Retinal ganglion cell axon progression from the optic chiasm to initiate optic tract development requires cell autonomous function of GAP-43

Pathfinding mechanisms underlying retinal ganglion cell (RGC) axon growth from the optic chiasm into the optic tract are unknown. Previous work has shown that mouse embryos deficient in GAP-43 have an enlarged optic chiasm within which RGC axons were reportedly stalled. Here we have found that the enlarged chiasm of GAP-43 null mouse embryos appears subsequent to a failure of the earliest RGC axons to progress laterally through the chiasm-tract transition zone to form the optic tract. Previous work has shown that ventral diencephalon CD44/stage-specific embryonic antigen (SSEA) neurons provide guidance information for RGC axons during chiasm formation. Here we found that in the chiasm-tract transition zone, axons of CD44/SSEA neurons precede RGC axons into the lateral diencephalic wall and like RGC axons also express GAP-43. However unlike RGC axons, CD44/SSEA axon trajectories are unaffected in GAP-43 null embryos, indicating that GAP-43-dependent guidance at this site is RGC axon specific or occurs only at specific developmental times. To determine whether the phenotype results from loss of GAP-43 in RGCs or in diencephalon components such as CD44/SSEA axons, wild-type, heterozygous, or homozygous GAP-43 null donor retinal tissues were grafted onto host diencephalons of all three genotypes, and graft axon growth into the optic tract region was assessed. Results show that optic tract development requires cell autonomous GAP-43 function in RGC axons and not in cellular elements of the ventral diencephalon or transition zone.     

Nerve fiber layer defects with normal visual fields. Do normal optic disc and normal visual field indicate absence of glaucomatous abnormality?

PURPOSE: When the optic disc has normal appearance with no abnormalities in routine automated perimetry, the subject is not considered to have glaucoma. The purpose of this study is to show how such patients may have localized retinal nerve fiber layer defects with corresponding functional abnormality. METHODS: The authors selected eight eyes of eight patients who had a localized retinal nerve fiber layer defect extending within a few degrees from fovea but in whom the optic disc appearance and Humphrey 30-2 visual fields were normal. Of the eight patients, three had positive family history of glaucoma, two had suspected retinal nerve fiber layer abnormality in routine eye examination, two had increased intraocular pressure (IOP), and one had advanced low-tension glaucoma in one eye with a normal fellow eye. The authors examined the central 10 degrees visual field with 1 degree resolution using Humphrey perimeter and the Ring and Centring programs of the high-pass resolution perimeter. RESULTS: A central field defect corresponding to retinal nerve fiber layer defect was found in six of eight patients: in both 10 degrees Humphrey field and Centring programs (2 eyes), in Humphrey only (2 eyes), and in Centring only (2 eyes). CONCLUSION: The results indicate that retinal nerve fiber layer photographs are helpful in diagnosing glaucoma because early glaucomatous abnormalities cannot be excluded without nerve fiber layer photography. Currently available routine perimetric examination programs do not always detect very early functional damage.     

Changes in the retinal ganglion cell layer and optic nerve of rats exposed neonatally to cocaine

In a study of 452 ex-prisoners in England in 1990, 66 people reported that they were tested for HIV antibodies when last in prison. The circumstances under which many of those who were tested were difficult: 36% found it an unpleasant experience, 17% had not taken the test voluntarily and 55% said they received no counselling. Further information was gathered about the experiences of those who were HIV positive or assumed to be. Most were accommodated in a 'special location', not allowed to associate with other prisoners and denied access to work or recreational facilities. These data highlight the difficulties arising from the policy of Viral Infectivity Restrictions, a set of regulations applied to the management of prisoners with HIV in English prisons. This policy created a distressing situation for those tested for HIV or identified as being HIV positive in prison. For the prison environment, these conditions may create a vicious circle reinforcing inaccurate beliefs and anxieties.     

Regenerating ganglion cell axons in the adult rat establish retinofugal topography and restore visual function

The mechanisms of neuronal network response to axotomy are poorly understood. In one of the favoured models used to study the fate of injured neurons in the adult rat visual system, appreciable numbers of retinal neurons survive optic nerve injury under conditions of microglia-targeted neuroprotection. Rescued neurons can regenerate their axons and become target-dependently stabilised after reconnection with their natural visual centres by means of a peripheral nerve graft, which, in addition to guidance, actively supports axonal growth. The mechanisms that control regenerative axonal growth and resynaptogenesis include coordinated cell-cell interactions between growing neurites and target cells in order to establish a meaningful reconnectivity. Here the function of the regenerating visual circuitry was first studied by monitoring the ability of animals to discriminate spatial patterns, and second by recording visual evoked cortical potentials (VEPs) in the same animals. These functions were correlated with neuroanatomical studies of the retinotopic organisation of regenerating axons. To achieve these goals, adult rats were behaviourally trained in a Y-maze to discriminate between vertical and horizontal stripes. Both optic nerves were transected, and the regenerating axons of one optic nerve were guided into the area of optic tract with a peripheral nerve graft according to the protocols of neuroprotection and simultaneous grafting, in order to enable large numbers of axons to reinnervate the major visual targets in the midbrain and thalamus. Postoperative testing of the animals showed a marked improvement of visual perception and behaviour. The VEPs of the same animals were measurable indicating a restoration of the visual circuitry including the ascending corticopedal connections. Neuroanatomical assessment of the fibre topography within the graft and the area of termination revealed a rough topographic organisation that may account for restoration of the function. These results suggest that interrupted central pathways can be functionally reconnected by providing a neuroprotective environment in combination with peripheral nerve grafts to bypass lesions.     

Retinal nerve fiber layer changes and visual field loss in idiopathic intracranial hypertension

PURPOSE: The authors retrospectively analyzed changes in the retinal nerve fiber layer in patients with idiopathic intracranial hypertension and studied their relation to visual field loss to determine the clinical usefulness of retinal nerve fiber analysis in the clinical management of patients with papilledema. METHODS: Retinal nerve fiber layer photographs and visual fields from 36 eyes of 21 patients with papilledema due to idiopathic intracranial hypertension were analyzed for abnormalities in a masked fashion. RESULTS: Nerve fiber layer changes were found in 67% of eyes studied. Superior areas within the nerve fiber layer were affected 5.4 times more frequently than inferior regions. Visual field loss was more prevalent in eyes with diffuse nerve fiber layer loss (89%) than in eyes with slit defects (29%). The location of the nerve fiber layer changes correlated with corresponding areas of visual field loss. Nerve fiber layer changes were as common in mild to moderate as in atrophic papilledema; however, slit defects predominated in patients with mild to moderate papilledema, and diffuse loss predominated in atrophic papilledema. CONCLUSIONS: Changes in the retinal nerve fiber layer observed in patients with idiopathic intracranial hypertension provide objective information regarding the status of their optic nerve and may improve their clinical management.     

Tritiated uridine uptake in the retinal ganglion cell layer of the cat during normal development and after visual cortex ablation

The short-term metabolic response of immature retinal ganglion cells to destruction of their target cells in the dorsal lateral geniculate nucleus (dLGN) was assessed in newborn cats. Retrograde degeneration of virtually all dLGN cells was induced by ablation of the 13 contiguous areas of visual cortex on the day of birth. The metabolic response of retinal ganglion cells to this loss of target cells in dLGN was determined by exposing the ganglion cell layer to tritiated uridine, a precursor of RNA. Control measurements were made from unoperated littermates. Following sectioning and processing of the retinae from both groups of kittens for autoradiography, silver grain densities overlying the cellular profiles in the ganglion cell layer were calculated. These calculations revealed levels of uridine incorporation at Postnatal Day 4 in both groups of kittens significantly higher than at either Postnatal Day 2 or 7, but no significant differences between the two groups on any day examined. These results show that the level of RNA synthesis in retinal ganglion cells increases temporarily during the first postnatal week and that this synthesis is unaffected by the death of target cells in the dLGN. The temporary increase may be related to the establishment of synaptic connections on retinal ganglion cells by their afferent bipolar and amacrine neurons in the inner nuclear layer.     

Intact visual imagery and impaired visual perception in a patient with visual agnosia.

Although it is now well accepted that visual mental imagery and visual perception share common underlying mechanisms, there are several reports in which they are dissociated. Evidence for the separability of these processes is provided by a 33-yr-old male patient who has a profound visual object recognition deficit attributable to an impairment in grouping or segmenting visual images. Despite this perceptual deficit, the patient was able to draw objects in considerable detail from memory, and his knowledge of the visual appearance of objects was preserved on a variety of mental imagery tasks. Together with previous cases, these findings confirm the double dissociation between object recognition and perception. Interestingly, the patient could also recognize newly constructed objects in his internal imagery. To accommodate these results, the authors propose a model in which imagery and perception are strongly associated but are also functionally specialized. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evaluation of coexisting optic nerve head drusen and glaucoma with optical coherence tomography

OBJECTIVE: Optic nerve head drusen often make evaluation of the nerve head difficult to interpret. In addition, visual field defects are known to occur in patients with optic disk drusen, resembling glaucomatous damage. The authors report two cases of coincident optic nerve head drusen and glaucoma, in which the use of optical coherence tomography (OCT) in evaluating the nerve fiber layer was beneficial. PARTICIPANTS: Two patients with both optic nerve head drusen and glaucoma, one with primary open angle glaucoma, the other with pseudoexfoliation glaucoma were evaluated. Both patients had asymmetric optic disk drusen, with clinically visible drusen only in one eye. INTERVENTION: Ophthalmologic examination, color and red-free photography, automated Humphrey visual field testing and OCT were performed. RESULTS: Nerve fiber layer loss as measured by OCT was found to be greater than expected by the appearance of the optic nerve head and red-free photography, with visual fields consistent with findings in case 1. In case 2, visual fields were full, despite nerve fiber layer thinning seen by OCT and red-free photography. CONCLUSIONS: There can be significant nerve fiber layer thinning in patients with both glaucoma and optic disk drusen, despite the appearance of the optic nerve head in these patients. The cup margin may be obscured by the drusen, giving rise to a falsely full-appearing disk. In such cases, OCT may provide a useful means to quantitatively measure the nerve fiber layer thickness and to aid in the management of these patients by detecting nerve fiber layer thinning earlier than would otherwise be possible.     

Quantitative relations in the retinal ganglion cell layer of the rat: neurons, glia and capillaries before and after optic nerve section

The severity of pulmonary fibrosis is the main prognostic factor for survival of patients with interstitial lung diseases (ILD). Unfortunately, lung biopsy, which is the best method to assess fibrosis quantitatively, is done only once during the evolution of the disease. In this study we analyzed the relationship between the degree of fibrosis and the exponential constant k, derived from the lung pressure-volume curve (LPVC) in 33 patients with chronic ILD, 19 with pigeon breeder's disease (PBD), and 14 with idiopathic pulmonary fibrosis (IPF). Pulmonary function tests, including the LPVC, were obtained before biopsy. A semiquantitative histologic assessment of the severity of fibrosis was performed on lung tissues. All patients showed a decrease of total lung capacity, residual volume, compliance, and Pao2. The mean value of the constant k was 0.08 +/- 0.06. When expressed as a percent of normal values, 25 patients exhibited values of k lower than 70% of predicted; of the remaining 8 patients whose values were above 70% of predicted, 7 had PBD and only one IPF. On morphologic analysis, 19 patients displayed more than 50% fibrosis. No significant correlations were found between the extent of the lesion or severity of lung fibrosis and the conventional pulmonary function tests. By contrast, a moderate but significant correlation was found between k and the severity of lung fibrosis (r = -0.38, p < 0.05). These findings show that the shape of the LPVC, represented by the constant k, predicts the degree of lung fibrosis and could be useful in the clinical assessment and follow-up of patients with ILD.     

Relation between size of optic disc and thickness of retinal nerve fibre layer in normal subjects

The genus Clinostomum is a cause of parasitic laryngo-pharyngitis. We report the 15th case of Clinostomum sp. infection in Japan. A 29-year-old female visited our hospital because of throat discomfort and expectoration of a worm by sneezing on November 17, 1997. The pharyngitis was caused by the worm. The worm was morphologically identified as the adult of the genus Clinostomum.     

Retinal ganglion cell depletion alters the phenotypic expression of GABA and GAD in the rat retina

We have looked at the phenotypic expression of gamma-aminobutyric acid (GABA) and the two isoforms of its synthetic enzyme [glutamic acid decarboxylase (GAD)-65 and -67] in adult rat retinas that had the superior colliculus, pretectum and optic tract lesioned unilaterally at birth. It has been shown previously that this type of manipulation induces retrograde degeneration of retinal ganglion cells presumably without affecting other intraretinal neurons. We present evidence that GABAergic amacrine cells are affected by such manipulation. The number of cells immunoreactive for GABA, GAD-65 and GAD-67 decreased in the inner nuclear layer. In the retinal ganglion cell layer, however, the number of GABA- and GAD-65-labelled cells increased, while the number of GAD-67-labelled cells did not change. Biochemical assay showed that overall GAD activity was not altered in retinas of lesioned animals. Our results support the notion that, while neonatal lesion reorganizes the expression of GABA and GAD in the retina, enzyme activity is maintained within normal levels.     

Quantitative estimation of retinal nerve fiber layer height in glaucoma and the relationship with optic nerve head topography and visual field

During the evolution of normal cells into cancer cells, the occurrence of multiple mutations results in genetic instability. Mutations in DNA repair genes such as those of mismatch and excision repair predispose the carriers of these mutations to cancer by increasing the level of genomic instability. A variety of chromosome aberrations, such as abnormal ploidy, whole chromosome loss or chromosome amplification are commonly observed in cancer cells. From one cell division to the next, mammalian cells pass through an organized series of controlled events referred to as the cell cycle. In order to pursue an ordered series of molecular events, the initiation of an event during cell cycle progression is dependent on the successful completion of an earlier event. The cell cycle is divided into two major phases, namely, M(mitotic) phase and interphase. Interphase can be further divided into three distinct phases termed G1 (gap 1), S(DNA synthesis) and G2(gap2) phases (Fig. 1). Along with the machinery that promotes cell cycle progression, cells are also equipped with cell cycle checkpoints that ensure correct ordering of events in the cell cycle. The idea of "the cell cycle checkpoint" was first introduced by Hartwell and Weinert (1989) as "the arrest of a cell at a particular phase of the cycle due to a lack of appropriate signals for cell cycle progression". Until the checkpoint machinery receives the appropriate signal, the cell will not be allowed to make transition from one phase of the cell cycle to the next. Thus, the major role of checkpoint control is to minimize somatic genetic alterations and/or events affecting cellular survival. When one or more components of a cell cycle checkpoint are mutated, the chances of genetic instability during one round of the cell cycle increase accordingly with consequent acceleration of cellular evolution from the normal to the cancerous state. Therefore, mutations in checkpoint controls may predispose cells to cancer by causing genomic instability. In this review, I will focus on the potential roles of cell cycle checkpoints in the progression of malignancy.     

A quantitative analysis of cells in the ganglion cell layer of the chick retina

This study investigated the organization of cells in the ganglion cell layer (GCL) using Nissl staining, retrograde cell degeneration with axotomy of the optic nerve, and retrograde cell labeling by injections of horseradish peroxidase (HRP) into the optic nerve of chicks (posthatching day 1 and 8, P-1 and P-8). The total number of cells in the GCL was 6.1 x 10(6) (P-1) and 4.9 x 10(6) (P-8), and the cell density was 14,300 cells/mm2 (P-1) and 10,400 cells/ mm2 (P-8) on average. Two high-density areas, the central area (CA) and the dorsal area (DA), were observed in the central and dorsal retinas in both P-1 (22,000 cells/mm2 in CA, 19,000 cells/mm2 in DA) and P-8 chicks (19,000 cells/mm2 in CA, 12,800 cells/mm2 in DA). The cell densities in the temporal periphery (TP) and the nasal (NP) peripheral retinas were 7,800 cells/mm2 and 12,500 cells/mm2, respectively, in P-1 and 5,000 cells/ mm2 and 8,000 cells/mm2, respectively, in P-8 chicks. The cell density in the temporal periphery was 35% (P-8) lower than in the nasal periphery in both P-1 and P-8 chicks. Thirty percent (1.9 x 10(6) cells in P-1) of the total cells in the GCL were resistant to axotomy of the optic nerve. The distribution of the axotomy-resistant cells showed two high-density areas in the central and dorsal retinas, corresponding to the CA (5,800 cells/mm2) and the DA (3,200 cells/mm2). These cells also exhibited a center-peripheral increase (2,200 cells/mm2 in the TP) in P-1 chicks, but the high-density area was not found in the dorsal retina of P-8 chicks. From these data and the HRP study, the number of presumptive ganglion cells in P-8 chicks was estimated to be 4 x 10(6) (8,600 cells/mm2 on average), and the density in each area was 13,500 (CA), 10,200 (DA), and 4,300 (TP) cells/mm2. The peripheral/ center ratios of the density of ganglion cells were significantly different along the nasotemporal and dorsoventral axes. The density of ganglion cells decreased more rapidly toward the temporal periphery (TP/CA ratio: 0.47 in P-1 and 0.32 in P-8) than toward the nasal periphery (NP/CA ratio: 0.67 in P-1 and 0.52 in P-8). In contrast, there was no significant difference in the peripheral/center ratios between the dorsal retina (DP/CA ratio: 0.6 in P-1 and 0.56 in P-8) and ventral retina (VP/CA ratio: 0.58 in P-1 and 0.51 in P-8). A small peak in the density of the presumptive ganglion cells was detected in the dorsal retina of both P-1 chicks (10,800 cells/mm2) and P-8 chicks (10,200 cells/mm2). The HRP-labeled cells were small in the CA (M +/- SD: 35.7 +/- 9.1 microm2) and DA (40.0 +/- 11.3 microm2), and their sizes increased toward the periphery (63.4 +/- 29.7 microm2 in the TP) accompanied by a decrease in the cell density. However, the axotomy-resistant cells did not significantly increase in size toward the peripheral retina (12.2 +/- 2.2 microm2 in the CA, 15.2 +/- 3.2 microm2 in the DA, 15.1 +/- 3.8 microm2 in the TP). The characteristic distribution of ganglion cells could be related to visual behavior based upon the specialization of avian visual fields.     

Proliferative diabetic retinopathy with a proliferative membrane that spread anteriorly from the optic disc

The authors report a case of proliferative diabetic retinopathy in which the proliferating membrane spread from the optic disc to the anterior of the eyeball, and did not appear to involve the posterior precortical vitreous pocket.     

Retinal dopamine depletion in young quail mimics some of the effects of ageing on visual function

The hypothesis that retinal dopaminergic (DA) neurones are involved in the visual functions of interest was tested. The retinal DA in young quail was partially depleted by intravitreal injection of 6-hydroxydopamine (6-OHDA). It was found that the refractive state of 6-OHDA-treated birds became more myopic than normal (untreated) young, whereas the pupil diameter was not affected. The contrast sensitivity of 6-OHDA treated quail was significantly lowered (two to three times) at all spatial frequencies studied (0.25-5 c/d), and the peak latency of pattern electro-retinogram (PERG) response was prolonged by 3-4 msec (9%). Furthermore, the visual acuity and maximal amplitude of PERG response of the 6-OHDA-treated young quail were lower than those of normals. From histochemical studies, it was revealed that the morphology of the DA cells of 6-OHDA-treated young appeared similar to those of the old quail; the DA cells of 6-OHDA-treated retinae were less fluorescent and 2.5-5 times less numerous than respective controls. Combining the PERG and the morphological results, it would seem that the retinal DA plays an important role in the visual functions studied, and that loss of retinal DA could underlie some of the visual changes which occur during ageing.     

Grasping spatial relationships: failure to demonstrate allocentric visual coding in a patient with visual form agnosia

The aim of this multicenter, double-masked study was to compare the efficacy and safety of two different doses of inhaled fluticasone propionate dry powder--50 micrograms and 100 micrograms--administered BID via a multidose powder inhaler with those of placebo in the treatment of children with persistent asthma. After a 2-week run-in period, 263 patients were randomized to treatment with twice-daily placebo (n = 92), fluticasone 50 micrograms (n = 85), or fluticasone 100 micrograms (n = 86) for 12 weeks. One hundred sixty-six (63%) patients were male, and 224 (85%) were white, with a mean age of 8 years. Two hundred twenty-one (84%) patients were atopic, and 167 (63%) had been asthmatic for 1 to 5 years. Baseline mean morning peak expiratory flow (PEF) values were 207 L/min, 199 L/min, and 194 L/min, and baseline percentages of predicted normal values were 86%, 80%, and 81% for the groups receiving placebo, fluticasone 50 micrograms, and fluticasone 100 micrograms, respectively. At the end of the first week of treatment, patients in both fluticasone groups had significantly greater improvements in morning PEF than did those receiving placebo. Patients experienced mean increases of 4 L/min, 22 L/min, and 26 L/min with placebo, fluticasone 50 micrograms, and fluticasone 100 micrograms, respectively. At the end point (the last evaluable visit), patients in both fluticasone groups continued to have significantly greater improvements in morning PEF than did patients receiving placebo. Patients experienced mean increases of 17 L/min, 50 L/min, and 57 L/min with placebo, fluticasone 50 micrograms, and fluticasone 100 micrograms, respectively. Changes in the percentage of predicted values by end point were 8%, 20%, and 26% with placebo, fluticasone 50 micrograms, and fluticasone 100 micrograms, respectively. The probability of remaining in the study, according to predefined withdrawal criteria, indicated a significant treatment difference in favor of fluticasone. Withdrawal criteria were met by 63%, 42%, and 29% of patients receiving placebo, fluticasone 50 micrograms, and fluticasone 100 micrograms, respectively. This study clearly demonstrates the superiority of fluticasone 50 and 100 micrograms BID over placebo in the treatment of persistent asthma in children.