Red-green colour blindness, which results from the absence of either the long- (L) or middle- (M) wavelength-sensitive visual photopigments, is the most common single locus genetic disorder. Here, the possibility of curing colour blindness using gene therapy was explored in experiments on adult monkeys that had been colour blind since birth. A third type of cone pigment was added to dichromatic retinas, providing the receptoral basis for trichromatic colour vision. This opened a new avenue to explore the requirements for establishing the neural circuits for a new dimension of colour sensation. Classic visual deprivation experiments1 have led to the expectation that neural connections established during development would not appropriately process an input that was not present from birth. Therefore, it was believed that treatment of congenital vision disorders would be ineffective unless administered to the very young. Here, however, addition of a third opsin in adult red-green colour-deficient primates was sufficient to produce trichromatic colour vision behaviour. Thus, trichromacy can arise from a single addition of a third cone class and it does not require an early developmental process. This provides a positive outlook for the potential of gene therapy to cure adult vision disorders.
The response of the rat visual system to flashes of blue light has been studied by blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI). The BOLD temporal response is dependent on the number of flashes presented and demonstrates a refractory period that depends on flash frequency. Activated brain regions included the primary and secondary visual cortex, superior colliculus (SC), dorsal lateral geniculate (DLG), and lateral posterior nucleus (LP), which were found to exhibit differing temporal responses. To explain these differences, the BOLD neurovascular response function was modeled. A second-order differential equation was developed and solved numerically to arrive at region-specific response functions. Included in the model are the light input from the diode (duty cycle), a refractory period, a transient response following onset and cessation of stimulus, and a slow adjustment to changes in the average level of the signal. Constants in the differential equation were evaluated for each region by fitting the model to the experimental BOLD response from a single flash, and the equation was then solved for multiple flashes. The simulation mimics the major features of the data; however, remaining differences in the frequency dependence of the response between the cortical and subcortical regions were unexplained. We hypothesized that these discrepancies were due to regional-specific differences in neuronal response to flash frequency. To test this hypothesis, cortical visual evoked potentials (VEPs) were recorded using the same stimulation protocol as the fMRI. Cortical VEPs were more suppressed than subcortical VEPs as flash frequency increased, supporting our hypothesis. This is the first report that regional differences in neuronal activation to the same stimulus lead to differential BOLD activation.
Recombinant adeno-associated virus (rAAV) is a promising vector for gene therapy of photoreceptor-based diseases. Previous studies have demonstrated that rAAV serotypes 2 and 5 can transduce both rod and cone photoreceptors in rodents and dogs, and it can target rods, but not cones in primates. Here we report that using a human cone-specific enhancer and promoter to regulate expression of a green fluorescent protein (GFP) reporter gene in an rAAV-5 vector successfully targeted expression of the reporter gene to primate cones, and the time course of GFP expression was able to be monitored in a living animal using the RetCam II digital imaging system.
Pain and itch are common after MThBI, are temporally and spatially concordant and cause significant impact on daily function. Further studies are needed to better understand pain and itch symptom pathogenesis after MThBI, to reduce the tremendous suffering and decline.
Approximately three quarters of major thermal burn injury (MThBI) survivors suffer from hypertrophic scarring (HTS) and over half experience chronic pain or itch. In survivors of MThBI, HTS and chronic pain or itch are considered one of the greatest unmet challenges of postburn injury care and psychosocial reintegration. Although scarring, itch, and pain have been clinically associated, there are no prospective, multisite studies examining tissue autograft site pain or itch and scar outcomes. The authors collected a representative cohort (n = 56) of MThBI survivors who received autografting within 14 days of injury and evaluated graft-site pain or itch severity (0-10 Numeric Rating Scale) and HTS using a validated scar photograph assessment scale 6 months following MThBI. Given that stress is known to influence wound healing, the authors also assessed the relationship between previous trauma exposure, peritraumatic stress, preburn overall health (SF-12), scarring, and chronic pain or itch severity using Spearman's correlation. Association between HTS and chronic pain or itch was significant in a linear regression model adjusted for age, sex, and ethnicity (β = 0.2, P = .033 for pain, β = 0.2, P = .019 for itch). Results indicate that prior trauma exposure is inversely correlated (r = -.363, P = .030) with scar severity, but not pain or itch severity 6 months after MThBI. Study results suggest that preburn chronic pain or itch is associated with pathological scarring 6 months following MThBI. Results also indicate that stress may improve scarring after MThBI. Further work to understand the mechanisms that underlie both HTS and chronic pain or itch and their relationship to chronic stress is critical to the development of novel therapies to assist burn survivors recover.
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