Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia.

Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a splicing mutation in elongator acetyltransferase complex subunit 1 (ELP1). This mutation leads to the skipping of exon 20 and a tissue-specific reduction of ELP1, mainly in the central and peripheral nervous systems. FD is a complex neurological disorder accompanied by severe gait ataxia and retinal degeneration. There is currently no effective treatment to restore ELP1 production in individuals with FD, and the disease is ultimately fatal. After identifying kinetin as a small molecule able to correct the ELP1 splicing defect, we worked on its optimization to generate novel splicing modulator compounds (SMCs) that can be used in individuals with FD. Here, we optimize the potency, efficacy, and bio-distribution of second-generation kinetin derivatives to develop an oral treatment for FD that can efficiently pass the blood-brain barrier and correct the ELP1 splicing defect in the nervous system. We demonstrate that the novel compound PTC258 efficiently restores correct ELP1 splicing in mouse tissues, including brain, and most importantly, prevents the progressive neuronal degeneration that is characteristic of FD. Postnatal oral administration of PTC258 to the phenotypic mouse model TgFD9;Elp1Δ20/flox increases full-length ELP1 transcript in a dose-dependent manner and leads to a 2-fold increase in functional ELP1 in the brain. Remarkably, PTC258 treatment improves survival, gait ataxia, and retinal degeneration in the phenotypic FD mice. Our findings highlight the great therapeutic potential of this novel class of small molecules as an oral treatment for FD.

Symmetry induced phonon renormalization in few layers of 2H-MoTe2 transistors: Raman and first-principles studies.

Understanding of electron-phonon coupling (EPC) in two-dimensional (2D) materials manifesting as phonon renormalization is essential to their possible applications in nanoelectronics. Here we report in situ Raman measurements of electrochemically top-gated 2, 3 and 7 layered 2H-MoTe2 channel based field-effect transistors. While the [Formula: see text] and B2g phonon modes exhibit frequency softening and linewidth broadening with hole doping concentration (p) up to ∼2.3 × 1013/cm2, A1g shows relatively small frequency hardening and linewidth sharpening. The dependence of frequency renormalization of the [Formula: see text] mode on the number of layers in these 2D crystals confirms that hole doping occurs primarily in the top two layers, in agreement with recent predictions. We present first-principles density functional theory analysis of bilayer MoTe2 that qualitatively captures our observations, and explain that a relatively stronger coupling of holes with [Formula: see text] or B2g modes as compared with the A1g mode originates from the in-plane orbital character and symmetry of the states at valence band maximum. The contrast between the manifestation of EPC in monolayer MoS2 and those observed here in a few-layered MoTe2 demonstrates the role of the symmetry of phonons and electronic states in determining the EPC in these isostructural systems.

The Alternaria alternata Mycotoxin Alternariol Suppresses Lipopolysaccharide-Induced Inflammation.

The Alternaria mycotoxins alternariol (AOH) and alternariol monomethyl ether (AME) have been shown to possess genotoxic and cytotoxic properties. In this study, the ability of AOH and AME to modulate innate immunity in the human bronchial epithelial cell line (BEAS-2B) and mouse macrophage cell line (RAW264.7) were investigated. During these studies, it was discovered that AOH and to a lesser extent AME potently suppressed lipopolysaccharide (LPS)-induced innate immune responses in a dose-dependent manner. Treatment of BEAS-2B cells with AOH resulted in morphological changes including a detached pattern of growth as well as elongated arms. AOH/AME-related immune suppression and morphological changes were linked to the ability of these mycotoxins to cause cell cycle arrest at the G2/M phase. This model was also used to investigate the AOH/AME mechanism of immune suppression in relation to aryl hydrocarbon receptor (AhR). AhR was not found to be important for the immunosuppressive properties of AOH/AME, but appeared important for the low levels of cell death observed in BEAS-2B cells.

Tilt and shift polymorphism in molecular perovskites.

Molecular perovskites, i.e. ABX3 coordination polymers with a perovskite structure, are a chemically diverse material platform for studying fundamental and applied materials properties such as barocalorics and improper ferroelectrics. Compared to inorganic perovskites, the use of molecular ions on the A- and X-site of molecular perovskites leads to new geometric and structural degrees of freedom. In this work we introduce the concept of tilt and shift polymorphism, categorising irreversible perovskite-to-perovskite phase transitions in molecular perovskites. As a model example we study the new molecular perovskite series [(nPr)3(CH3)N]M(C2N3)3 with M = Mn2+, Co2+, Ni2+, and nPr = n-propyl, where different polymorphs crystallise in the perovskite structure but with different tilt systems depending on the synthetic conditions. Tilt and shift polymorphism is a direct ramification of the use of molecular building units in molecular perovskites and as such is unknown for inorganic perovskites. Given the role of polymorphism in materials science, medicine and mineralogy, and more generally the relation between physicochemical properties and structure, the concept introduced herein represents an important step in classifying the crystal chemistry of molecular perovskites and in maturing the field.

Prognostic preoperative factors for successful outcome of surgery in horizontal strabismus.

CONTEXT: Surgery for horizontal strabismus reportedly has a success rate of 60%-80%. However, which preoperative factors are predictive of this success is not clear. AIMS: To identify prognostic factors those are predictive of successful outcome in horizontal strabismus surgery. SETTINGS AND DESIGN: Observational analytical study using multiple logistic regression (MLR). SUBJECTS AND METHODS: We assessed the medical records of patients who had undergone first-time horizontal muscle strabismus surgery between 2002 and 2013, where complete follow-up data were available for ≥6 weeks, and also, we collected data prospectively on patients operated between January 2014 and September 2015. Successful outcome was defined as a postoperative angle of deviation within 10 prism diopter of orthophoria at ≥6 weeks postoperatively. Independent variables considered were age at onset, age at surgery, duration, gender, deviation - type and amount, logMAR visual acuity (VA) - mean and of the poorer eye, mean refractive error, amount of anisometropia, and presence of dense amblyopia. Only those with P < 0.2 on univariate analyses (UAs) were included in the MLR, with significance set at P ≤ 0.05. STATISTICAL ANALYSES: UA (Chi-square for categorical variables and t-tests for continuous variables), followed by logistic regression analysis. RESULTS: Of 113 patients, on UA, type of deviation (P = 0.01), age at surgery (P = 0.16), absence of dense amblyopia (P = 0.002), and logMAR VA of the poorer eye (P = 0.005) qualified for the inclusion in MLR. On MLR, esotropia (ET) (odds ratio [OR]: 4.46) and absence of dense amblyopia (OR: 5.90) were associated with success. CONCLUSIONS: With an overall success rate of 83%, ET and absence of dense amblyopia were significantly predictive of surgical success.

Plication as an alternative to resection in horizontal strabismus: A randomized clinical trial.

PURPOSE: Resections and plications tighten recti although the latter are less traumatic, potentially reversible, quicker, and vascularity preserving. To compare inflammation, scarring, and alignment in horizontal strabismus, operated uniocularly by either resections or plications (with recessions): recession and resection (R&R) or recession and plication (R&P) groups. This was a prospective, patient and assessor blind, randomized trial. METHODS: All consenting strabismus patients qualifying for the first-time uniocular horizontal rectus surgeries underwent detailed ocular examination and were randomized into standard R&R or R&P groups. For the latter, we folded the tendon-muscle strap the desired amount using 6-0 polyglactin, suturing it to its insertion, entailing no disinsertion. We compared the groups for inflammatory grades (individually for congestion, chemosis, discharge, foreign-body sensation, and drop intolerance and aggregated to a total inflammatory score (TIS), scar visibility (SV) at 1 m, and successful alignment (≤10 prism diopter of orthotropia). We used Mann-Whitney and Fisher's exact tests, with significance at P ≤ 0.05. RESULTS: We randomized 40 patients: 22 to R&R and 18 to R&P. The groups were comparable in age, strabismus onset and duration, and strabismus amount. The inflammatory scores, both individual and TIS, were comparable at all time-points: all P > 0.05. SV proportions were not significantly different: 16/22 in R&R versus 9/18 in R&P; P = 0.19. There were no significant differences in success rates: 14/22 versus 10/18, P = 0.74. CONCLUSION: Our study shows that plication is similarly effective as resection, when combined with recession in horizontal strabismus, and should be resorted to more frequently.

Direct, spontaneous carotid-cavernous fistula with a contracted kidney: A rare association.

We report a case of a 20-year-old female having systemic hypertension who presented with right-sided proptosis, chemosis, and diminished vision, preceded by an acute episode of unilateral throbbing headache. Imaging studies revealed a right-sided direct, spontaneous carotid-cavernous fistula (CCF), aneurysm of internal carotid artery, bleed in the parieto-frontal lobe, and swelling of extraocular muscles. Abdominal ultrasound revealed a small contracted right kidney measuring 64 mm × 27 mm. A direct spontaneous CCF can occur spontaneously following rupture of intracranial aneurysm without any history of trauma or connective tissue disorder. Prompt diagnosis of intravascular malformations at initial presentation can prevent neurological complications and vision loss. A team approach including emergency physicians, neurosurgeons, and ophthalmologists is needed for the proper management of such patients.

One glasses too many: A case report of Benson's syndrome.

We report a case of Benson's Syndrome, a form of occipital Alzheimer's disease, with posterior cortical atrophy on magnetic resonance imaging, in a 62-year-old male, who presented with visual problems, ascribed to the eyes, and had even undergone cataract/intraocular lens surgery in the right eye; and change of glasses 21 times over the past 2 years, with no apparent benefit. This case is of interest both on account of its rarity, and to highlight its features since the diagnosis may be missed in an ophthalmological setting where such patient may go for first consult.

Cost-effectiveness analysis should continually assess competing health care options especially in high volume environments like cataract surgery.

CONTEXT: Cost-effectiveness analysis should continually assess competing health care options especially in high volume environments like cataract surgery. AIMS: To compare the cost effectiveness of phacoemulsification (PE) versus manual small-incision cataract surgery (MSICS). SETTINGS AND DESIGN: Prospective randomized controlled trial. Tertiary care hospital setting. SUBJECTS AND METHODS: A total of 52 consenting patients with age-related cataracts, were prospectively recruited, and block randomized to PE or MSICS group. Preoperative and postoperative LogMAR visual acuity (VA), visual function-14 (VF-14) score and their quality-adjusted life years (QALYs) were obtained, and the change in their values calculated. These were divided by the total cost incurred in the surgery to calculate and compare the cost effectiveness and cost utility. Surgery duration was also compared. STATISTICAL ANALYSIS USED: Two group comparison with Student's t-test. Significance set at P < 0.05; 95% confidence interval (CI) quoted where appropriate. RESULTS: Both the MSICS and PE groups achieved comparative outcomes in terms of change (difference in mean [95% CI]) in LogMAR VA (0.03 [-0.05-0.11]), VF-14 score (7.92 [-1.03-16.86]) and QALYs (1.14 [-0.89-3.16]). However, with significantly lower costs (INR 3228 [2700-3756]), MSICS was more cost effective, with superior cost utility value. MSICS was also significantly quicker (10.58 min [6.85-14.30]) than PE. CONCLUSIONS: MSICS provides comparable visual and QALY improvement, yet takes less time, and is significantly more cost-effective, compared with PE. Greater push and penetration of MSICS, by the government, is justifiably warranted in our country.