Detecting Common Eye Diseases Using the First Teleophthalmology GlobeChek Kiosk in the United States: A Pilot Study.

PURPOSE: The aim of this study was to assess the benefit and feasibility of the teleophthalmology GlobeChek kiosk in a community-based program. DESIGN: Single-site, nonrandomized, cross-sectional, teleophthalmologic study. METHODS: Participants underwent comprehensive evaluation that consists of a questionnaire form, brief systemic evaluation, screening visual field (VF), and GlobeChek kiosk screening, which included but not limited to intraocular pressure, pachymetry, anterior segment optical coherence tomography, posterior segment optical coherence tomography, and nonmydriatic fundus photography. The results were evaluated by a store-and-forward mechanism and follow-up questionnaires were obtained through phone calls. RESULTS: A total of 326 participatents were screened over 4 months. One hundred thirty-three (40.79%) participants had 1 condition in either eye, and 47 (14.41%) had >1 disease. Seventy (21.47%) had glaucoma, 37 (11.34%) narrow-angles, 6 (1.84%) diabetic retinopathy, 4 (1.22%) macular degeneration, and 43 (13.10%) had other eye disease findings. Age >65, history of high blood pressure, diabetes mellitus, not having a dental examination >5 years, hemoglobn A1c measurement of ≥5.6, predibates risk score of ≥9, stage 2 hypertension, and low blood pressure were found to be significant risk factors. As for the ocular parameters, all but central corneal thickness, including an intraocular pressure >21 mm Hg, vertical cup to disc ratio >0.7, visual field abnormalities, and retinal nerve fiber layer thinning were found to be significant. CONCLUSIONS: GlobeChek kiosk is both workable and effective in increasing access to care and identifying the most common causes of blindness and their risk factors.

Quantitative trait loci for interhemispheric commissure development and social behaviors in the BTBR T⁺ tf/J mouse model of autism.

BACKGROUND: Autism and Agenesis of the Corpus Callosum (AgCC) are interrelated behavioral and anatomic phenotypes whose genetic etiologies are incompletely understood. We used the BTBR T⁺ tf/J (BTBR) strain, exhibiting fully penetrant AgCC, a diminished hippocampal commissure, and abnormal behaviors that may have face validity to autism, to study the genetic basis of these disorders. METHODS: We generated 410 progeny from an F2 intercross between the BTBR and C57BL/6J strains. The progeny were phenotyped for social behaviors (as juveniles and adults) and commisural morphology, and genotyped using 458 markers. Quantitative trait loci (QTL) were identified using genome scans; significant loci were fine-mapped, and the BTBR genome was sequenced and analyzed to identify candidate genes. RESULTS: Six QTL meeting genome-wide significance for three autism-relevant behaviors in BTBR were identified on chromosomes 1, 3, 9, 10, 12, and X. Four novel QTL for commissural morphology on chromosomes 4, 6, and 12 were also identified. We identified a highly significant QTL (LOD score = 20.2) for callosal morphology on the distal end of chromosome 4. CONCLUSIONS: We identified several QTL and candidate genes for both autism-relevant traits and commissural morphology in the BTBR mouse. Twenty-nine candidate genes were associated with synaptic activity, axon guidance, and neural development. This is consistent with a role for these processes in modulating white matter tract development and aspects of autism-relevant behaviors in the BTBR mouse. Our findings reveal candidate genes in a mouse model that will inform future human and preclinical studies of autism and AgCC.

LTP induction translocates cortactin at distant synapses in wild-type but not Fmr1 knock-out mice.

Stabilization of long-term potentiation (LTP) depends on reorganization of the dendritic spine actin cytoskeleton. The present study tested whether this involves activity-driven effects on the actin-regulatory protein cortactin, and whether such effects are disturbed in the Fmr1 knock-out (KO) model of fragile X syndrome, in which stabilization of both actin filaments and LTP is impaired. LTP induced by theta burst stimulation (TBS) in hippocampal slices from wild-type mice was associated with rapid, broadly distributed, and NMDA receptor-dependent decreases in synapse-associated cortactin. The reduction in cortactin content was blocked by blebbistatin, while basal levels were reduced by nocodazole, indicating that cortactin's movements into and away from synapses are regulated by microtubule and actomyosin motors, respectively. These results further suggest that synapse-specific LTP influences cytoskeletal elements at distant connections. The rapid effects of TBS on synaptic cortactin content were absent in Fmr1 KOs as was evidence for activity-driven phosphorylation of the protein or its upstream kinase, ERK1/2. Phosphorylation regulates cortactin's interactions with actin, and coprecipitation of the two proteins was reduced in the KOs. We propose that, in the KOs, excessive basal phosphorylation of ERK1/2 disrupts its interactions with cortactin, thereby blocking the latter protein's use of actomyosin transport systems. These impairments are predicted to compromise the response of the subsynaptic cytoskeleton to learning-related afferent activity, both locally and at distant sites.

Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent Shank3 null mutant mice.

Mutations in the synaptic scaffolding protein gene SHANK3 are strongly implicated in autism and Phelan-McDermid 22q13 deletion syndrome. The precise location of the mutation within the Shank3 gene is key to its phenotypic outcomes. Here, we report the physiological and behavioral consequences of null and heterozygous mutations in the ankyrin repeat domain in Shank3 mice. Both homozygous and heterozygous mice showed reduced glutamatergic transmission and long-term potentiation in the hippocampus with more severe deficits detected in the homozygous mice. Three independent cohorts were evaluated for magnitude and replicability of behavioral endophenotypes relevant to autism and Phelan-McDermid syndrome. Mild social impairments were detected, primarily in juveniles during reciprocal interactions, while all genotypes displayed normal adult sociability on the three-chambered task. Impaired novel object recognition and rotarod performance were consistent across cohorts of null mutants. Repetitive self-grooming, reduced ultrasonic vocalizations, and deficits in reversal of water maze learning were detected only in some cohorts, emphasizing the importance of replication analyses. These results demonstrate the exquisite specificity of deletions in discrete domains within the Shank3 gene in determining severity of symptoms.

Low sociability in BTBR T+tf/J mice is independent of partner strain.

Inbred mouse strains differ greatly in social behaviors, making them a valuable resource to study genetic and non-genetic mechanisms underlying social deficits relevant to autism spectrum disorders. A hallmark symptom of autism is a lack of ability to understand other people's thoughts and intentions, which leads to impairments in adjusting behaviors in response to ever-changing social situations in daily life. We compared the ability of BTBR T+tf/J (BTBR), a strain with low sociability, and C57BL/6J (B6), a strain with high sociability, for their abilities to modulate responses to social cues from different partners in the reciprocal social interaction test. Results indicate that BTBR exhibited low sociability toward different partners and displayed minimal ability to modify behaviors toward different partners. In contrast, B6 showed high sociability toward different partners and was able to modify social behaviors toward different partners. Consistent results were found in two independent cohorts of different ages, and in both sexes. In the three-chambered test, high sociability in B6 and low sociability in BTBR were independent of strain of the novel mouse. Since social deficits in BTBR could potentially be caused by physical disabilities in detecting social olfactory cues, or in cognitive abilities, we tested BTBR and B6 mice on measures of olfaction and cognition. BTBR mice displayed more sniffing of social odors emitted by soiled bedding than of an odorless novel object, but failed to show a preference for a live novel mouse over a novel object. On olfactory habituation/dishabituation to a sequence of odors, BTBR displayed discrimination abilities across three non-social and two social odors. However, as compared to B6, BTBR displayed less sniff time for both non-social and social odors, and no significant dishabituation between cage odors from two different novel mouse strains, findings that will be important to investigate further. BTBR was generally normal in spatial acquisition on the Morris water maze test, but showed deficits in reversal learning. Time spent freezing on contextual and cued fear conditioning was lower in BTBR than in B6. Our findings suggest that BTBR has poor abilities to modulate its responses to different social partners, which may be analogous to social cognition deficits in autism, adding to the value of this strain as a mouse model of autism.

Social peers rescue autism-relevant sociability deficits in adolescent mice.

Behavioral therapies are currently the most effective interventions for treating the diagnostic symptoms of autism. We employed a mouse model of autism to evaluate components of behavioral interventions that improve sociability in mice. BTBR T+tf/J (BTBR) is an inbred mouse strain that exhibits prominent behavioral phenotypes with face validity to all three diagnostic symptom categories of autism, including robust and well-replicated deficits in social approach and reciprocal social interactions. To investigate the role of peer interactions in the development of sociability, BTBR juvenile mice were reared in the same home cage with juvenile mice of a highly social inbred strain, C57BL/6J (B6). Subject mice were tested as young adults for sociability and repetitive behaviors. B6 controls reared with B6 showed their strain-typical high sociability. BTBR controls reared with BTBR showed their strain-typical lack of sociability. In contrast, BTBR reared with B6 as juveniles showed significant sociability as young adults. A 20-day intervention was as effective as a 40-day intervention for improving social approach behavior. High levels of repetitive self-grooming in BTBR were not rescued by peer-rearing with B6, indicating specificity of the intervention to the social domain. These results from a robust mouse model of autism support the interpretation that social enrichment with juvenile peers is a beneficial intervention for improving adult outcome in the social domain. This novel paradigm may prove useful for discovering factors that are essential for effective behavioral treatments, and biological mechanisms underlying effective behavioral interventions.

Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication.

BACKGROUND: SHANK3 is a protein in the core of the postsynaptic density (PSD) and has a critical role in recruiting many key functional elements to the PSD and to the synapse, including components of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA), metabotropic glutamate (mGlu) and N-methyl-D-aspartic acid (NMDA) glutamate receptors, as well as cytoskeletal elements. Loss of a functional copy of the SHANK3 gene leads to the neurobehavioral manifestations of 22q13 deletion syndrome and/or to autism spectrum disorders. The goal of this study was to examine the effects of haploinsufficiency of full-length Shank3 in mice, focusing on synaptic development, transmission and plasticity, as well as on social behaviors, as a model for understanding SHANK3 haploinsufficiency in humans. METHODS: We used mice with a targeted disruption of Shank3 in which exons coding for the ankyrin repeat domain were deleted and expression of full-length Shank3 was disrupted. We studied synaptic transmission and plasticity by multiple methods, including patch-clamp whole cell recording, two-photon time-lapse imaging and extracellular recordings of field excitatory postsynaptic potentials. We also studied the density of GluR1-immunoreactive puncta in the CA1 stratum radiatum and carried out assessments of social behaviors. RESULTS: In Shank3 heterozygous mice, there was reduced amplitude of miniature excitatory postsynaptic currents from hippocampal CA1 pyramidal neurons and the input-output (I/O) relationship at Schaffer collateral-CA1 synapses in acute hippocampal slices was significantly depressed; both of these findings indicate a reduction in basal neurotransmission. Studies with specific inhibitors demonstrated that the decrease in basal transmission reflected reduced AMPA receptor-mediated transmission. This was further supported by the observation of reduced numbers of GluR1-immunoreactive puncta in the stratum radiatum. Long-term potentiation (LTP), induced either with θ-burst pairing (TBP) or high-frequency stimulation, was impaired in Shank3 heterozygous mice, with no significant change in long-term depression (LTD). In concordance with the LTP results, persistent expansion of spines was observed in control mice after TBP-induced LTP; however, only transient spine expansion was observed in Shank3 heterozygous mice. Male Shank3 heterozygotes displayed less social sniffing and emitted fewer ultrasonic vocalizations during interactions with estrus female mice, as compared to wild-type littermate controls. CONCLUSIONS: We documented specific deficits in synaptic function and plasticity, along with reduced reciprocal social interactions in Shank3 heterozygous mice. Our results are consistent with altered synaptic development and function in Shank3 haploinsufficiency, highlighting the importance of Shank3 in synaptic function and supporting a link between deficits in synapse function and neurodevelopmental disorders. The reduced glutamatergic transmission that we observed in the Shank3 heterozygous mice represents an interesting therapeutic target in Shank3-haploinsufficiency syndromes.