中枢神経系疾患の治療は正常細胞（ニューロン）の機能維持を目的とするが，脳血管障害のように機能障害の原因が細胞の死滅に基づくことは多い．一方，脳腫瘍の治療においては薬物療法や放射線療法といった腫瘍細胞の死滅を目標とするものが大きな位置を占める．いずれの場合にも，細胞死の機序を理解することは各種病態や治療法の理解のうえで重要である．現在のところ最も研究の進んでいる細胞死の型はアポトーシスである．そのなかで重要な位置を占めるミトコンドリアにおける反応および抗アポトーシス因子について概要を紹介する．

Neuroscience 細胞死：最近の知見

Homeostasis of Eye Growth and the Question of Myopia

How genetic is school myopia

PURPOSE—Given the prominence of central vision in humans, it has been assumed that visual signals from the fovea dominate emmetropization. The purpose of this study was to examine the impact of peripheral vision on emmetropization. METHODS—Bilateral, peripheral form deprivation was produced in 12 infant monkeys by rearing them with diffusers that had either 4- or 8-mm apertures centered on the pupils of each eye, to allow 24° or 37° of unrestricted central vision, respectively. At the end of the lens-rearing period, an argon laser was used to ablate the fovea in one eye of each of seven monkeys. Subsequently, all the animals were allowed unrestricted vision. Refractive error and axial dimensions were measured along the pupillary axis by retinoscopy and A-scan ultrasonography, respectively. Control data were obtained from 21 normal monkeys and 3 infants reared with binocular plano lenses. RESULTS—Nine of the 12 treated monkeys had refractive errors that fell outside the 10th- and 90th-percentile limits for the age-matched control subjects, and the average refractive error for the treated animals was more variable and significantly less hyperopic/more myopic (+0.03 ± 2.39 D vs. +2.39 ± 0.92 D). The refractive changes were symmetric in the two eyes of a given animal and axial in nature. After lens removal, all the treated monkeys recovered from the induced refractive errors. No interocular differences in the recovery process were observed in the animals with monocular foveal lesions.

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Peripheral vision can influence eye growth and refractive development in infant monkeys.

The role of optical defocus in regulating refractive development in infant monkeys.

PURPOSE. To provide baseline measurements on the postnatal changes in refractive error, corneal curvature, and axial elongation of the eyes of normal monkeys. Little is known about the course of normal eye growth from birth to adolescence, particularly how refractive parameters co-vary during development. In animal models of ametropia, usually one eye is manipulated and the fellow eye serves as a control. However, given individual differences, and without baseline data, it is impossible to determine whether either eye develops normally. METHODS. Measurements were obtained on 237 rhesus monkeys, whose ages ranged from birth to 5 years. Examinations included cycloplegic refraction by retinoscopy, keratometry measurements, and A-scan ultrasound measurements of axial length. The time course of development was evaluated using a growth curve analysis appropriate for a mixture of cross-sectional and longitudinal data. RESULTS. At birth, all three parameters were normally distributed and only weakly correlated. Monkeys had + 7 D (SD = 2.3 D) of hyperopia, corneal power of 58 D (SD = 1 D), and axial length of 13.2 mm (SD = 0.4 mm). Refractive error ranged from +0.5 D to + 14.5 D, with a mean difference between the two eyes of 0.5 D. Corneal curvature ranged from 61 D to 54 D, with a mean difference between the two eyes of 0.8 D. Axial length ranged from 12.0 mm to 14.2 mm, with a mean difference between the two eyes of 0.1 mm. Although the degree of hyperopia achieved asymptote, of + 2 D, shortly after 1 year of age, corneal curvature and axial length did not achieve asymptote until nearly 5 years of age. By this time, refractive error had declined by 5 D, corneal curvature had declined by 7 D, and axial length had increased by 6 mm. CONCLUSIONS. The magnitude of the individual differences that can occur in a small sample of experimental subjects is large enough to necessitate reference to age norms derived from a large population. ()ur results provide a baseline for studies of normal and abnormal eye growth and ametropia in primates. Our results also led to the confirmation of a set of rules that have been offered as an explanation of how these three parameters interact during emmetropization.

Emmetropization in the rhesus monkey (Macaca mulatta): birth to young adulthood.

Background Early in life, at ages corresponding to the rapid infantile phase of ocular growth in humans, visual feedback can modulate refractive development in monkeys and many other species. To determine if vision-dependent mechanisms can still influence refractive development in primates during the slow juvenile phase of ocular growth, the time period when myopia typically develops in human children, we examined the effects of form deprivation on adolescent monkeys. Methods Unilateral, form deprivation was produced in four rhesus monkeys by surgically fusing the eyelids of one eye. The onset of deprivation was between 3.7 and 5 years of age, which corresponds to onset ages between approximately 15 and 20 human years. The ocular effects of form deprivation were assessed by cycloplegic retinoscopy and A-scan ultrasonography. Results At the onset of form deprivation all four monkeys were isometropic and the axial dimensions in the two eyes were well matched. After 71 to 80 weeks of form deprivation, all of the deprived eyes had become relatively more myopic than their fellow non-treated eyes (mean anisometropia = -2.03 +/- 0.78 D) and they exhibited relative increases in vitreous chamber depth (mean = 0.55 +/- 0.31 mm) and axial length (mean = 0.49 +/- 0.35 mm). Discussion Our results demonstrate that vision-dependent mechanisms can influence ocular growth and refractive development in "teenage" monkeys. These results raise the possibility that visual experience may be involved in the genesis of school-age myopia in children.

Form deprivation myopia in adolescent monkeys.

Latent nystagmus (LN) is the by-product of fusion maldevelopment in infancy. Because fusion maldevelopment--in the form of strabismus and amblyopia--is common, LN is a prevalent form of pathologic nystagmus encountered in clinical practice. It originates as an afferent visual pathway disorder. To unravel the mechanism for LN, we studied patients and nonhuman primates with maldeveloped fusion. These experiments have revealed that loss of binocular connections within striate cortex (area V1) in the first months of life is the necessary and sufficient cause of LN. The severity of LN increases systematically with longer durations of binocular decorrelation and greater losses of V1 connections. Decorrelation durations that exceed the equivalent of 2-3 months in human development result in an LN prevalence of 100%. No manipulation of brain stem motor pathways is required. The binocular maldevelopment originating in area V1 is passed on to downstream extrastriate regions of cerebral cortex that drive conjugate gaze, notably MSTd. Conjugate gaze is stable when MSTd neurons of the right and left cerebral hemispheres have balanced binocular activity. Fusion maldevelopment in infancy causes unbalanced monocular activity. If input from one eye dominates and the other is suppressed, MSTd in one hemisphere becomes more active. Acting through downstream projections to the ipsilateral nucleus of the optic tract, the eyes are driven conjugately to that side. The unbalanced MSTd drive is evident as the nasalward gaze-holding bias of LN when viewing with either eye.

The neural mechanism for Latent (fusion maldevelopment) nystagmus.

Introduction: The appropriate age for surgical correction of esotropic strabismus in human infants is controversial; some clinicians advocate surgery before age 6 months, and others recommend observation and surgery at older ages. Infantile (congenital) esotropia in humans and monkeys is known to be accompanied by a constellation of eye movement abnormalities caused by maldevelopment of cerebral visual motor pathways. The purpose of this study was to determine how early versus delayed correction of strabismus influences development and/or maldevelopment of these eye movement pathways. Methods: Optical strabismus was created in infant macaques by fitting them with prism goggles on day 1 of life. The early correction group (2 experimental and 1 control) wore the goggles for a period of 3 weeks (the equivalent of 3 months before surgical repair in humans). The delayed correction group (3 experimental and 1 control) wore the goggles for a period of 3 or 6 months (the equivalent of 12 or 24 months before surgical repair in humans). Several months after the goggles were removed, the monkeys were trained to perform visual fixation, smooth pursuit, and optokinetic nystagmus (OKN) tasks for a juice reward. Eye movements were recorded using binocular search coils. The performance of the early versus delayed infant monkey groups was also compared with that of a group of adult monkeys who had unrepaired, naturally occurring infantile esotropia. Results: Early correction monkeys developed normal eye movements and exhibited ocular motor behaviors that were indistinguishable from normal control animals. They regained normal binocular eye alignment and showed stable fixation (no latent nystagmus). Monocular horizontal smooth pursuit and large field OKN were symmetric. In contrast, delayed correction monkeys showed persistent esotropia, latent fixation nystagmus, dissociated vertical deviation, and pursuit/OKN asymmetry. Animals who had the longest delay in correction of the optical strabismus exhibited eye movement abnormalities as severe as those of adult animals with uncorrected, natural esotropia. Conclusions: Early correction of strabismus in primates prevents maldevelopment of eye movements driven by cerebral motor pathways. Our results provide additional evidence that early strabismus correction may be beneficial for brain development in human infants. (J AAPOS 2003;7:200 ‐209)

Early versus delayed repair of infantile strabismus in macaque monkeys: I. ocular motor effects.

PURPOSE. To determine the effect of continuous light exposure on ocular growth and emmetropization in infant monkeys. METHODS. Nine infant rhesus monkeys were reared with the normal vivarium lights on continuously. The 24-hour light cycle was initiated between 1 and 4 weeks of age and maintained for 6 months. The ocular effects of continuous light were assessed by cycloplegic retinoscopy, keratometry, and A-scan ultrasonography. Longitudinal control data were obtained from 23 normal infants that were reared with an illumination cycle that included defined light and dark phases (either 12-hour light:12-hour dark or 8.5-hour light: 15.5 hour dark). RESULTS. In contrast to previous studies involving light-reared chickens, no monkeys exhibited exaggerated ocular growth. There were no significant differences between treated and control monkeys in corneal radius, overall eye size, or the axial dimensions of individual ocular components. At the end of the treatment period, eight of the nine experimental monkeys also exhibited the moderate hyperopic errors (range, 11.5 to 13.4 D) that are typically found in normal animals. Aspects of emmetropization were, however, unusual for three monkeys. One monkey manifested a 20.50 D myopic error that was associated with an abnormally steep cornea but had normal axial lengths. Two additional monkeys developed persistent axial anisometropias. CONCLUSIONS. In infant primates constant light exposure does not promote the constellation of ocular changes (in particular corneal flattening, a decrease in anterior chamber depth, and an increase in vitreous chamber depth) that has been observed in light-reared chickens. The slight variations from the expected developmental sequence observed in three infants may reflect individual differences. However, it is also possible that aspects of the emmetropization process may not operate as effectively under constant light as they do under an ordinary light/dark cycle. (Invest Ophthalmol Vis Sci. 2001;42: 1146 ‐1152)

Dolores Bradley

Papers

Emmetropization in the rhesus monkey (Macaca mulatta): birth to young adulthood.

Form deprivation myopia in adolescent monkeys.

The neural mechanism for Latent (fusion maldevelopment) nystagmus.

Early versus delayed repair of infantile strabismus in macaque monkeys: I. ocular motor effects.

Continuous ambient lighting and eye growth in primates.