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While most cases of superior oblique (SO) hypofunction represent contractile weakness due to denervation, sometimes the lesion is exclusively in the tendon. This study sought to distinguish the pattern of incomitant strabismus caused by deficiency of SO oculorotary force caused by tendon abnormalities versus that of neurogenic palsy. Clinical and magnetic resonance imaging (MRI) findings of 7 cases of unilateral SO tendon interruption or extirpation were compared with 11 cases of age matched unilateral SO palsy having intact tendons. We compared angles of misalignment with high-resolution MRI in central gaze and deorsumversion. Muscle bellies in neurogenic palsy were markedly atrophic with maximal cross sections averaging 6.5 ± 2.7 mm2, in contrast with 13.5 ± 3.0 mm2 contralesionally (P <.0001). In contrast, SO muscle bellies ipsilateral to tendon interruption had maximum cross sections averaging 15.1 ± 3.0 mm2 occurring more posterior than on the contralesional side whose maximum averaged 12.1 ± 2.4 mm2. While cross sections of SO bellies ipsilateral to tendon interruption exhibited normal contractile increase in infraduction (P <.0005), there was nevertheless strabismus with incomitance similar to that in SO atrophy. Binocular alignment was statistically similar (P >.5) in the two groups for all diagnostic positions, including head tilt, except in deorsumversion, where cases with SO tendon abnormalities averaged 20.5 ± 6.9Δ ipsilateral hypertropia, significantly more than 8.5 ± 6.6Δ in neurogenic SO atrophy (P =.001). The average difference in hypertropia Hypertropia averaged 9D greater in deorsumversion than central gaze in tendon abnormalities, but 4.1Δ less in SO atrophy (P<.019). In contralesional version, average overelevation in adduction was 1.7 (scale of 0–4) in tendon abnormalities, and 2.6 in SO atrophy (P =.23), while average underdepression in adduction was −2.3 in cases of tendon abnormalities and −1.6 in SO atrophy (P =.82). Repair of the SO tendon in three cases was effective, while alternative procedures were performed when repair was infeasible. While both denervation and tendon interruption impair SO oculorotary function, interruption causes greater hypertropia in infraversion. Surgical tightening of interrupted SO tendons may have particularly gratifying effects. Posterior SO thickening and large hypertropia in infraversion suggest SO tendon interruption that may guide a surgical strategy of tendon repair. [ABSTRACT FROM AUTHOR]

BACKGROUND Injectable fillers have become an integral part of facial rejuvenation, but vascular occlusion is a dreaded complication of such injections. OBJECTIVE To determine the force required by the fingertip onto the plunger of the syringe to cause retrograde migration. METHODS In this cadaver study, twelve 2-cm arterial segments and 4 fillers were tested. Injection pressure required to force a column of filler for 1 cm was measured. Five oculoplastics specialists were subsequently recruited and asked to inject the filler at a typical injection pressure. RESULTS The nonhyaluronic acid filler required significantly more pressure to cause propagation of the material compared with all other fillers (p < .01). None of the other fillers differed significantly from each other. Typical injection pressures generated by experienced injectors were significantly lower than that required to cause propagation of filler at the desired velocity and significantly lower than mean arterial pressure. Measured pressure required to cause filler propagation was well within the normal range of the finger strength that can be generated by humans. CONCLUSION Typical injection pressures from fingertip to plunger are lower than required to cause propagation of filler intravascularly. [ABSTRACT FROM AUTHOR]

We aimed to characterize the connective tissue microanatomy, elastin abundance, and fiber orientation in the human optic nerve sheath, also known as the optic nerve dura mater, for correlation with its biomechanical properties. Seven whole human orbits aged 4–93 years, and five isolated human optic nerve sheaths aged 26–75 years were formalin fixed, paraffin embedded, coronally sectioned, stained by Masson trichrome and van Gieson's elastin methods, and analyzed quantitatively for elastin fiber abundance and orientation. Elastin area fraction was defined as area stained for elastin divided by total area. While unilaminar in children, the adult ON sheath exhibited distinct inner and outer layers. Collagen was denser and more compact in the inner layer. Elastin area fraction was significantly greater at 6.0 ± 0.4% (standard error of mean) in the inner than outer layer at 3.6 ± 0.4% (P < 10−5). Elastin fibers had three predominant orientations: longitudinal, diagonal, and circumferential. Of circumferential fibers, 63 ± 4.7% were in the inner and 37 ± 4.7% in the outer layer (P < 10−4). Longitudinal and diagonal fibers were uniformly distributed in both layers. Elastin density and sheath thickness increased significantly with age (P <.01). The adult human optic nerve sheath is bilaminar, with each layer containing elastin fibers oriented in multiple directions consistent with isotropic properties. Differences in laminar elastin density and orientation may reflect greater tensile loading in the inner than in the outer layer. [ABSTRACT FROM AUTHOR]

Purpose: Corneal collagen cross-linking by ultraviolet light activation of riboflavin has been used clinically to enhance corneal stiffness. We sought to determine if cross-linking differentially affects scleral regions. Methods: Adjacent, parallel strips of sclera were cut from superolateral, superomedial, inferolateral, and inferomedial quadrants of posterior and equatorial sclera of 12 human cadaver eyes. One of each pair served as control while the other was cross-linked by immersion in 0.1% riboflavin and 365 nm exposure at 6 mW/cm2 irradiance for 30 min. Behavior of strips was characterized using a microtensile load cell. Preloaded strips were imaged using orthogonally mounted cameras and optical coherence tomography to determine specimen dimensions including cross-sectional area. Tension was measured during 0.1 mm/s constant rate elongation. Results: Young's modulus (YM), the slope of the relationship relating tensile stress to strain, was calculated at 8% strain, and increased significantly after cross-linking (P <.001). In posterior sclera, mean (± standard error of mean, SEM) YM is increased in the superolateral, superomedial, inferolateral, and inferomedial quadrants by 46 ± 15%, 32 ± 11%, 67 ± 20%, and 53 ± 11%, respectively. In equatorial sclera, YM is increased by 139 ± 43%, 68 ± 27%, 143 ± 92%, and 68 ± 14%, respectively. The YM of pooled equatorial quadrants increased significantly more than that of the pooled posterior quadrants. Conclusions: Scleral collagen cross-linking by ultraviolet activation of riboflavin differentially increases scleral YM more in the equatorial than posterior sclera, and most in the lateral, equatorial sclera. Cross-linking might be used to arrest progressive myopia or to prevent staphyloma formation. [ABSTRACT FROM AUTHOR]

Purpose Using high-resolution magnetic resonance imaging (MRI), we investigated whether rectus pulleys are significantly displaced in superior oblique (SO) palsy and whether displacements account for strabismus patterns. Design Prospective case-control study. Participants Twenty-four patients diagnosed with SO palsy based on atrophy of the SO muscle on MRI and 19 age-matched orthotropic control subjects. Methods High-resolution, surface coil MRI scans were obtained in multiple, contiguous, quasicoronal planes during monocular central gaze fixation. Pulley locations in oculocentric coordinates in the following subgroups of patients with SO palsy were compared with normal results in subgroups of patients with SO palsy: unilateral versus bilateral, congenital versus acquired, and isotropic (round) versus anisotropic (elongated) SO atrophy. Expected effects of pulley displacements were modeled using Orbit 1.8 (Eidactics, San Francisco, CA) computational simulation. Main Outcome Measures Rectus pulley positions and ocular torsion. Results Rectus pulleys typically were displaced in SO palsy. In unilateral SO palsy, on average the medial rectus (MR) pulley was displaced 1.1 mm superiorly, the superior rectus (SR) pulley was displaced 0.8 mm temporally, and the inferior rectus (IR) pulley was displaced 0.6 mm superiorly and 0.9 mm nasally from normal. Displacements were similar in bilateral SO palsy, with the SR pulley additionally displaced 0.9 mm superiorly. However, the lateral rectus pulley was not displaced in either unilateral or bilateral SO palsy. The SR and MR pulleys were displaced in congenital SO palsy, whereas the IR and MR pulleys were displaced in acquired palsy. Pulley positions did not differ between isotropic and anisotropic palsy or between patients with cyclotropia of less than 7° versus cyclotropia of 7° or more. Simulations predicted that the observed pulley displacements alone could cause patterns of incomitant strabismus typical of SO palsy, without requiring any abnormality of SO or inferior oblique strength. Conclusions Rectus pulley displacements alone, without abnormal oblique muscle contractility, can create the clinical patterns of incomitant strabismus in SO palsy. This finding supports accumulating evidence that clinical binocular misalignment patterns are not reliable indicators of contractile function of the SO muscle. Ocular torsion does not correlate with and thus cannot account for pulley displacements in SO palsy. [ABSTRACT FROM AUTHOR]

Purpose: We employed automated analysis of scanning laser ophthalmoscopy (SLO) to determine if mechanical strains imposed on disc, and retinal and choroidal vessels during horizontal duction in children differ from those of adults. Methods: Thirty-one children aged 11.3 ± 2.7 (standard deviation) years underwent SLO in central gaze, and 35° ab- and adduction. Automated registration with deep learning-based optical flow analysis quantified vessel deformations as horizontal, vertical, shear, and equivalent strains. Choroidal vessel displacements in lightly pigmented fundi, and central disc vessel displacements, were also observed. Results: As in adults, strain in vessels during horizontal duction was greatest at the disc and decreased with distance from it. Strain in the pediatric disc was similar to published values in young adults,1 but in the peripapillary region was greater and propagated significantly more peripherally to at least three disc radii from it. During adduction in children, the nasal disc was compressed and disc vessels distorted, but the temporal half experienced tensile strain, while peripapillary tissues were compressed. The pattern was similar but strains were less in abduction (p <.001). Choroidal vessels were visualized in 24 of the 62 eyes and shifted directionally opposite overlying retinal vessels. Conclusions: Horizontal duction deforms the normal pediatric optic disc, central retinal vessels, peripapillary retina, and choroid, shearing the inner retina over the choroid. These mechanical effects occur at the sites of remodeling of the disc, sclera, and choroid associated with typical adult features that later emerge later, including optic cup enlargement, temporal disc tilting, and peripapillary atrophy. [ABSTRACT FROM AUTHOR]

The adult human optic nerve (ON) sheath has recently been recognized to be bilaminar, consisting of inner layer (IL) and outer layer (OL). Since the ON and sheath exert tension on the globe in large angle adduction as these structures transmit reaction force of the medial rectus muscle to the globe, this study investigated the laminar biomechanics of the human ON sheath. Biomechanical characterization was performed in ON sheath specimens from 12 pairs of fresh, post-mortem adult eyes. Some ON sheath specimens were tested completely, while others were separated into IL and OL. Uniaxial tensile loading under physiological temperature and humidity was used to characterize a linear approximation as Young's modulus, and hyperelastic non-linear behavior using the formulation of Ogden. Micro-indentation was performed by imposing small compressive deformations with small, hard spheres. Specimens of the same sheaths were paraffin embedded, sectioned at 10 micron thickness, and stained with van Gieson's stain for anatomical correlation. Mean (± standard error of the mean, SEM) tensile Young's modulus of the inner sheath at 19.8 ± 1.6 MPa significantly exceeded that for OL at 9.7 ± 1.2 MPa; the whole sheath showed intermediate modulus of 15.4 ± 1.1 MPa. Under compression, the inner sheath was stiffer (7.9 ± 0.5 vs 5.2 ± 0.5 kPa) and more viscous (150.8 ± 10.6 vs 75.6 ± 6 kPa s) than outer sheath. The inner sheath had denser elastin fibers than outer sheath, correlating with greater stiffness. We conclude that maximum tensile stiffness occurs in the elastin-rich ON sheath IL that inserts near the lamina cribrosa where tension in the sheath exerted during adduction tethering may be concentrated adjacent the ON head. [ABSTRACT FROM AUTHOR]

Purpose To determine whether rectus extraocular muscle (EOM) sizes and pulley locations contribute to exotropia, we used magnetic resonance imaging (MRI) to measure these factors in normal control participants and in patients with concomitant and pattern exotropia. Design Prospective case-control study. Participants Nine patients with concomitant exotropia, 6 patients with pattern exotropia, and 21 orthotropic normal control participants. Methods High-resolution surface-coil MRI scans were obtained in contiguous, quasicoronal planes. Rectus pulley locations were determined in oculocentric coordinates for central gaze, supraduction, and infraduction. Cross sections in 4 contiguous image planes were summed and multiplied by the 2-mm slice thickness to obtain horizontal rectus posterior partial volumes (PPVs). Main Outcome Measures Rectus pulley locations and horizontal rectus PPVs. Results Rectus pulleys were located differently in patients with A-pattern, versus V- and Y-pattern, exotropia. The lateral rectus (LR) pulleys were displaced significantly superiorly, the medial rectus (MR) pulleys were displaced inferiorly, and the inferior rectus pulleys were displaced laterally in A-pattern exotropia. However, the array of all rectus pulleys was excyclorotated in V- and Y-pattern exotropia. The PPV of the medial rectus muscle was statistically subnormal by approximately 29% in concomitant, but not pattern, exotropia ( P < 0.05). The ratio of the PPV of the LR relative to the MR muscles in concomitant exotropia was significantly greater than in control participants and those with pattern exotropia ( P < 0.05). Conclusions Abnormalities of EOMs and pulleys contribute differently in pattern versus concomitant exotropia. Abnormal rectus pulley locations derange EOM pulling directions that contribute to pattern exotropia, but in concomitant exotropia, pulley locations are normal, and relatively small medial rectus size reduces relative adducting force. [ABSTRACT FROM AUTHOR]

Interleukin-2 (IL-2) is a cytokine required for effector T cell expansion, survival, and function, especially for engineered T cells in adoptive cell immunotherapy, but its pleiotropy leads to simultaneous stimulation and suppression of immune responses as well as systemic toxicity, limiting its therapeutic use. We engineered IL-2 cytokine-receptor orthogonal (ortho) pairs that interact with one another, transmitting native IL-2 signals, but do not interact with their natural cytokine and receptor counterparts. Introduction of orthoIL-2Rβ into T cells enabled the selective cellular targeting of orthoIL-2 to engineered CD4+ and CD8+ T cells in vitro and in vivo, with limited off-target effects and negligible toxicity. OrthoIL-2 pairs were efficacious in a preclinical mouse cancer model of adoptive cell therapy and may therefore represent a synthetic approach to achieving selective potentiation of engineered cells. [ABSTRACT FROM AUTHOR]

Abstract: Conditional responses in rodents such as locomotion have been reported for drugs of abuse and similar to the placebo response in humans, may be associated with the expectation of reward. We examined several conditional opioid-like responses and the influence of drug expectation on conditioned place preference and concomitant conditional locomotion. Male C57BL/6J mice were conditioned with the selective mu opioid receptor agonist fentanyl (0.2mg/kg, i.p.) in a novel context and subsequently given a vehicle injection. In separate experiments, locomotor activity, Straub tail, hot plate sensitivity, and conditioned place preference (CPP) were measured. Mice exhibited multiple conditional opioid-like responses including conditional hyperlocomotion, a conditional pattern of opioid-like locomotion, Straub tail, analgesia, and place preference. Modulating drug expectation via administration of fentanyl to “demonstrator” mice in the home cage did not affect the expression of conditioned place preference or the concomitant locomotor activity in “observer” mice. In summary, Pavlovian conditioning of an opioid in a novel context induced multiple conditional opioid-like behaviors and provides a model for studying the neurobiological mechanisms of the placebo response in mice. [Copyright &y& Elsevier]

Abstract: Primary refractory acute leukemia (AL) has a poor prognosis, although some patients can be salvaged with allogeneic stem cell transplantation (SCT). Induction of complete remission (CR) with conventional chemotherapy before SCT may improve outcome in this patient population. Between March 1991 and October 2003, 59 adults with primary refractory AL were treated with continuous-infusion etoposide (VP) 2.4 to 3.0 g/m2 followed by cyclophosphamide (Cy) 6.0-7.2 g/m2 intravenously over 3 to 4 days with the intention of proceeding to SCT in CR1. Forty-two patients had acute myelogenous leukemia (AML), 13 patients had acute lymphoblastic leukemia (ALL), and 4 patients had acute biphenotypic leukemia. The most frequent nonhematologic toxicities were oral mucosal, gastrointestinal, and hepatic toxicities (44%, 20%, and 15% of patients, respectively). Thirty-two (57%) of 56 evaluable patients entered CR1 with a median time to platelet and neutrophil recovery of 22 and 26 days, respectively. CR1 rates were similar in AML (54%) and ALL/acute biphenotypic leukemia (67%; P = .52), and analysis of baseline characteristics did not reveal any predictors of response to VP/Cy. Twenty-nine of 32 CR1 patients subsequently underwent SCT (24 allogeneic and 5 autologous). Estimated 5-year event-free survival (EFS) and overall survival for the entire cohort are 23% and 26%, respectively. In the allogeneic SCT group, 5-year EFS was 52% for AML patients and 14% for ALL patients (P = .04), and only male sex was predictive of a favorable outcome (P = .03). VP/Cy is able to induce CR1 in most patients with primary refractory AL with an acceptable toxicity profile. Subsequent allogeneic SCT can lead to long-term EFS in a significant proportion of patients. [Copyright &y& Elsevier]