Cell-to-cell transmission of C9orf72 poly-(Gly-Ala) triggers key features of ALS/FTD.

The C9orf72 repeat expansion causes amyotrophic lateral sclerosis and frontotemporal dementia, but the poor correlation between C9orf72-specific pathology and TDP-43 pathology linked to neurodegeneration hinders targeted therapeutic development. Here, we addressed the role of the aggregating dipeptide repeat proteins resulting from unconventional translation of the repeat in all reading frames. Poly-GA promoted cytoplasmic mislocalization and aggregation of TDP-43 non-cell-autonomously, and anti-GA antibodies ameliorated TDP-43 mislocalization in both donor and receiver cells. Cell-to-cell transmission of poly-GA inhibited proteasome function in neighboring cells. Importantly, proteasome inhibition led to the accumulation of TDP-43 ubiquitinated within the nuclear localization signal (NLS) at lysine 95. Mutagenesis of this ubiquitination site completely blocked poly-GA-dependent mislocalization of TDP-43. Boosting proteasome function with rolipram reduced both poly-GA and TDP-43 aggregation. Our data from cell lines, primary neurons, transgenic mice, and patient tissue suggest that poly-GA promotes TDP-43 aggregation by inhibiting the proteasome cell-autonomously and non-cell-autonomously, which can be prevented by inhibiting poly-GA transmission with antibodies or boosting proteasome activity with rolipram.

Cytoplasmic poly-GA aggregates impair nuclear import of TDP-43 in C9orf72 ALS/FTLD.

A repeat expansion in the non-coding region of C9orf72 gene is the most common mutation causing frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Sense and antisense transcripts are translated into aggregating dipeptide repeat (DPR) proteins in all reading frames (poly-GA,-GP,-GR,-PA and -PR) through an unconventional mechanism. How these changes contribute to cytoplasmic mislocalization and aggregation of TDP-43 and thereby ultimately leading to neuron loss remains unclear. The repeat RNA itself and poly-GR/PR have been linked to impaired nucleocytoplasmic transport. Here, we show that compact cytoplasmic poly-GA aggregates impair nuclear import of a reporter containing the TDP-43 nuclear localization (NLS) signal. However, a reporter containing a non-classical PY-NLS was not affected. Moreover, poly-GA expression prevents TNFα induced nuclear translocation of p65 suggesting that poly-GA predominantly impairs the importin-α/ß-dependent pathway. In neurons, prolonged poly-GA expression induces partial mislocalization of TDP-43 into cytoplasmic granules. Rerouting poly-GA to the nucleus prevented TDP-43 mislocalization, suggesting a cytoplasmic mechanism. In rescue experiments, expression of importin-α (KPNA3, KPNA4) or nucleoporins (NUP54, NUP62) restores the nuclear localization of the TDP reporter. Taken together, inhibition of nuclear import of TDP-43 by cytoplasmic poly-GA inclusions causally links the two main aggregating proteins in C9orf72 ALS/FTLD pathogenesis.

Facial Asymmetry in Unilateral Duane Retraction Syndrome.

SIGNIFICANCE: The overall objective of this study was to evaluate facial asymmetry in patients with unilateral Duane retraction syndrome (DRS). The results showed a high frequency of facial asymmetry parameters of the opposite side of head turn in unilateral DRS patients. PURPOSE: The purposes of this study were to evaluate the characteristics of facial asymmetry in unilateral exotropic and esotropic DRS and to compare the findings with orthotropic subjects. METHODS: This cross-sectional comparative case series study was performed in 44 consecutive patients with head turn caused by DRS and 44 orthotropic subjects from 2016 to 2019. Four pictures were taken from the patients' faces. The first and second pictures were taken when patients had head turn and when the head was completely straight for calculating the facial angle and relative facial size, respectively. The third and fourth pictures were taken when the head was positioned downward (to compare the size of the cheek) and upward (to evaluate nose asymmetry). RESULTS: The mean ± SD age of DRS patients and orthotropic subjects was 16.23 ± 9.92 and 20.68 ± 11.82 years, respectively. The frequency of facial asymmetry and all facial parameters (cheek compression, nasal tip and columella deviation, and compression of one of the nostrils) was significantly higher in DRS patients compared with orthotropic subjects (P < .001). In DRS patients with facial asymmetry, columella and nasal tip deviation (P = .006) and cheek and face compression (P = .03) were significantly more prevalent in the opposite direction of head turn. In the DRS group, the mean ± SD age of the patients with and without facial asymmetry was 17.37 ± 9.76 and 7.40 ± 6.54 years, respectively (P = .02). CONCLUSIONS: The frequency of facial asymmetry and all facial parameters was significantly higher in DRS patients compared with orthotropic subjects. In unilateral DRS patients, the face was more commonly affected on the opposite side of head turn.

Effect of axial length and anterior chamber depth on the peripheral refraction profile.

AIM: To evaluate the effect of axial length (AL) and anterior chamber depth (ACD) on peripheral refractive profile in myopic patients compared to emmetropic participants. METHODS: This cross-sectional study was conducted in right eyes of 58 participants of whom 38 were emmetropic and 20 were myopic. Central and peripheral refraction were measured at 10°, 20°, and 30° eccentricities in nasal and temporal fields using an open-field autorefractor. The Lenstar LS900 was used to measure ACD and AL. The participants were divided into three groups of short (<22.5 mm), normal (22.5-24.5 mm), and long eye (>24.5 mm) according to AL and three groups of low ACD (<3.00 mm), normal ACD (3.00-3.60 mm), and high ACD (>3.60 mm) according to ACD. RESULTS: The mean age of the participants was 22.26±3.09y (range 18-30y). The peripheral mean spherical refractive error showed a hypermetropic shift in myopic and emmetropic groups although this shift was more pronounced in the myopic group. The results showed significant changes in the spherical equivalent, J0, and J45 astigmatism in all gazes with an increase in eccentricity (P<0.001). The pattern of refractive error changes was more noticeable in long and short eyes versus normal AL eyes. Moreover, the pattern of peripheral refractive changes was much more prominent in the high ACD group versus the normal ACD group and in the normal ACD group versus the low ACD group. CONCLUSION: Peripheral refraction changes are greater in participants with AL values outside the normal range and deeper ACD values compared to participants with normal AL and ACD.

The prevalence of strabismus types in strabismic Iranian patients.

PURPOSE: To determine the frequency of different types of strabismus and amblyopia in the patients of strabismus clinics from 2008 to 2014. METHODS: This retrospective cross-sectional study was conducted using data from the archives of Farabi Hospital in Tehran, Iran, from 2008 to 2014. The study consisted of using records of strabismic patients. From these, strabismus types and associated abnormalities, types of amblyopia and other ocular pathological findings were recorded. RESULTS: In this study, 1174 strabismic patients were studied. Accommodative esotropia (ET) was the most prevalent type of strabismus accounting for 25.04% of all strabismic patients while intermittent exotropia (XT), nonaccommodative ET and partially accommodative ET, with 12.09%, 11.24% and 10.39%, respectively, were relatively common. Also, 63.03% of all strabismic patients had esodeviation with XT coming second accounting for 24.53% of patients. Other ocular pathologic findings in addition to strabismus were found in 236 (20.1%) patients. The most common association with those types of strabismus was inferior oblique over action accounting for 11.07% of all cases, and 88 patients had nystagmus in addition to strabismus. Significantly 45% of patients had no amblyopia and 37% of patients had a combined type of amblyopia which was the most common type of amblyopia found in strabismic patients. CONCLUSION: The prevalence of ET was two and a half times more than XT and almost half of strabismic patients suffer from amblyopia. This study suggests that strabismus screening of children could be useful in the early detection of strabismus, appropriate management of it and prevention of strabismic amblyopia.

Characteristics of Posterior Corneal Astigmatism in Different Stages of Keratoconus.

PURPOSE: To evaluate the magnitudes and axis orientation of anterior corneal astigmatism (ACA) and posterior corneal astigmatism (PCA), the ratio of ACA to PCA, and the correlation between ACA and PCA in the different stages of keratoconus (KCN). METHODS: This retrospective case series comprised 161 eyes of 161 patients with KCN (104 men, 57 women; mean age, 22.35 ± 6.10 years). The participants were divided into four subgroups according to the Amsler-Krumeich classification. A Scheimpflug imaging system was used to measure the magnitude and axis orientation of ACA and PCA. The posterior-anterior corneal astigmatism ratio was also calculated. The results were compared among different subgroups. RESULTS: The average amounts of anterior, posterior, and total corneal astigmatism were 4.08 ± 2.21 diopters (D), 0.86 ± 0.46 D, and 3.50 ± 1.94 D, respectively. With-the-rule, against-the-rule, and oblique astigmatisms of the posterior surface of the cornea were found in 61 eyes (37.9%), 67 eyes (41.6%), and 33 eyes (20.5%), respectively; corresponding figures in the anterior corneal surface were 55 eyes (32.4%), 56 eyes (34.8%), and 50 eyes (31.1%), respectively. A strong correlation (P ≤ 0.001, r = 0.839) was found between ACA and PCA in the different stages of KCN; the correlation was weaker in eyes with grade 3 (P ≤ 0.001, r = 0.711) and grade 4 (P ≤ 0.001, r = 0.717) KCN. The maximum posterior-anterior corneal astigmatism ratio (PCA/ACA, 0.246) was found in patients with stage 1 KCN. CONCLUSION: Corneal astigmatism in anterior surface was more affected than posterior surface by increasing in the KCN severity, although PCA was more affected than ACA in an early stage of KCN.

Comparison between Pentacam HR and Orbscan II after Hyperopic Photorefractive Keratectomy.

PURPOSE: The aim of this study was to determine the agreement between Pentacam HR (Scheimpflug imaging, Oculus) and Orbscan II (scanning slit topography, Bausch and Lomb) in measuring corneal parameters after photorefractive keratectomy (PRK) for hyperopia. METHODS: In this prospective cross-sectional study, 38 hyperopic eyes undergoing PRK were examined before refractive surgery and 8 to 10 months postoperatively using Pentacam HR and Orbscan II. Ultrasound (US) pachymetry was also used to measure central corneal thickness (CCT). The radius of anterior (A-) and posterior (P-) best-fit sphere size (BFS), central elevation (CE), and anterior maximum tangential power in 3 mm (TG3) and 3-5 mm (TG5) zones, anterior chamber depth (ACD), and central corneal thickness (CCT) were collected and used in the analyses. To study the agreement between the measurements made by the two devices, the method described by Bland and Altman was used and the 95% limits of agreement were calculated. RESULTS: The 95% limits of agreement show reasonable agreement between the measurements by Pentacam HR and Orbscan II for A-BFS, P-BFS, A-TG3, and CCT, but not for A-CE, P-CE, A-TG5, or ACD. CCT values obtained by both Pentacam HR and Orbscan II correlated well with the values determined by US pachymetry. CONCLUSION: Pentacam HR and Orbscan II after PRK for hyperopia show reasonable agreement for determining A-BFS, P-BFS, A-TG3, and CCT, but not for A-CE, P-CE, A-TG5, or ACD. CCT measurements with Pentacam HR have reasonable agreement with US pachymetry.

Characteristics of Astigmatism after MyoRing Implantation.

Considering the rising number of MyoRing implantation procedures in keratoconic corneas and the refractive outcomes associated with this treatment modality, this study aimed to evaluate and compare the magnitude and axis orientation of total and corneal astigmatism between before and after MyoRing implantation in 34 eyes of 28 patients with keratoconus (KCN) (mean age: 29.41 ± 7.0 years). The inclusion criterion was a reliable diagnosis of clinical KCN based on corneal biomicroscopic and tomographic findings. The mean total astigmatism of ocular refraction decreased significantly from -4.27 ± 3.15 D (before MyoRing implantation) to -2.18 ± 1.63 D (after MyoRing implantation) (P < 0.001). The mean astigmatism in the anterior and posterior surface of the cornea decreased significantly by 1.16 D (P = 0.001) and 0.24 D (P = 0.009), respectively, after MyoRing implantation. Before MyoRing implantation, the axis orientation of total ocular astigmatism for with-the-rule, oblique, and against-the-rule astigmatism was 21%, 42%, and 37%, respectively; at 6 months after MyoRing implantation, it was 18%, 24%, and 58%, respectively. Before MyoRing implantation, the axis orientation for with-the-rule, against-the-rule, and oblique astigmatism of the anterior surface of the cornea was 59%, 24%, and 17%, respectively; at 6 months after MyoRing implantation, it was 52%, 24%, and 24%, respectively. Before MyoRing implantation, the axis orientation of with-the-rule, oblique, and against-the-rule astigmatism of the posterior surface of the cornea was 68%, 29%, and 3%, respectively; at 6 months after MyoRing implantation, it was 67%, 12%, and 12%, respectively. MyoRing implantation significantly decreased the amount of total, anterior, and posterior corneal astigmatism.

Higher order aberration comparison between two aspherical intraocular lenses: MC6125AS and Akreos advanced optics.

AIM: To compare higher order aberrations in two aspherical intraocular lenses (IOLs): Akreos advanced optics (AO) and Dr. Schmidt Microcrystalline 6125 aspheric anterior surface (MC6125AS) with each other. METHODS: Forty eyes of 39 patients underwent phacoemulsification and Akreos AO and MC6125AS were implanted in their eyes in a random manner. Three months post-operatively, higher order aberrations including spherical aberration, coma aberration, and total aberrations were measured and compared. RESULTS: The total aberration was 0.24±0.17 in eyes with Dr. Schmidt and 0.20±0.01 in eyes with Akreos AO (P=0.361). The mean of coma aberration was 0.17±0.21 and 0.09±0.86 in Dr. Schmidt and Akreos lenses, respectively (P=0.825). Total spherical aberration was almost the same in both groups (Mean: 0.05, P=0.933). Best corrected visual acuity in Akreos AO (0.10±0.68) and Dr. Schmidt (0.09±0.67) did not differ significantly (P=0.700). CONCLUSION: There is no statistically significant difference in the higher order aberrations between these two aspherical lenses.