Goldenhar syndrome associated with lacrimal system agenesis: A case report.

Purpose: To report a case of lacrimal system agenesis in a patient with Goldenhar syndrome. Observations: A one-month-old female preterm twin with Goldenhar syndrome presented with left upper eyelid coloboma, left central corneal ulcer and inferotemporal epibulbar dermoid. The corneal ulcer was treated and healed to a mild stromal scar. Examination under anesthesia prior to surgery revealed agenesis of the upper and lower eyelids canaliculi. Surgery was performed to correct left upper eyelid coloboma. At a second stage, the epibulbar dermoid was excised and ocular surface was repaired with amniotic membrane graft. Conclusion and importance: Goldenhar syndrome is a rare congenital anomaly arising from the abnormal development of the first and second branchial arches. Anomalies of lacrimal drainage system are uncommon in Goldenhar including nasolacrimal duct obstruction and common canalicular obstruction. Agenesis of the lacrimal system has not been described in cases of Goldenhar syndrome. This case represents a unique and uncommonly seen feature.

Upper Limit of Retinal Nerve Fibre Layer Thickness in Patients with Pseudopapilloedema.

An initial misdiagnosis of papilloedema in a patient with optic nerve head swelling can be anxiety-provoking and may result in unnecessary, invasive, and costly tests. Cirrus high definition, spectral domain-optical coherence tomography (Cirrus HD-OCT) may provide a rapid and non-invasive test. We sought to determine an upper limit of average retinal nerve fibre layer (RNFL) thickness in patients with pseudopapilloedema without visible drusen using Cirrus HD-OCT that could be utilised in conjunction with the clinical presentation and physical examination when managing patients with optic nerve head swelling. Inclusion criteria consisted of at least two neuro-ophthalmological visits and repeated imaging of the optic nerve head with Cirrus HD-OCT at least 6 months apart. Exclusion criteria included clinically visible drusen along with previous or concomitant diagnosis of retinal or other optic nerve pathology. Thirty-eight eyes from 19 patients with pseudopapilloedema were included in this study. The upper limit of average RNFL thickness was defined as two standard deviations above the mean of the average RNFL thickness and was calculated to be 158.65 µm for scans obtained with Cirrus HD-OCT devices. A patient with suspected optic nerve head swelling, an average RNFL thickness less than 158.65 µm, and no other evidence of papilloedema or neurological signs or symptoms can be managed with serial follow-ups with OCT imaging for at least 6 months. If the patient continues to have no clinical symptoms suggesting increased intracranial pressure and the average RNFL thickness is stable, the likelihood of papilloedema is minimal.

A Warburg-like metabolic program coordinates Wnt, AMPK, and mTOR signaling pathways in epileptogenesis.

Epilepsy is a complex neurological condition characterized by repeated spontaneous seizures and can be induced by initiating seizures known as status epilepticus (SE). Elaborating the critical molecular mechanisms following SE are central to understanding the establishment of chronic seizures. Here, we identify a transient program of molecular and metabolic signaling in the early epileptogenic period, centered on day five following SE in the pre-clinical kainate or pilocarpine models of temporal lobe epilepsy. Our work now elaborates a new molecular mechanism centered around Wnt signaling and a growing network comprised of metabolic reprogramming and mTOR activation. Biochemical, metabolomic, confocal microscopy and mouse genetics experiments all demonstrate coordinated activation of Wnt signaling, predominantly in neurons, and the ensuing induction of an overall aerobic glycolysis (Warburg-like phenomenon) and an altered TCA cycle in early epileptogenesis. A centerpiece of the mechanism is the regulation of pyruvate dehydrogenase (PDH) through its kinase and Wnt target genes PDK4. Intriguingly, PDH is a central gene in certain genetic epilepsies, underscoring the relevance of our elaborated mechanisms. While sharing some features with cancers, the Warburg-like metabolism in early epileptogenesis is uniquely split between neurons and astrocytes to achieve an overall novel metabolic reprogramming. This split Warburg metabolic reprogramming triggers an inhibition of AMPK and subsequent activation of mTOR, which is a signature event of epileptogenesis. Interrogation of the mechanism with the metabolic inhibitor 2-deoxyglucose surprisingly demonstrated that Wnt signaling and the resulting metabolic reprogramming lies upstream of mTOR activation in epileptogenesis. To augment the pre-clinical pilocarpine and kainate models, aspects of the proposed mechanisms were also investigated and correlated in a genetic model of constitutive Wnt signaling (deletion of the transcriptional repressor and Wnt pathway inhibitor HBP1). The results from the HBP1-/- mice provide a genetic evidence that Wnt signaling may set the threshold of acquired seizure susceptibility with a similar molecular framework. Using biochemistry and genetics, this paper outlines a new molecular framework of early epileptogenesis and advances a potential molecular platform for refining therapeutic strategies in attenuating recurrent seizures.

Analyzing Relative Blood Flow Speeds in Choroidal Neovascularization Using Variable Interscan Time Analysis OCT Angiography.

PURPOSE: Longitudinally visualizing relative blood flow speeds within choroidal neovascularization (CNV) may provide valuable information regarding the evolution of CNV and the response to vascular endothelial growth factor (VEGF) inhibitors. DESIGN: Retrospective, longitudinal case series conducted at the New England Eye Center. PARTICIPANTS: Patients with either treatment-naïve or previously treated CNV secondary to neovascular age-related macular degeneration. METHODS: Optical coherence tomography angiography (OCTA) was performed using a 400-kHz, 1050-nm swept-source OCT system with a 5-repeat B-scan protocol. Variable interscan time analysis (VISTA) was used to compute relative flow speeds from pairs of B-scans having 1.5- and 3.0-ms separations; VISTA signals then were mapped to a color space for display. MAIN OUTCOME MEASURES: Quantitative outcomes included OCTA-based area and volume measurements of CNV at initial and follow-up visits. Qualitative outcomes included VISTA OCTA analysis of relative blood flow speeds, along with analysis of contraction, expansion, densification, and rarefication of CNV. RESULTS: Seven eyes of 6 patients (4 women and 2 men) with neovascular age-related macular degeneration were evaluated. Two eyes were treatment naïve at the initial visit. Choroidal neovascularization in all eyes at each visit showed relatively higher flow speeds in the trunk, central, and larger vessels and lower flow speed in the small vessels, which generally were located at the periphery of the CNV complex. Overall, the CNV appeared to expand over time despite retention of good visual acuity in all patients. In the treatment-naïve patients, slower-flow-speed vessels contracted with treatment, whereas the larger vessels with higher flow speed remained constant. CONCLUSIONS: Variable interscan time analysis OCTA allows for longitudinal observations of relative blood flow speeds in CNV treated with anti-VEGF intravitreal injections. A common finding in this study is that the main trunk and larger vessels seem to have relatively faster blood flow speeds compared with the lesions' peripheral vasculature. Moreover, an overall growth of chronically treated CNV was seen despite retention of good visual acuity. The VISTA framework may prove useful for developing clinical end points, as well as for studying hemodynamics, disease pathogenesis, and treatment response.

The current state of ab initio calculations of optical rotation and electronic circular dichroism spectra.

The current ability of ab initio models to compute chiroptical properties such as optical rotatory dispersion and electronic circular dichroism spectra is reviewed. Comparison between coupled cluster linear response theory and experimental data (both gas and liquid phase) yields encouraging results for small to medium-sized chiral molecules including rigid species such as (S)-2-chloropropionitrile and (P)-[4]triangulane, as well as conformationally flexible molecules such as (R)-epichlorohydrin. More problematic comparisons are offered by (S)-methyloxirane, (S)-methylthiirane, and (1S,4S)-norbornenone, for which the comparison between theory and experiment is much poorer. The impact of basis-set incompleteness, electron correlation, zero-point vibration, and temperature are discussed. In addition, future prospects and obstacles for the development of efficient and reliable quantum chemical models of optical activity are discussed, including the problem of gauge invariance, scaling of the coupled cluster approach with system size, and solvation.

Chiroptical properties of (R)-3-chloro-1-butene and (R)-2-chlorobutane.

Coupled cluster and density functional models of specific rotation and vacuum UV (VUV) absorption and circular dichroism spectra are reported for the conformationally flexible molecules (R)-3-chloro-1-butene and (R)-2-chlorobutane. Coupled cluster length- and modified-velocity-gauge representations of the Rosenfeld optical activity tensor yield significantly different specific rotations for (R)-3-chloro-1-butene, with the latter providing much closer comparison (within 3%) to the available gas-phase experimental data at 355 and 633 nm. Density functional theory overestimates the experimental rotations for (R)-3-chloro-1-butene by approximately 80%. For (R)-2-chlorobutane, on the other hand, all three models give reasonable comparison to experiment. The theoretical specific rotations of the individual conformers of (R)-3-chloro-1-butene are much larger than those of (R)-2-chlorobutane, in disagreement with previous studies of the temperature dependence of the experimental rotations in solution. Simulations of VUV absorption and circular dichroism spectra reveal large differences between the coupled cluster and density functional excitation energies and the rotational strengths. However, while these differences lead to very different specific rotations for (R)-3-chloro-1-butene, they have much less impact on the computed specific rotations for (R)-2-chlorobutane. In addition, the coupled cluster VUV absorption spectrum of (R)-2-chlorobutane compares well to experiment.

Ab initio determination of optical rotatory dispersion in the conformationally flexible molecule (R)-epichlorohydrin.

Ab initio optical rotation data from linear-response coupled-cluster and density-functional methods are compared to both gas-phase and liquid-phase polarimetry data for the small, conformationally flexible molecule epichlorohydrin. Three energy minima exist along the C-C-C-Cl dihedral angle, each with strong, antagonistic specific rotations ranging from ca. -450 to +500 deg/[dm (g/mL)] at 355 nm. Density-functional theory (specifically the B3LYP functional) consistently overestimates the optical rotations of each conformer relative to coupled-cluster theory (in agreement with our earlier observations for conformationally rigid species), and we attribute this to density-functional theory's underestimation of the lowest-lying excitation energies of epichlorohydrin. Length- and velocity-gauge formulations of the coupled-cluster response function lead to slightly different specific rotations (ca. 7% at short wavelengths). We have determined well-converged Gibbs free energy differences among the conformers using complete-basis-set extrapolations of coupled-cluster energies including triple excitations to obtain Boltzmann-averaged specific rotations for comparison to the gas-phase results. The length-gauge coupled-cluster data agree remarkably well with experiment, with the velocity-gauge coupled-cluster and density-functional data bracketing the experimental results from below and above, respectively. Liquid-phase conformer populations reported earlier by Polavarapu and co-workers from combined infrared absorption and theoretical analyses differ markedly from the gas-phase populations, particularly for polar solvents. Nevertheless, Boltzmann-averaged specific rotations from both coupled-cluster and density-functional calculations agree well with the corresponding experimental intrinsic rotations, although the theoretical specific rotations for the individual conformers do not take solvent effects into account. PCM-based estimates of conformer populations lead to poor agreement with experiment.

Ab initio calculation of optical rotation in (P)-(+)-[4]triangulane.

Optical rotation, the angle through which plane-polarized light rotates when passed through an enantiomerically pure medium, plays a vital role in the determination of the absolute configurations of chiral molecules such as natural products. We describe new quantum mechanical methodology designed to assist in this endeavor by providing high-accuracy computational optical rotatory dispersion data for matching to experimental results. Comparison between theory and experiment for the rigid, helical molecule trispiro[2.0.0.2.1.1]nonane [also known as (P)-(+)-[4]triangulane], recently synthesized with enantiomeric purity, shows that the coupled cluster quantum chemical model provides superb agreement for optical rotation across a wide range of wavelengths (589-365 nm), with errors averaging only 1%.

A family of decamethylmetallocene charge-transfer salt magnets using methyl tricyanoethylenecarboxylate (MTCE) as the electron acceptor.

Methyl tricyanoethylenecarboxylate, MTCE, has been used as a one-electron acceptor building block for the synthesis of isomorphous decamethylmetallocene charge-transfer salt magnets of the formula [MCp*2][MTCE], M = Cr, Mn, and Fe. Functionally and electrochemically, MTCE is a hybrid between tetracyanoethylene (TCNE) and dimethyl dicyanofumarate (DMeDCF), two acceptors that have previously been found to support ferromagnetism. The X-ray crystal structure of the chromium analogue, [CrCp*2][MTCE], shows it to exist in the expected mixed stack structure in the orthorhombic space group Pnma with a = 14.739(3) A, b = 10.7869(19) A, and c = 15.771(3) A and Z = 4. As anticipated, all three family members exhibit dominant ferromagnetic coupling, which is presumed to reflect intrastack interactions. However, the bulk magnetic properties mostly differ from simple interpolations or extrapolations of the properties of their TCNE and DMeDCF analogues. Density functional theory calculations have been used to shed some light on this observation.

Coupled cluster calculations of optical rotatory dispersion of (S)-methyloxirane.

Coupled cluster (CC) and density-functional theory (DFT) calculations of optical rotation, [alpha](lambda), have been carried out for the difficult case of (S)-methyloxirane for comparison to recently published gas-phase cavity ringdown polarimetry data. Both theoretical methods are exquisitely sensitive to the choice of one-electron basis set, and diffuse functions have a particularly large impact on the computed values of [alpha](lambda). Furthermore, both methods show a surprising sensitivity to the choice of optimized geometry, with [alpha](355) values varying by as much as 15 deg dm(-1) (g/mL)(-1) among molecular structures that differ only negligibly. Although at first glance the DFT/B3LYP values of [alpha](355) appear to be superior to those from CC theory, the success of DFT in this case appears to stem from a significant underestimation of the lowest (Rydberg) excitation energy in methyloxirane, resulting in a shift of the first-order pole in [alpha](lambda) (the Cotton effect) towards the experimentally chosen incident radiation lines. This leads to a fortuitous positive shift in the value of [alpha](355) towards the experimental result. The coupled cluster singles and doubles model, on the other hand, correctly predicts the position of the absorption pole (to within 0.05 eV of the experimental result), but fails to describe correctly the shape/curvature of the ORD region lambda=355, resulting in an incorrect prediction of both the magnitude and the sign of the optical rotation.