A role for ciliary neurotrophic factor as an inducer of reactive gliosis, the glial response to central nervous system injury.

Within the central nervous system (CNS) ciliary neurotrophic factor (CNTF) is expressed by astrocytes where it remains stored as an intracellular protein; its release and function as an extracellular ligand are thought to occur in the event of cellular injury. We find that overexpression of CNTF in transgenic mice recapitulates the glial response to CNS lesion, as does its injection into the uninjured brain. These results demonstrate that CNTF functions as an inducer of reactive gliosis, a condition associated with a number of neurological diseases of the CNS.

Ciliary muscle in avian is derived from mesenchymal and epithelial cells

It has long been maintained that the ciliary muscle derives from mesenchymal cells. The embryonic development of the avian ciliary muscle was studied in chick embryos from stage 25 HH to the time of hatching. Serial sections of the eye were stained routinely or immunocytochemically using the monoclonal antibody 13F4, which recognizes a cytoplasmic antigen specific for all types of muscle cells. We found that the mesenchymal immunoreactive cells, at stage 37 HH, are arranged in two distinct orientations forming the anterior and posterior portions of the ciliary muscle. At stages 38 and 39 HH the pigmented epithelium contained 13F4 positive cells, which detach from the epithelium and apparently migrate into stroma. These epithelial cells may differentiate into muscle cells. Within this same time period a progressive accumulation of myoblasts was detected between the pigmented epithelium and the ciliary muscle. Some myoblasts containing melanin were also observed. At stage 40 HH the internal portion of the ciliary muscle was visible. These findings indicate that the immunopositive epithelial cells participate in the formation of the internal portion of the muscle. We conclude that the ciliary muscle derives not only from the mesenchymal cells but also from the pigmented epithelium.

Systematic review of cholinergic drugs for neuroleptic-induced tardive dyskinesia: a meta-analysis of randomized controlled trials

The authors evaluated the efficacy of cholinergic drugs in the treatment of neuroleptic-induced tardive dyskinesia (TD) by a systematic review of the literature on the following agents: choline, lecithin, physostigmine, tacrine, 7-methoxyacridine, ipidacrine, galantamine, donepezil, rivastigmine, eptastigmine, metrifonate, arecoline, RS 86, xanomeline, cevimeline, deanol, and meclofenoxate. All relevant randomized controlled trials, without any language or year limitations, were obtained from the Cochrane Schizophrenia Group's Register of Trials. Trials were classified according to their methodological quality. For binary and continuous data, relative risks (RR) and weighted or standardized mean differences (SMD) were calculated, respectively. Eleven trials with a total of 261 randomized patients were included in the meta-analysis. Cholinergic drugs showed a minor trend for improvement of tardive dyskinesia symptoms, but results were not statistically significant (RR 0.84, 95% confidence interval (CI) 0.68 to 1.04, p=0.11). Despite an extensive search of the literature, eligible data for the meta-analysis were few and no results reached statistical significance. In conclusion, we found no evidence to support administration of the old cholinergic agents lecithin, deanol, and meclofenoxate to patients with tardive dyskinesia. In addition, two trials were found on novel cholinergic Alzheimer drugs in tardive dyskinesia, one of which was ongoing. Further investigation of the clinical effects of novel cholinergic agents in tardive dyskinesia is warranted. (C) 2004 Elsevier Inc. All rights reserved.

The effect of ageing on in vivo human ciliary muscle morphology and contractility

Purpose. To assess the effect of ageing on in vivo human ciliary muscle morphology and contractility during accommodation. Methods. Seventy-nine subjects, aged 19–70 years were recruited. High-resolution images were acquired of nasal and temporal ciliary muscle in the relaxed state, and at stimulus vergence levels of -4 and -8 D, using anterior segment optical coherence tomography (AS-OCT). Objective refractions and axial lengths were also recorded. Linear regression analysis was performed to determine the effect of age on nasal and temporal ciliary muscle morphologic characteristics. Results. Ciliary muscle anterior length decreased significantly with age both nasally (R = 0.461, P = 0.001) and temporally (R = 0.619, P < 0.001) in emmetropic eyes. In a subset of 37 participants, ciliary muscle maximum width increased significantly with age, by 2.8 µm/year nasally (R = 0.54, P < 0.001) and 3.0 µm/year temporally (R = 0.44, P = 0.007), while the distance from the inner apex of the ciliary muscle to the scleral spur decreased significantly with age on both the nasal and temporal aspects (R = 0.47; P = 0.004 and R = 0.43; P = 0.009, respectively). During accommodation, changes to ciliary muscle thickness and length remained constant throughout life. Conclusions. The human ciliary muscle undergoes age-dependent changes in morphology that suggest an antero-inwards displacement of muscle mass, particularly in emmetropic eyes. However, the morphologic changes observed appear not to affect the ability of the muscle to contract during accommodation, even in established presbyopes, thus supporting a lenticular model of presbyopia development.

In vivo analysis of ciliary muscle morphologic changes with accommodation and axial ametropia

Purpose. To use anterior segment optical coherence tomography (AS-OCT) to analyze ciliary muscle morphology and changes with accommodation and axial ametropia. Methods. Fifty prepresbyopic volunteers, aged 19 to 34 years were recruited. High-resolution images were acquired of nasal and temporal ciliary muscles in the relaxed state and at stimulus vergence levels of -4 and -8 D. Objective accommodative responses and axial lengths were also recorded. Two-way, mixed-factor analyses of variance (ANOVAs) were used to assess the changes in ciliary muscle parameters with accommodation and determine whether these changes are dependent on the nasal–temporal aspect or axial length, whereas linear regression analysis was used to analyze the relationship between axial length and ciliary muscle length. Results. The ciliary muscle was longer (r = 0.34, P = 0.02), but not significantly thicker (F = 2.84, P = 0.06), in eyes with greater axial length. With accommodation, the ciliary muscle showed a contractile shortening (F = 42.9. P < 0.001), particularly anteriorly (F = 177.2, P < 0.001), and a thickening of the anterior portion (F= 46.2, P < 0.001). The ciliary muscle was thicker (F = 17.8, P < 0.001) and showed a greater contractile response on the temporal side. Conclusions. The accommodative changes observed support an anterior, as well as centripetal, contractile shift of ciliary muscle mass.

Effect of β-adrenoceptor antagonists on autonomic control of ciliary smooth muscle

Purpose: Pharmacological intervention with peripheral sympathetic transmission at ciliary smooth muscle neuro-receptor junctions has been used against a background of controlled parasympathetic activity to investigate the characteristics of autonomic control of ocular accommodation. Methods: A continuously recording infrared optometer was used to measure accommodation on a group of five visually normal emmetropic subjects under open- and closed-loop conditions. A double-blind protocol between saline, timolol and betaxolol was used to differentiate between the localised action on ciliary smooth muscle and effects induced by changes in stimulus conditions. Data were collected before and 45 min following the instillation of saline, timolol or betaxolol. Open-loop post-task decay was investigated following 3 min sustained near fixation of a stimulus placed 3 D above the subject's pre-task tonic accommodation level. Closed-loop dynamic responses were recorded for each treatment condition while subjects viewed sinusoidally (0.05-0.6 Hz) or stepwise vergence-modulated targets over a 2 D range (2-4 D). Results: Open-loop data demonstrate a rapid post-task regression to pre-task tonic accommodation levels for saline and betaxolol control conditions. A slow positive post-task shift was induced by timolol indicating that sympathetic inhibition contributes to accommodative adaptation during sustained near vision. Closed-loop accommodation responses to temporally modulated sinusoidal stimuli showed characteristic features for both saline and betaxolol control conditions. Timolol induced a reduced gain for low- and mid-temporal frequencies (< 0.3 Hz) but did not affect the response at higher temporal frequencies. Response times to stepwise stimuli increased following the instillation of timolol for the near-to-far fixation condition compared with the controls and was related to the period of sustained prior fixation. Conclusions: Modulation of accommodation under open- and closed-loop conditions by a non-selective β-blocker is consistent with the temporal and inhibitory features of sympathetic innervation to ciliary smooth muscle. Although parasympathetic innervation predominates there is evidence to support a role for sympathetic innervation in the control of ocular accommodation. © 2002 The College of Optometrists.

Ocular biometric correlates of ciliary muscle thickness in human myopia

Purpose - Anterior segment optical coherent tomography (AS-OCT) is used to further examine previous reports that ciliary muscle thickness (CMT) is increased in myopic eyes. With reference to temporal and nasal CMT, interrelationships between biometric and morphological characteristics of anterior and posterior segments are analysed for British-White and British-South-Asian adults with and without myopia. Methods - Data are presented for the right eyes of 62 subjects (British-White n = 39, British-South-Asian n = 23, aged 18–40 years) with a range of refractive error (mean spherical error (MSE (D)) -1.74 ± 3.26; range -10.06 to +4.38) and separated into myopes (MSE (D) <-0.50, range -10.06 to -0.56; n = 30) and non-myopes (MSE (D) =-0.50, -0.50 to +4.38; n = 32). Temporal and nasal ciliary muscle cross-sections were imaged using a Visante AS-OCT. Using Visante software, manual measures of nasal and temporal CMT (NCMT and TCMT respectively) were taken in successive posterior 1 mm steps from the scleral spur over a 3 mm distance (designated NCMT1, TCMT1 et seq). Measures of axial length and anterior chamber depth were taken with an IOLMaster biometer. MSE and corneal curvature (CC) measurements were taken with a Shin-Nippon auto-refractor. Magnetic resonance imaging was used to determine total ocular volume (OV) for 31 of the original subject group. Statistical comparisons and analyses were made using mixed repeated measures anovas, Pearson's correlation coefficient and stepwise forward multiple linear regression. Results - MSE was significantly associated with CMT, with thicker CMT2 and CMT3 being found in the myopic eyes (p = 0.002). In non-myopic eyes TCMT1, TCMT2, NCMT1 and NCMT2 correlated significantly with MSE, AL and OV (p < 0.05). In contrast, myopic eyes failed generally to exhibit a significant correlation between CMT, MSE and axial length but notably retained a significant correlation between OV, TCMT2, TCMT3, NCMT2 and NCMT3 (p < 0.05). OV was found to be a significantly better predictor of TCMT2 and TCMT3 than AL by approximately a factor of two (p < 0.001). Anterior chamber depth was significantly associated with both temporal and nasal CMT2 and CMT3; TCMT1 correlated positively with CC. Ethnicity had no significant effect on differences in CMT. Conclusions - Increased CMT is associated with myopia. We speculate that the lack of correlation in myopic subjects between CMT and axial length, but not between CMT and OV, is evidence that disrupted feedback between the fovea and ciliary apparatus occurs in myopia development.

Sympathetic innervation of ciliary muscle and oculomotor function in emmetropic and myopic young adults

Purpose: Evidence exists for an additional inhibitory accommodative control system mediated by the sympathetic branch of the autonomic nervous system (ANS). This work aims to show the relative prevalence of sympathetic inhibition in young emmetropic and myopic adults, and to evaluate the effect of sympathetic facility on accommodative and oculomotor function. Methods: Profiling of ciliary muscle innervation was carried out in 58 young adult subjects (30 emmetropes, 14 early onset myopes, 14 late onset myopes) by examining post-task open-loop accommodation responses, recorded continuously by a modified open-view infrared optometer. Measurements of amplitude of accommodation, tonic accommodation, accommodative lag at near, AC/A ratio, and heterophoria at distance and near were made to establish a profile of oculomotor function. Results: Evidence of sympathetic inhibitory facility in ciliary smooth muscle was observed in 27% of emmetropes, 21% of early-onset myopes and 29% of late-onset myopes. Twenty-six percent of all subjects demonstrated access to sympathetic facility. Closed-loop oculomotor function did not differ significantly between subjects with sympathetic facility, and those with sympathetic deficit. Conclusions: Emmetropic and myopic groups cannot be distinguished in terms of the relative proportions having access to sympathetic inhibition. Presence of sympathetic innervation does not have a significant effect on accommodative function under closed-loop viewing conditions. © 2005 Elsevier Ltd. All rights reserved.

A program to analyse optical coherence tomography images of the ciliary muscle

Purpose: To describe and validate bespoke software designed to extract morphometric data from ciliary muscle Visante Anterior Segment Optical Coherence Tomography (AS-OCT) images. Method: Initially, to ensure the software was capable of appropriately applying tiered refractive index corrections and accurately measuring orthogonal and oblique parameters, 5 sets of custom-made rigid gas-permeable lenses aligned to simulate the sclera and ciliary muscle were imaged by the Visante AS-OCT and were analysed by the software. Human temporal ciliary muscle data from 50 participants extracted via the internal Visante AS-OCT caliper method and the software were compared. The repeatability of the software was also investigated by imaging the temporal ciliary muscle of 10 participants on 2 occasions. Results: The mean difference between the software and the absolute thickness measurements of the rigid gas-permeable lenses were not statistically significantly different from 0 (t = -1.458, p = 0.151). Good correspondence was observed between human ciliary muscle measurements obtained by the software and the internal Visante AS-OCT calipers (maximum thickness t = -0.864, p = 0.392, total length t = 0.860, p = 0.394). The software extracted highly repeatable ciliary muscle measurements (variability ≤6% of mean value). Conclusion: The bespoke software is capable of extracting accurate and repeatable ciliary muscle measurements and is suitable for analysing large data sets.

The ciliary GTPase Arl13b regulates cell migration and cell cycle progression

Funding This work was supported by grants from British Council China (Sino-UK higher Education for PhD studies) to YD and CM, The Carnegie Trust for the Universities of Scotland (70190) and The NHS Grampian Endowment Funds (14/09) to BL, and National Natural Science Foundation of China (31528011) to BL and YD.

Ciliary muscle morphology in emmetropia and ocular biometric correlates

Purpose: Recent studies have documented a link between axial myopia and ciliary muscle morphology; yet, the variation in biometric characteristics of the emmetropic ciliary muscle are not fully known. Ciliary muscle morphology, including symmetry, was investigated between both eyes of emmetropic participants and correlated to ocular biometric parameters. Methods: Anterior segment optical coherence tomography (Zeiss, Visante) was utilised to image both eyes of 49 emmetropic participants (mean spherical equivalent refractive error (MSE) ≥ -0.55; < +0.75 D), aged 19 to 26 years. High resolution images were obtained of nasal and temporal aspects of the ciliary muscle in the relaxed state. MSE of both eyes was recorded using the Grand Seiko WAM 5500; axial length (AXL), anterior chamber depth (ACD) and lens thickness (LT) of the right eye were obtained using the Haag-streit Lenstar LS 900 biometer. A bespoke semi-objective analysis programme was used to measure a range of ciliary muscle parameters. Results: Temporal ciliary muscle overall length (CML) was greater than nasal CML, in both eyes (right: 3.58 ± 0.40 mm and 3.85 ± 0.39 mm for nasal and temporal aspects, respectively, P < 0.001; left: 3.65 ± 0.35 mm and 3.88 ± 0.41 mm for nasal and temporal aspects, respectively, P < 0.001). Temporal ciliary muscle thickness (CMT) was greater than nasal CMT at 2 mm and 3 mm from the scleral spur (CM2 and CM3, respectively) in each eye (right CM2: 0.29 ± 0.05 mm and 0.32 ± 0.05 mm for nasal and temporal aspects, respectively, P < 0.001; left CM2: 0.30 ± 0.05 mm and 0.32 ± 0.05 mm for nasal and temporal aspects, respectively, P < 0.001; right CM3: 0.13 ± 0.05 mm and 0.16 ± 0.04 mm for nasal and temporal aspects, respectively, P < 0.001; left CM3: 0.14 ± 0.04 mm and 0.17 ± 0.05 mm for nasal and temporal aspects, respectively, P < 0.001). AXL was positively correlated with ciliary muscle anterior length (AL) (e.g. P < 0.001, r2 = 0.262 for left temporal aspect), CML (P = 0.003, r2 = 0.175 for right nasal aspect) and ACD (P = 0.01, r2 = 0.181). Conclusions: Morphological characteristics of the ciliary muscle in emmetropic eyes display high levels of symmetry between the eyes. Greater CML and AL are linked to greater AXL and ACD, indicating ciliary muscle growth with normal ocular development.

Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, dyskinesia and sensorial deficiencies, and mitochondrial complex I instability

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TRPV4 activation triggers the release of melatonin from human non-pigmented ciliary epithelial cells

Melatonin is a neurohormone mainly produced in the pineal gland; nevertheless, various ocular structures such as the ciliary body, lens and the retina produce it. One of the roles of melatonin in the eye is the modulation of intraocular pressure, although little is known about the mechanisms that causes its presence in the aqueous humour. TRPV4 is a membrane channel which is activated by both physical and chemical stimuli. Therefore, this channel is sensitive to osmotic and hydrostatic pressure. As a consequence, TRPV4 results as an interesting candidate to study the relation between the activation of the TRPV4 channel and the production of melatonin. In this sense we have studied the role of the TRPV4 agonist GSK1016790A to modulate the production of melatonin in a cell line derived from human non-pigmented ciliary epithelial cells. The stimulation of the TRPV4 produced an increase in the extracellular melatonin levels changing from 8.5 ± 0.6 nM/well/30 min (control) to 23.3 ± 2.1 nM/well/30 min after 10 nM GSK1016790A application, this action being blocked by the selective antagonist RN 1734. The activation of the TRPV4 by GSK1016790A permitted to observe a melatonin increase which was concentration-dependent, and provided a pD2 value of −8.5 ± 0.1 (EC50 of 3.0 nM). In conclusion, the activation of the TRPV4 present in human non-pigmented ciliary epithelial cells can modulate the presence of extracellular melatonin, this being of relevance since this substance controls the dynamics of the aqueous humour.

Ocular characteristics of anisometropia

Animal models of refractive error development have demonstrated that visual experience influences ocular growth. In a variety of species, axial anisometropia (i.e. a difference in the length of the two eyes) can be induced through unilateral occlusion, image degradation or optical manipulation. In humans, anisometropia may occur in isolation or in association with amblyopia, strabismus or unilateral pathology. Non-amblyopic myopic anisometropia represents an interesting anomaly of ocular growth, since the two eyes within one visual system have grown to different endpoints. These experiments have investigated a range of biometric, optical and mechanical properties of anisometropic eyes (with and without amblyopia) with the aim of improving our current understanding of asymmetric refractive error development. In the first experiment, the interocular symmetry in 34 non-amblyopic myopic anisometropes (31 Asian, 3 Caucasian) was examined during relaxed accommodation. A high degree of symmetry was observed between the fellow eyes for a range of optical, biometric and biomechanical measurements. When the magnitude of anisometropia exceeded 1.75 D, the more myopic eye was almost always the sighting dominant eye. Further analysis of the optical and biometric properties of the dominant and non-dominant eyes was conducted to determine any related factors but no significant interocular differences were observed with respect to best-corrected visual acuity, corneal or total ocular aberrations during relaxed accommodation. Given the high degree of symmetry observed between the fellow eyes during distance viewing in the first experiment and the strong association previously reported between near work and myopia development, the aim of the second experiment was to investigate the symmetry between the fellow eyes of the same 34 myopic anisometropes following a period of near work. Symmetrical changes in corneal and total ocular aberrations were observed following a short reading task (10 minutes, 2.5 D accommodation demand) which was attributed to the high degree of interocular symmetry for measures of anterior eye morphology, and corneal biomechanics. These changes were related to eyelid shape and position during downward gaze, but gave no clear indication of factors associated with near work that might cause asymmetric eye growth within an individual. Since the influence of near work on eye growth is likely to be most obvious during, rather than following near tasks, in the third experiment the interocular symmetry of the optical and biometric changes was examined during accommodation for 11 myopic anisometropes. The changes in anterior eye biometrics associated with accommodation were again similar between the eyes, resulting in symmetrical changes in the optical characteristics. However, the more myopic eyes exhibited slightly greater amounts of axial elongation during accommodation which may be related to the force exerted by the ciliary muscle. This small asymmetry in axial elongation we observed between the eyes may be due to interocular differences in posterior eye structure, given that the accommodative response was equal between eyes. Using ocular coherence tomography a reduced average choroidal thickness was observed in the more myopic eyes compared to the less myopic eyes of these subjects. The interocular difference in choroidal thickness was correlated with the magnitude of spherical equivalent and axial anisometropia. The symmetry in optics and biometrics between fellow eyes which have undergone significantly different visual development (i.e. anisometropic subjects with amblyopia) is also of interest with respect to refractive error development. In the final experiment the influence of altered visual experience upon corneal and ocular higher-order aberrations was investigated in 21 amblyopic subjects (8 refractive, 11 strabismic and 2 form deprivation). Significant differences in aberrations were observed between the fellow eyes, which varied according to the type of amblyopia. Refractive amblyopes displayed significantly higher levels of 4th order corneal aberrations (spherical aberration and secondary astigmatism) in the amblyopic eye compared to the fellow non-amblyopic eye. Strabismic amblyopes exhibited significantly higher levels of trefoil, a third order aberration, in the amblyopic eye for both corneal and total ocular aberrations. The results of this experiment suggest that asymmetric visual experience during development is associated with asymmetries in higher-order aberrations, proportional to the magnitude of anisometropia and dependent upon the amblyogenic factor. This suggests a direct link between the development of higher-order optical characteristics of the human eye and visual feedback. The results from these experiments have shown that a high degree of symmetry exists between the fellow eyes of non-amblyopic myopic anisometropes for a range of biomechanical, biometric and optical parameters for different levels of accommodation and following near work. While a single specific optical or biomechanical factor that is consistently associated with asymmetric refractive error development has not been identified, the findings from these studies suggest that further research into the association between ocular dominance, choroidal thickness and higher-order aberrations with anisometropia may improve our understanding of refractive error development.