩产妇产道细菌性感染（不包括衣原体）对于新生儿眼结膜炎的发病影响，加强围产期保健，防止婴幼儿视力损害。方法对148例新生儿眼结膜炎患者作结膜囊渗出物细菌培养和药敏试验，根据培养结果将患儿分为A组：培养阴性（无菌生长）组，B组：培养阳性组（有菌生长），同时相应将A组、B组患儿母亲分为产妇A组和产妇B组，作阴道分泌物涂片革兰染色检查相对照。结果产妇A组检出病原菌者5例（17．2％），清洁度正常，未检出病原菌及滴虫者24例（82．8％）。患儿B组检出淋病奈瑟氏菌13株（10．9％），其它各属菌株106株（89．1％）。产妇B组涂片见有白细胞内外革兰阴性双球菌者11例（9．2％）；其它病原菌及念珠菌、滴虫感染者76例（63．9％），清洁度正常，未检出病原菌及滴虫者32例（26．9％）。产妇A组产道感染阳性率17．2％，B组阳性率73．1％，两者比较差异有极显著性（P〈0.001）。结论新生儿眼结膜炎与产妇产道感染有密切相关性，应加强对妊娠中晚期孕妇的生殖道感染防治，减少新生儿经产道感染的几率。     

Visual and vergence eye movement-related responses of pursuit neurons in the caudal frontal eye fields to motion-in-depth stimuli

The caudal parts of the frontal eye fields (FEF) contain smooth-pursuit related neurons. Previous studies show that most FEF pursuit neurons carry visual signals in relation to frontal spot motion and discharge before the initiation of smooth-pursuit. It has also been demonstrated that most FEF pursuit neurons discharge during vergence tracking. Accurate vergence tracking requires information about target motion-in-depth. To further understand the role of the FEF in vergence tracking and to determine whether FEF pursuit neurons carry visual information about target motion-in-depth, we examined visual and vergence eye movement-related responses of FEF pursuit neurons to sinusoidal spot motion-in-depth. During vergence tracking, most FEF pursuit neurons exhibited both vergence eye position and velocity sensitivity. Phase shifts (re target velocity) of most neurons remained virtually constant up to 1.5 Hz. About half of FEF pursuit neurons exhibited visual responses to spot motion-in-depth. The preferred directions for visual responses of most neurons were similar to those during vergence tracking. Visual responses of most of these neurons exhibited sensitivity to the velocity of spot motion-in-depth. Phase shifts of most of the responding neurons remained virtually constant up to 2.0 Hz. Neurons that exhibited visual responses in-depth were mostly separate from neurons that showed visual responses in the frontal plane. To further examine whether FEF pursuit neurons could participate in initiation of vergence tracking, we examined latencies of neuronal responses with respect to vergence eye movements induced by step target motion-in-depth. About half of FEF pursuit neurons discharged before the onset of vergence eye movements with lead times longer than 20 ms. These results together with previous observations suggest that the caudal FEF carries visual signals appropriate to be converted into motor commands for pursuit in depth and frontal plane.     

Formoterol inhaled as dry powder or via pressurized metered-dose inhaler in a cumulative dose-response study

Formoterol administered by a dry-powder (DP) capsule inhaler was compared with a pressurized metered-dose inhaler (pMDI) with regard to bronchodilating and systemic effects. The study used a double-blind, crossover, double-dummy technique. Twelve patients with moderate reversible asthma in a stable phase were examined on two separate study days, and the inhalers were given in randomized order. After baseline measurements, increasing doses of formoterol were given at intervals of 75 min. FEV₁ and heart rate and tremor measurements were repeated after each dose, and the doses were 12 + 12 + 24 + 48 μg, giving a total dose of 96 μg. The peak expiratory flow rate (PEFR) was recorded in the morning before the first dose, after the last dose, and then repeatedly at home until 19 h after the last dose. There was an equal increase in ventilatory capacity at each dose level, independent of inhaler device. Repeated PEFR measurements after the last dose did not reveal any differences in duration of effect. There was a slight but statistically significant increase in heart rate and tremor after the highest doses of the DP formulation compared to the pMDI. These systemic effects can probably be explained by the reduced oral deposition of the aerosol caused by using a spacer. This study indicates that the DP and pMDI formulations of formoterol are equipotent in bronchodilation.     

Neural control of fast-regular saccades and antisaccades: an investigation using positron emission tomography

 Regional cerebral blood flow changes related to the performance of two oculomotor tasks and a central fixation task were compared in ten healthy human subjects. The tasks were: (a) performance of fast-regular saccades; (b) performance of voluntary antisaccades away from a peripheral cue; (c) passive maintenance of central visual fixation in the presence of irrelevant peripheral stimulation. The saccadic task was associated with a relative increase in activity in a number of occipitotemporal areas. Compared with both the fixation and the saccadic task, the performance of antisaccades activated a set of areas including: the superior and inferior parietal lobules, the precentral and prefrontal cortex, the cingulate cortex, and the supplementary motor area. The results of the present study suggest that: (a) compared with self-determined saccadic responses the performance of fast regular, reflexive saccades produces a limited activation of the frontal eye fields; (b) in the antisaccadic task the inferior parietal lobes subserve operations of sensory-motor integration dealing with attentional disengagement from the initial peripheral cue (appearing at an invalid spatial location) and with the recomputation of the antisaccadic vector on the basis of the wrong (e.g., spatially opposite) information provided by the same cue. Received: 20 May 1996 / Accepted: 28 January 1997     

The effects of head and trunk position on torsional vestibular and optokinetic eye movements in humans

We measured torsional vestibular and optokinetic eye movements in human subjects with the head and trunk erect, with the head supine and the trunk erect, and with the head and trunk supine, in order to quantify the effects of otolithic and proprioceptive modulation. During active head movements, the torsional vestibulo-ocular reflex (VOR) had significantly higher gain with the head upright than with the head supine, indicating that dynamic otolithic inputs can supplement the semicircular canal-ocular reflex. During passive earth-vertical axis rotation, torsional VOR gain was similar with the head and trunk supine and with the head supine and the trunk erect. This finding implies that static proprioceptive information from the neck and trunk has little effect upon the torsional VOR. VOR gain with the head supine was not increased by active, self-generated head movement compared with passive, whole body rotation, indicating that the torsional VOR is not augmented by dynamic proprioceptive inputs or by an efference copy of a command for head movement. Viewing earth-fixed surroundings enhanced the torsional VOR, while fixating a chair-fixed target suppressed the VOR, especially at low frequencies. Torsional optokinetic nystagmus (OKN) evoked by a full-field stimulus had a mean slow-phase gain of 0.22 for 10°/s drum rotation, but gain fell to 0.06 for 80°/s stimuli. Despite this fall in gain, mean OKN slow-phase velocities increased with drum speed, reaching maxima of 2.5°/s–8.0°/s in our subjects. Optokinetic afternystagmus (OKAN) was typically absent. Torsional OKN and OKAN were not modified by otolithic or proprioceptive changes caused by altering head and trunk position with respect to gravity. Torsional velocity storage is negligible in humans, regardless of head orientation.Presented in part at the Society for Neuroscience Annual Meeting, October 31, 1989, Phoenix, AZ     

Ultrasound-guided in utero injections allow studies of the development and function of the eye

Ultrasound-guided in utero injections into the brain of murine embryos has been shown to facilitate gene delivery. We investigated whether these methods would allow gene transfer into ocular structures. Gene transfer using retroviral vectors or electroporation was found to be quite effective. We determined the window of time, as well as compared several strains of mice, that yield a high degree of survival and successful gene transfer. Several retroviral constructs were tested for expression and coexpresssion of two genes in retinal cell types. In addition, a retroviral vector was engineered to give cone photoreceptor-enriched expression, and a retroviral vector was demonstrated to provide RNAi-mediated loss-of-function. These methods enable access to early ocular structures and provide a more rapid method of assessment of gene and promoter function than possible using genetically engineered mice.     

Eye tracking as an objective measure of hyperphagia in children with Prader‐Willi syndrome

This study examined sensitivity of eye tracking measures to hyperphagia severity in Prader‐Willi syndrome (PWS). Gaze data were collected in 57 children with PWS, age 3–11 years, and 47 typically developing peers at two study sites during free visual exploration of complex stimulus arrays that included images of food, animals, and household objects. Analysis of the number and duration of fixations as well as gaze perseverations revealed that food items are not exceptionally salient for children with PWS. Instead, increased attention to food in the context of other high‐interest items (e.g., animals) was associated with caregiver reports of more severe hyperphagia and more advanced nutritional phase. The study also provided preliminary evidence of possible genetic subtype and sex differences as well as demonstrated that multiple investigators in a wide range of settings can effectively implement the eye tracking protocol. The results indicate that gaze characteristics derived from eye tracking may be a promising objective marker of hyperphagia in PWS for use in research and clinical trials.