Randomised trial of three treatments for amblyopia: Vision therapy and patching, perceptual learning and patching alone.

BACKGROUND: Active vision therapy for amblyopia shows good results, but there is no standard vision therapy protocol. This study compared the results of three treatments, two combining patching with active therapy and one with patching alone, in a sample of children with amblyopia. METHODS: Two protocols have been developed: (a) perceptual learning with a computer game designed to favour the medium-to-high spatial frequency-tuned achromatic mechanisms of parvocellular origin and (b) vision therapy with a specific protocol and 2-h patching. The third treatment group used patching only. Fifty-two amblyopic children (aged 4-12 years), were randomly assigned to three monocular treatment groups: 2-h patching (n = 18), monocular perceptual learning (n = 17) and 2-h patching plus vision therapy (n = 17). Visual outcomes were analysed after 3 months and compared with a control group (n = 36) of subjects with normal vision. RESULTS: Visual acuity (VA) and stereoacuity (STA) improved significantly after treatment for the three groups with the best results for patching plus vision therapy, followed by monocular perceptual learning, with patching only least effective. Change in the interocular difference in VA was significant for monocular perceptual learning, followed by patching. Differences in STA between groups were not significant. For VA and interocular differences, the final outcomes were influenced by the baseline VA and interocular difference, respectively, with greater improvements in subjects with poorer initial values. CONCLUSIONS: Visual acuity and STA improved with the two most active treatments, that is, vision therapy followed by perceptual learning. Patching alone showed the worst outcome. These results suggest that vision therapy should include monocular accommodative exercises, ocular motility and central fixation exercises where the fovea is more active.

Soft Contact Lens Engraving Characterization by Wavefront Holoscopy.

Permanent engravings on contact lenses provide information about the manufacturing process and lens positioning when they are placed on the eye. The inspection of their morphological characteristics is important, since they can affect the user's comfort and deposit adhesion. Therefore, an inverted wavefront holoscope (a lensless microscope based on Gabor's principle of in-line digital holography) is explored for the characterization of the permanent marks of soft contact lenses. The device, based on an in-line transmission configuration, uses a partially coherent laser source to illuminate the soft contact lens placed in a cuvette filled with a saline solution for lens preservation. Holograms were recorded on a digital sensor and reconstructed by back propagation to the image plane based on the angular spectrum method. In addition, a phase-retrieval algorithm was used to enhance the quality of the recovered images. The instrument was experimentally validated through a calibration process in terms of spatial resolution and thickness estimation, showing values that perfectly agree with those that were theoretically expected. Finally, phase maps of different engravings for three commercial soft contact lenses were successfully reconstructed, validating the inverted wavefront holoscope as a potential instrument for the characterization of the permanent marks of soft contact lenses. To improve the final image quality of reconstructions, the geometry of lenses should be considered to avoid induced aberration effects.

Factors affecting the benefit of glasses alone in treating childhood amblyopia: an analysis of PEDIG data.

BACKGROUND: To evaluate factors associated with better outcomes from optical treatment alone in amblyopic children from 3 up to 7 years. METHODS: Data extracted from two studies with similar protocols, Amblyopic Treatment Studies 5 (n = 152) and 13 (n = 128) from the Pediatric Eye Disease Investigator Group database, were used to determine by regression analysis the factors associated with improvements in visual acuity in the amblyopic eye, inter-ocular visual acuity difference and stereoacuity. Input variables were aetiology of amblyopia (anisometropic, strabismic and combined-mechanism amblyopia), treatment compliance, visual acuity, interocular visual acuity difference, stereoacuity, tropia size at distance and near, age and refractive error at baseline. RESULTS: Despite the range of clinical factors considered, our models explain only a modest proportion of the variance in optical treatment outcomes. The better predictors of the degree of optical treatment success in amblyopic children are visual acuity of the amblyopic eye, interocular visual acuity difference, stereoacuity, treatment compliance and the amblyopic eye spherical-equivalent refractive error. While the aetiology of the amblyopia does not exert a major influence upon treatment outcome, combined-mechanism amblyopes experience the smallest improvement in visual acuity, tropia and stereoacuity and may need longer optical treatment periods. CONCLUSIONS: While results identify the factors influencing optical treatment outcome in amblyopic children, clinicians will be unable to predict accurately the benefits of optical treatment in individual patients. Whether this is because relevant clinical or non-clinical factors (e.g. nature and volume of daily activities undertaken) influences the outcomes from optical treatment has not yet been identified and remains to be discovered.

Technical Report: Repeatability of Contrast Sensitivity Test in Children.

Contrast sensitivity (CS) in children is not routinely measured in the clinical setting, although CS losses have been found in amblyopic and premature children. Thus simple visual acuity measurements do not completely assess their quality of vision. To evaluate contrast sensitivity in children, a reliable and easy test, sampling the entire spatial frequency range, is necessary. PURPOSE: This study aimed to evaluate the repeatability and normal range of the contrast sensitivity function measured using the Topcon CC-100 instrument, in children aged between 4 and 9 years, for use as a diagnostic tool. METHODS: Contrast sensitivity was measured in 25 children, 11 boys and 14 girls, with normal or corrected-to-normal visual acuity, normal binocular function, and stereopsis. Two measurements were performed, 3 months apart, with a Topcon CC-100 device using achromatic sinusoidal gratings of 1.5, 3, 6, 12, and 18 cycles per degree (cpd) with random orientation in a circular window with sharp edges. RESULTS: The normal range in the first visit is wider than in the second. Coefficients of variation are better for the middle-range spatial frequencies (6.6 and 7.8% at 3 and 6 cpd, respectively) and worst at 18 cpd (18.2%), with intermediate values at 1.5 cpd (11.3%) and 12 cpd (13.7%), and better for older than for younger children. No significant sex differences were found (P > .05, Mann-Whitney U test). CONCLUSIONS: Repeatability measured by the coefficient of variation is better for the middle frequency range (3 and 6 cpd) than for low (1.5 cpd) and high frequencies (12 and 18 cpd). The variability of the differences between the first and second measurements suggests that the participants were not able to maintain a stable response criterion. The test seems to be subject to a learning effect, and the standard normality range may not be adequate for children.

Cognitive deterioration in schizophrenia: aging and cerebrovascular disease.

Today, cognitive dysfunction is accepted as a feature of schizophrenia. As the patients age, this dysfunction is higher and harder to evaluate due to the interaction among aging, other somatic diseases, psychoactive drugs, etc.

Studies of Jak/STAT3 expression and signalling in psoriasis identifies STAT3-Ser727 phosphorylation as a modulator of transcriptional activity.

Jak/Tyk proteins have recently aroused as possible therapeutic targets for the treatment of psoriasis. In psoriasis, these proteins signal through STAT molecules including STAT3, and STAT3 expression and activation has been shown augmented in psoriatic lesions. Here, we characterized the expression of Jak/Tyk proteins in lesional compared with non-lesional psoriatic skin. Jak1, Jak2 mRNA and protein and Tyk2 mRNA appeared to be downregulated, whereas Jak3 mRNA expression was increased. Moreover, STAT3 expression and activation was examined in psoriasis. STAT3 is activated at two phosphorylation sites: Tyr705 and Ser727. Both phosphorylation sites were phosphorylated in lesional psoriatic skin. The activation of STAT3 by Jak/Tyk proteins was studied in cultured normal human keratinocytes. Tyr705 phosphorylation was induced by IL-6 and IL-20 in a Jak2-dependent manner, and moreover, phosphorylation of Tyr705 produced a strong increase in STAT3 transcriptional activity. TNFα, 12-O-Tetradecanoylphorbol 13-acetate (TPA) and UVB irradiation induced Ser727 phosphorylation of STAT3 in an ERK1/2- and p38 MAPK-dependent manner, which resulted in a modulatory effect on STAT3 transcriptional activity. Our results demonstrate how different signalling pathways can integrate and lead to regulation of STAT3 transcriptional activity.

Potential antipsoriatic effect of chondroitin sulfate through inhibition of NF-κB and STAT3 in human keratinocytes.

Chondroitin sulfate (CS) is a natural glycosaminoglycan, formed by the 1-3 linkage of d-glucuronic acid to N-acetylgalactosamine, present in the extracellular matrix. It is used as a slow acting disease modifying agent in the treatment of osteoarthritis, and part of its beneficial effects are due to its antiinflammatory properties that result from an inhibitory effect on NF-κB signaling pathway. This ability raises the hypothesis that CS might be effective in other chronic inflammatory processes such as psoriasis, in which a deregulation of NF-κB is a key feature. In addition, psoriasis is characterized by an upregulation of STAT3 signaling pathway that is related to the epidermal hyperplasia. In the present study we report the pharmacological modulation of the NF-κB and STAT3 signaling pathways by CS in normal human keratinocytes. CS inhibited NF-κB activation and the release of some of the key psoriatic cytokines such as TNFα, IL-8, IL-6 and CCL27. Moreover, it impaired STAT3 translocation to the nucleus and significantly reduced STAT3 transcriptional activity by a mechanism that was independent from STAT3 phosphorylation. Our results confirm the interest of CS as a candidate for future drug research in the therapeutics of psoriasis given the need of more effective and safer oral medications for these patients.

Vecto-keratometry: determination of anterior corneal astigmatism in manual keratometers using power vectors.

BACKGROUND: A new keratometric routine that employs power vector management for manual keratometers is described. This study evaluates the agreement of the new proposed keratometric technique with the classical one. RESEARCH DESIGN AND METHODS: The applicability of a new keratometric routine was verified using Helmholtz's and Javal's keratometers. Results were obtained by two different and well-trained examiners over two different samples, one including 65 and the other 74 eyes, respectively. Both conventional keratometry and the newly proposed routine (named vecto-keratometry) were used in each eye to obtain the results. The clinical agreement between the methods was evaluated using Bland-Altman and Passing-Bablok analysis. RESULTS: For Helmholtz's keratometer, Bland-Altman plots showed good agreement between methods for both astigmatic components being J0 = 0.04 ± 0.20 D and J45 = -0.07 ± 0.17 D. For Javal's keratometer, Passing-Bablok regression test determined regression line for J0 difference as y0 = 1.03, confidence interval: [0.98, 1.10] and regression line for J45 difference as y45 = 0.97, confidence interval: [0.83, 1.12]. CONCLUSIONS: Vecto-keratometry provides accurate clinical results. It has been demonstrated that there are no significant differences between methods in any of the power vector astigmatic components; thus, both methods can be applied interchangeably.

Syntaxin-1 is necessary for UNC5A-C/Netrin-1-dependent macropinocytosis and chemorepulsion.

Introduction: Brain connectivity requires correct axonal guidance to drive axons to their appropriate targets. This process is orchestrated by guidance cues that exert attraction or repulsion to developing axons. However, the intricacies of the cellular machinery responsible for the correct response of growth cones are just being unveiled. Netrin-1 is a bifunctional molecule involved in axon pathfinding and cell migration that induces repulsion during postnatal cerebellar development. This process is mediated by UNC5 homolog receptors located on external granule layer (EGL) tracts. Methods: Biochemical, imaging and cell biology techniques, as well as syntaxin-1A/B (Stx1A/B) knock-out mice were used in primary cultures and brain explants. Results and discussion: Here, we demonstrate that this response is characterized by enhanced membrane internalization through macropinocytosis, but not clathrin-mediated endocytosis. We show that UNC5A, UNC5B, and UNC5C receptors form a protein complex with the t-SNARE syntaxin-1. By combining botulinum neurotoxins, an shRNA knock-down strategy and Stx1 knock-out mice, we demonstrate that this SNARE protein is required for Netrin1-induced macropinocytosis and chemorepulsion, suggesting that Stx1 is crucial in regulating Netrin-1-mediated axonal guidance.

A signaling mechanism coupling netrin-1/deleted in colorectal cancer chemoattraction to SNARE-mediated exocytosis in axonal growth cones.

Directed cell migration and axonal guidance are essential steps in neural development. Both processes are controlled by specific guidance cues that activate the signaling cascades that ultimately control cytoskeletal dynamics. Another essential step in migration and axonal guidance is the regulation of plasmalemma turnover and exocytosis in leading edges and growth cones. However, the cross talk mechanisms linking guidance receptors and membrane exocytosis are not understood. Netrin-1 is a chemoattractive cue required for the formation of commissural pathways. Here, we show that the Netrin-1 receptor deleted in colorectal cancer (DCC) forms a protein complex with the t-SNARE (target SNARE) protein Syntaxin-1 (Sytx1). This interaction is Netrin-1 dependent both in vitro and in vivo, and requires specific Sytx1 and DCC domains. Blockade of Sytx1 function by using botulinum toxins abolished Netrin-1-dependent chemoattraction of axons in mouse neuronal cultures. Similar loss-of-function experiments in the chicken spinal cord in vivo using dominant-negative Sytx1 constructs or RNAi led to defects in commissural axon pathfinding reminiscent to those described in Netrin-1 and DCC loss-of-function models. We also show that Netrin-1 elicits exocytosis at growth cones in a Sytx1-dependent manner. Moreover, we demonstrate that the Sytx1/DCC complex associates with the v-SNARE (vesicle SNARE) tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP) and that knockdown of TI-VAMP in the commissural pathway in the spinal cord results in aberrant axonal guidance phenotypes. Our data provide evidence of a new signaling mechanism that couples chemotropic Netrin-1/DCC axonal guidance and Sytx1/TI-VAMP SNARE proteins regulating membrane turnover and exocytosis.

Syntaxin 1 is required for DCC/Netrin-1-dependent chemoattraction of migrating neurons from the lower rhombic lip.

Directed cell migration and axonal guidance are essential steps in neural development that share many molecular mechanisms. The guidance of developing axons and migrating neurons is likely to depend on the precise control of plasmalemma turnover in selected regions of leading edges and growth cones, respectively. Previous results provided evidence of a signaling mechanism that couples chemotropic deleted in colorectal cancer (DCC)/Netrin-1 axonal guidance and exocytosis through Syntaxin1(Sytx1)/TI-VAMP SNARE proteins. Here we studied whether Netrin-1-dependent neuronal migration relies on a similar SNARE mechanism. We show that migrating neurons in the lower rhombic lip (LRL) express several SNARE proteins, and that DCC co-associates with Sytx1 and TI-VAMP in these cells. We also demonstrate that cleavage of Sytx1 by botulinum toxin C1 (BoNT/C1) abolishes Netrin-1-dependent chemoattraction of migrating neurons, and that interference of Sytx1 functions with shRNAs or Sytx1-dominant negatives disrupts Netrin-1-dependent chemoattraction of LRL neurons. These findings indicate that a Sytx1/DCC interaction is required for Netrin-1 guidance of migrating neurons, thereby highlighting a relationship between guidance signaling and SNARE proteins that regulate membrane turnover.

Defining the Profile of Obstructive Sleep Apnea in Women Compared to Men.

Background: The importance of understanding the presentation of obstructive sleep apnea (OSA) in women has been increasingly recognized. Although there is some insight that there are significant differences in presentation between women and men, the consequences of such differences, particularly for treatment have not yet been fully identified. Thus, the objective of this study was to determine the phenotype of OSA in women. Materials and Methods: Study of a population-based clinical cohort of 2022 patients with OSA confirmed by polygraphy or polysomnography (apnea-hypopnea index [AHI] >5/hour). Comorbidities, symptoms, physical examination, current medical treatments, and sleep parameters were recorded. Results: A total of 709 women and 1313 men were included in this study. After adjustment for anthropometric characteristics, morphological alterations, and previous treatment, women were found to have lower AHI values (25.3 ± 1.2 vs. 35.0 ± 0.9; p < 0.001), desaturation index (24.4 ± 1.2 vs. 33.2 ± 0.9; p < 0.001), and saturation time <90% (18.8 ± 1.3 vs. 24.1 ± 1.0; p < 0.001) compared with men. Furthermore, women had a lower risk of witnessed apnea (odds ratio adjusted [ORa] for baseline characteristics and sleep parameters), (ORa: 0.53, 95% confidence interval [CI]: 0.40-0.71), reduced sensation of restful sleep (ORa: 0.50, 95% CI: 0.38-0.66), greater fatigue (ORa: 2.68, 95% CI: 1.86-3.86), headache (ORa: 3.00, 95% CI: 2.26-3.97), memory disorders (ORa: 1.836, 95% CI: 1.40-2.41), insomnia (ORa: 2.09, 95% CI: 1.50-2.93), and excessive daytime sleepiness (ORa: 1.41, 95% CI: 1.03-1.92), with interference in their daily activities (ORa: 1.54, 95% CI: 1.17-2.03). Likewise, after adjustment for anthropometric characteristics and sleep parameters, women also showed higher risk of depression (ORa: 4.31, 95% CI: 3.15-5.89) and anxiety (ORa: 3.18, 95% CI: 2.38-4.26). Conclusions: Our findings suggest that women present a specific OSA phenotype, with a probable implication for clinical, diagnostic, and therapeutic management.

Prevalence of High Blood Pressure in Pediatric Patients with Sleep-Disordered Breathing, Reversibility after Treatment: The KIDS TRIAL Study Protocol.

Current data support an increase in the prevalence of high blood pressure (HBP) in pediatric patients with sleep-disordered breathing (SDB). Adeno-tonsillectomy has been shown to be an effective treatment for most patients. Our objective was to determine the prevalence of HBP in pediatric patients with SDB and the impact of adeno-tonsillectomy with a multicenter, longitudinal, and prospective study that included 286 children referred for suspected SDB. The diagnosis of SDB was established by polysomnography (PSG) and the diagnosis of HBP by 24-h ambulatory blood pressure monitoring (ABPM). In patients without SDB and SDB without treatment indication, these tests were repeated six months after the baseline visit. For patients with medical treatment for SDB, the tests were repeated six months after the treatment initiation. Finally, in patients with surgery indication, ABPM was performed just before surgical treatment and ABPM and PSG six months after the intervention. The study contributes to elucidating the association between SDB and HBP in pediatric patients. Moreover, it contributes to determining if intervention with adeno-tonsillectomy is associated with BP reduction. The results have direct implications for the management of SDB, providing essential information on treatment indications for existing clinical guidelines. NCT03696654.

Adult onset Hallervorden-Spatz disease with psychotic symptoms.

Hallervorden-Spatz disease is a rare neurological disorder characterized by pyramidal and extrapyramidal manifestations, dysarthria and dementia. Its onset is usually in childhood and most patients have a fatal outcome in few years. A high percentage of cases are hereditary with a recessive autosomal pattern. In the majority of the patients reported, a mutation of the gene that encodes the pantothenate kinase (PANK2) located in the 20p13-p12.3 chromosome that causes iron storage in the basal ganglia of the brain has been found. Its diagnosis is based on clinical symptoms as well as specific MRI imaging findings. The most common psychiatric features are cognitive impairment as well as depressive symptoms. There are few documented cases with psychotic disorders. We present the case of a patient with late onset Hallervorden-Spatz disease and psychotic symptoms that preceded the development of neurological manifestations. The pathophysiology and the treatment of psychotic symptomatology are presented and discussed. Key words: Psicosis, Hallervorden-Spatz, late onset, Basal ganglia.

A New Cerkl Mouse Model Generated by CRISPR-Cas9 Shows Progressive Retinal Degeneration and Altered Morphological and Electrophysiological Phenotype.

Purpose: Close to 100 genes cause retinitis pigmentosa, a Mendelian rare disease that affects 1 out of 4000 people worldwide. Mutations in the ceramide kinase-like gene (CERKL) are a prevalent cause of autosomal recessive cause retinitis pigmentosa and cone-rod dystrophy, but the functional role of this gene in the retina has yet to be fully determined. We aimed to generate a mouse model that resembles the phenotypic traits of patients carrying CERKL mutations to undertake functional studies and assay therapeutic approaches. Methods: The Cerkl locus has been deleted (around 97 kb of genomic DNA) by gene editing using the CRISPR-Cas9 D10A nickase. Because the deletion of the Cerkl locus is lethal in mice in homozygosis, a double heterozygote mouse model with less than 10% residual Cerkl expression has been generated. The phenotypic alterations of the retina of this new model have been characterized at the morphological and electrophysiological levels. Results: This CerklKD/KO model shows retinal degeneration, with a decreased number of cones and progressive photoreceptor loss, poorly stacked photoreceptor outer segment membranes, defective retinal pigment epithelium phagocytosis, and altered electrophysiological recordings in aged retinas. Conclusions: To our knowledge, this is the first Cerkl mouse model to mimic many of the phenotypic traits, including the slow but progressive retinal degeneration, shown by human patients carrying CERKL mutations. This useful model will provide unprecedented insights into the retinal molecular pathways altered in these patients and will contribute to the design of effective treatments.

Defective Induction of COX-2 Expression by Psoriatic Fibroblasts Promotes Pro-inflammatory Activation of Macrophages.

Fibroblasts play an important role as members of the innate immune system through the secretion of COX-2-derived inflammatory mediators such as prostaglandin E2 (PGE2). However, it has been described that dermal fibroblasts behave like mesenchymal stem cells reducing lymphocyte recruitment and dendritic cell activation through PGE2 release. As the role of fibroblasts in psoriasis remains poorly characterized, in the present study we have evaluated the possible influence of PGE2 derived from dermal fibroblasts as modulator of the immune response in psoriatic skin. Our results indicate that under inflammatory conditions, psoriatic fibroblasts showed defective induction of COX-2, which resulted in diminished production of PGE2, in contrast to healthy fibroblasts. This phenotype correlated with deficient c-Jun N-terminal kinase (JNK) activation, in accordance with the hypothesis that alterations in members of the JNK pathway are associated with psoriasis. Furthermore, conditioned medium from psoriatic fibroblasts promoted the polarization of monocytic cells toward a pro-inflammatory profile, effect that was mimicked in healthy fibroblasts after pre-incubation with indomethacin. These results are consistent with a prominent role of dermal fibroblasts in the regulation of inflammatory response through the participation of COX-derived metabolites. This resolutive behavior seems to be defective in psoriatic fibroblasts, offering a possible explanation for the chronification of the disease and for the exacerbation triggered by nonsteroidal anti-inflammatory drugs (NSAIDS) such as indomethacin.

Regulation of sympathetic neuron differentiation by endogenous nerve growth factor and neurotrophin-3.

Nerve growth factor (NGF) and neurotrophin-3 (NT3) play distinctive roles in sympathetic axon growth and target field innervation and are required for sympathetic neuron survival in vivo. To ascertain if these neurotrophins selectively regulate the expression of genes that determine the functional characteristics of differentiated sympathetic neurons, we measured the mRNA levels for several such genes in the superior cervical ganglion of NGF(-/-), NT3(-/-) and wild type mouse embryos at a stage before excessive neuronal loss occurs in the absence of these neurotrophins. Despite the extensively documented ability of NGF to regulate the noradrenergic phenotype of sympathetic neurons, we found that tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DbetaH) mRNA levels were normal in NGF(-/-) embryos, but significantly reduced in NT3(-/-) embryos. In contrast, the beta2 nicotinic acetylcholine receptor and PACAP receptor 1 mRNA levels were normal in NT3(-/-) embryos, but significantly reduced in NGF(-/-) embryos. Studies of mice lacking neurotrophin receptors suggested that the effects of NGF on gene expression require TrkA whereas those of NT3 require TrkA and p75(NTR). These findings demonstrate that endogenous NGF and NT3 have distinctive and separate effects on gene expression in early sympathetic neurons and that these selective effects on gene expression require a different combination of neurotrophin receptors.

Syntaxin-1/TI-VAMP SNAREs interact with Trk receptors and are required for neurotrophin-dependent outgrowth.

SNARE proteins are essential components of the machinery that regulates vesicle trafficking and exocytosis. Their role is critical for the membrane-fusion processes that occur during neurotransmitter release. However, research in the last decade has also unraveled the relevance of these proteins in membrane expansion and cytoskeletal rearrangements during developmental processes such as neuronal migration and growth cone extension and attraction. Neurotrophins are neurotrophic factors that are required for many cellular functions throughout the brain, including neurite outgrowth and guidance, synaptic formation, and plasticity. Here we show that neurotrophin Trk receptors form a specific protein complex with the t-SNARE protein Syntaxin 1, both in vivo and in vitro. We also demonstrate that blockade of Syntaxin 1 abolishes neurotrophin-dependent growth of axons in neuronal cultures and decreases exocytotic events at the tip of axonal growth cones. 25-kDa soluble N-ethylmaleimide-sensitive factor attachment protein and Vesicle-associated membrane protein 2 do not participate in the formation of this SNARE complex, while tetanus neurotoxin-insensitive vesicle-associated membrane protein interacts with Trk receptors; knockdown of this (v) SNARE impairs Trk-dependent outgrowth. Taken together, our results support the notion that an atypical SNARE complex comprising Syntaxin 1 and tetanus neurotoxin-insensitive vesicle-associated membrane protein is required for axonal neurotrophin function.