James N. Ver Hoeve

Apnea and sudden unexpected death in infants with achondroplasia

Thirteen infants with achondroplasia and sudden unexpected death or unexplained apnea were discovered through nonsystematic retrospective case collection. Most were initially thought to have died from sudden infant death syndrome. However, historical and pathologic findings suggest that many of these infants had apnea and sudden unexpected death secondary to acute or chronic compression of the lower brainstem or cervical spinal cord. Infants with achondroplasia evidently are at considerably increased risk for such deaths between 1 month and 1 year of age. Appropriate intervention, given these previously unrecognized risks, may include cervical restraint, polysomnographic evaluation, and apnea monitoring.

Threshold and suprathreshold spatiotemporal response throughout adulthood

The effect of age on spatiotemporal contrast sensitivity at both threshold and suprathreshold levels was studied in 63 adults ranging in age from 13 to 67 years. Sensitivity for low spatial frequencies modulated at 0 to 15 Hz was not affected by age, but a progressive age-related elevation of threshold was found for combinations of high spatial and temporal frequencies. The magnitude of the effect ascribed to age on spatial frequency was larger than the effect of age on temporal frequency. For most combinations of spatial and temporal frequencies, elevation of thresholds started at approximately 45 years of age. No age-related effects were observed in a contrast-matching task performed at suprathreshold levels.

The beginning of conversation: Early patterns of mother-infant vocal responsiveness☆

Abstract Microanalytic techniques were used to characterize the structure of the prespeech communication of 4-month-old infants and their mothers. Two observers continuously recorded the interactive behavior of mothers and their infants during hour-long observations in the homes of 25 families. Loglinear models were used to examine the extent to which the vocal behavior of one person was conditional upon the vocal behavior of the partner. Within the limits of this microanalytic approach, analyses indicated that patterns of mother-infant vocal exchange were structurally similar to patterns of adult conversation. Initial vocal responses were followed by suppression of vocalization, allowing the partner to join the conversation. The comparative effectiveness of vocal behavior as an elicitor of vocalization and as a response to vocalization was shown for mothers and infants relative to the other behaviors observed. Vocalization served as a modulator of visual attentiveness: When the partner was not visually attentive, vocalization elicited visual attention.

Photopigment basis for dichromatic color vision in the horse

Horses, like other ungulates, are active in the day, at dusk, dawn, and night; and, they have eyes designed to have both high sensitivity for vision in dim light and good visual acuity under higher light levels (Walls, 1942). Typically, daytime activity is associated with the presence of multiple cone classes and color-vision capacity (Jacobs, 1993). Previous studies in other ungulates, such as pigs, goats, cows, sheep and deer, have shown that they have two spectrally different cone types, and hence, at least the photopigment basis for dichromatic color vision (Neitz & Jacobs, 1989; Jacobs, Deegan II, Neitz, Murphy, Miller, & Marchinton, 1994; Jacobs, Deegan II, & Neitz, 1998). Here, electroretinogram flicker photometry was used to measure the spectral sensitivities of the cones in the domestic horse (Equus caballus). Two distinct spectral mechanisms were identified and are consistent with the presence of a short-wavelength-sensitive (S) and a middle-to-long-wavelength-sensitive (M/L) cone. The spectral sensitivity of the S cone was estimated to have a peak of 428 nm, while the M/L cone had a peak of 539 nm. These two cone types would provide the basis for dichromatic color vision consistent with recent results from behavioral testing of horses (Macuda & Timney, 1999; Macuda & Timney, 2000; Timney & Macuda, 2001). The spectral peak of the M/L cone photopigment measured here, in vivo, is similar to that obtained when the gene was sequenced, cloned, and expressed in vitro (Yokoyama & Radlwimmer, 1999). Of the ungulates that have been studied to date, all have the photopigment basis for dichromatic color vision; however, they differ considerably from one another in the spectral tuning of their cone pigments. These differences may represent adaptations to the different visual requirements of different species.

Functional and Anatomic Consequences of Subretinal Dosing in the Cynomolgus Macaque

OBJECTIVE To characterize functional and anatomic sequelae of a bleb induced by subretinal injection. METHODS Subretinal injections (100 μL) of balanced salt solution were placed in the superotemporal macula of 1 eye in 3 cynomolgus macaques. Fellow eyes received intravitreal injections (100 μL) of balanced salt solution. Fundus photography, ocular coherence tomography, and multifocal electroretinography were performed before and immediately after injection and again at intervals up to 3 months postinjection. Histopathologic analyses included transmission electron microscopy and immunohistochemistry for glial fibrillary acidic protein, rhodopsin, M/L-cone opsin, and S-cone opsin. RESULTS Retinas were reattached by 2 days postinjection (seen by ocular coherence tomography). Multifocal electroretinography waveforms were suppressed post-subretinal injection within the subretinal injection bleb and, surprisingly, also in regions far peripheral to this area. Multifocal electroretinography amplitudes were nearly completely recovered by 90 days. The spectral-domain ocular coherence tomography inner segment-outer segment line had decreased reflectivity at 92 days. Glial fibrillary acidic protein and S-cone opsin staining were unaffected. Rhodopsin and M/L-cone opsins were partially displaced into the inner segments. Transmission electron microscopy revealed disorganization of the outer segment rod (but not cone) discs. At all postinjection intervals, eyes with intravitreal injection were similar to baseline. CONCLUSIONS Subretinal injection is a promising route for drug delivery to the eye. Three months post-subretinal injection, retinal function was nearly recovered, although reorganization of the outer segment rod disc remained disrupted. Understanding the functional and anatomic effects of subretinal injection is important for interpretation of the effects of compounds delivered to the subretinal space. CLINICAL RELEVANCE Subretinal injection is a new potential route for drug delivery to the eye. Separating drug effects from the procedural effects is critical.

The artifact of retinoscopy revisited: comparison of refractive error measured by retinoscopy and visual evoked potential in the rat.

Purpose. The validity of retinoscopy in small eyes has not been clearly established due to uncertainty regarding the source of the ocular reflections assessed during this procedure. A widely cited model which proposes that their origin is the inner limiting membrane of the retina was evaluated in the rat by comparing refractive errors measured by retinoscopy to those measured by visual evoked potentials (VEPs). Methods. Ten rats were refracted both by cycloplegic streak retinoscopy and by VEP while viewing 0.05 to 0.15 cpd square-wave gratings reversed at 1.875 Hz. Spherical aberration of the rat eye was assessed as a potentially confounding variable in VEP refraction by sequential retinoscopic refractions across the rats natural pupil through a 1.5-mm pinhole. Results. All animals were moderately to highly hyperopic by both methods (range=+4.5 to +18.5 D). Spherical aberration was minimal (median=3.5 D of overcorrected aberration). The median difference between retinoscopic refractions and those by VEP was not significant (+1.94 D more hyperopia by retinoscopy; p=0.062, Wilcoxon signed rank) but was significantly less than the +9.64 D difference predicted by an inner limiting membrane model (upper 95% limit=+3.76 D). Conclusion. This suggests that the origin of the retinoscopic reflex is located in the outer retina rather than at the inner limiting membrane. Correction factors for retinoscopy in small eyes may be smaller than previously assumed.

VEP and PERG acuity in anesthetized young adult rhesus monkeys.

This study used the swept spatial-frequency method to compare retinal and cortical acuity in anesthetized young adult rhesus monkeys. Visual evoked potentials (VEPs) and pattern electroretinographic responses (PERGs) were recorded from 25 monkeys (age range: 4-12 years) anesthetized with a continuous infusion of propofol. The stimuli were temporally countermodulated sine-wave gratings that increased in spatial frequency within a 10.24-s period. All animals were refracted using acuity estimated from the zero micro-volt intercept of the linear regression of evoked potential amplitude on spatial frequency. Average sweep acuities were 23.7 cycles/deg +/- 1.5 S.E.M. and 23.1 cycles/deg +/- 1.8 S.E.M. for the PERG and VEP, respectively. VEP and PERG acuities were within the range expected based on acuities estimated from behavioral studies in macaques. PERG and VEP acuities were highly correlated (r = 0.90) and equally sensitive to spherical blur. On a subset of animals, test-retest reliability of animals, and interocular correlations, were high (r = 0.87 and r = 0.83, respectively). Increasing propofol dosage 8-fold did not degrade PERG or VEP acuity. This study demonstrates that high spatial-frequency acuities can be rapidly obtained from young adult rhesus monkeys under a wide dose range of propofol anesthesia using the swept spatial-frequency method.

Photobiomodulation for the Treatment of Retinal Injury and Retinal Degenerative Diseases

Retinal injury and retinal degenerative diseases are a leading causes of visual impairment in the developed world. Mitochondrial dysfunction and oxidative stress play key roles in the pathogenesis of retinal injury and disease. The development and testing of strategies designed to improve mitochondrial function and attenuate oxidative stress are essential for combating retinal disease. One strategy involves the use of photobiomodulation. Photobiomodulation, low-energy photon irradiation by light in the far-red to near-infrared (NIR) range using low energy lasers or light-emitting diode (LED) arrays, has been applied clinically in the treatment soft tissue injuries and acceleration of wound healing for more than 30 years. The therapeutic effects of photobiomodulation have been hypothesized to be mediated by intracellular signaling mechanisms triggered by the interaction of farred to NIR photons with the mitochondrial photoacceptor molecule cytochrome oxidase which culminate in improved mitochondrial energy metabolism, increased synthesis of cytoprotective factors and cell survival.

Spondylometaphyseal dysplasia with cone-rod dystrophy.

The co‐occurrence of ophthalmologic abnormality and intrinsic skeletal dysplasia is uncommon. We describe eight instances of a unique form of spondylometaphyseal dysplasia (SMD) associated with cone‐rod dystrophy (although documentation is insufficient to be certain of that diagnosis in some). This is a new, syndromic form of SMD for which there is evidence for autosomal recessive transmission. Recognition of the specific bony features described here should precipitate comprehensive ophthalmologic assessment, since vision impairment becomes significantly disabling with age.

Multifocal Visual Evoked Potentials in the Anesthetized Non-human Primate

Purpose: To evaluate monkey multifocal visual evoked cortical potentials (mfVEPs) recorded from central and peripheral fields for reliability and isolation from electroretinographic (ERG) activity. Methods: The mfVEP stimulus consisted of a 7-element hexagonal array that subtended 80 degrees of the central visual field. Recordings were made under intravenous pentobarbital sodium (15 mg/kg) anesthesia. Two monkeys with absent optic nerve and ganglion cell function after combined unilateral optic nerve transection and experimental ocular hypertension (ONT/OHT) were followed longitudinally. In a second study, 16 ophthalmologically normal monkeys were tested once. Results: Testing of the non-transected eye in two transected animals revealed robust first- and second-order kernel, first slice (K1 and K2.1) mfVEPs. Stimulation of the transected eye revealed no contamination of the mfVEP from the concurrently recorded multifocal ERGs. There was complete separation of the root-mean-square (RMS) mfVEP amplitudes from the transected and the fellow eyes tested repeatedly across a 4- to 17- month period. The largest amplitude mfVEP was generated by the central element; however, mfVEPs were recorded from outside the central 20 degrees element. The 16 normal animals showed waveforms similar to the normal eyes of the ONT/OHT animals both in shape and distribution throughout the visual field. A scalar-product measure showed both K1 and K2.1 mfVEPs from central and some peripheral elements were statistically distinct from noise. Conclusions: mfVEPs can be reliably recorded from non-human primates anesthetized with pentobarbital. Under the recording conditions described, mfVEPs are not contaminated by ERG activity. mfVEPs may be useful in animal models of diseases that differentially affect macular and peripheral visual field responsiveness.