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1.  Cataract Surgery in the Glaucoma Patient 
To summarize the role of cataract surgery in the glaucoma patient, in terms of the effect on intraocular pressure (IOP) as well as diagnostic and therapeutic considerations for those with both conditions. Recent evidence suggests that cataract extraction may produce a significant and sustained IOP reduction in individuals with open-angle glaucoma, ocular hypertension, and angle-closure glaucoma. Cataract removal may improve the practitioner's ability to interpret perimetric testing, and re-establishing perimetric and optic nerve imaging baselines is recommended after cataract surgery. The sequence of cataract surgery relative to glaucoma surgery impacts the likelihood of complications and surgical success. There are multiple benefits to perform cataract surgery prior to glaucoma surgery while cataract surgery after trabeculectomy increases the risk of subsequent filtration failure. As “minimally invasive glaucoma surgeries” continue to improve in terms of efficacy, there is an evolving role for combined cataract and glaucoma surgery in patients with early to moderate stages of glaucoma.
PMCID: PMC4302462  PMID: 25624668
Cataract; Glaucoma; Surgery
2.  Crystal structure of Vδ1 T cell receptor in complex with CD1d-sulfatide shows MHC-like recognition of a self-lipid by human γδ T cells 
Immunity  2013;39(6):10.1016/j.immuni.2013.11.001.
The nature of the antigens recognized by γδ T cells and their potential recognition of major histocompatibility complex (MHC)-like molecules has remained unclear. The CD1 family of lipid-presenting molecules are suggested ligands for Vδ1 TCR-expressing γδ T cells, the major γδ lymphocyte population in epithelial tissues. We crystallized a Vδ1 TCR in complex with CD1d and the self-lipid sulfatide, revealing an unusual recognition of CD1d by germline Vδ1 residues spanning all complementarity determining region (CDR) loops, with sulfatide recognition separately encoded by non-germline CDR3δ residues. Binding and functional analysis showed that CD1d presenting self-lipids, including sulfatide, was widely recognized by gut Vδ1 + γδ T cells. These findings provide structural demonstration of MHC-like recognition of a self-lipid by γδ T cells and reveal the prevalence of lipid recognition by innate-like T cell populations.
PMCID: PMC3875342  PMID: 24239091
3.  Nonclassical Innervation Patterns In Mammalian Extraocular Muscles 
Current eye research  2012;37(9):761-769.
The abducens (CN6) and oculomotor (CN3) nerves (nn) enter target extraocular muscles (EOMs) via their global surfaces; the trochlear (CN4) nerve enters the superior oblique (SO) muscle on its orbital surface. Motor nn are classically described as entering the EOMs in their middle thirds. We investigated EOM innervation that does not follow the classic pattern.
Intact, whole orbits of two humans and one each monkey, cow, and rabbit were paraffin embedded, serially sectioned in coronal plane, and prepared with Masson’s trichrome and by choline acetyltransferase (ChAT) immunohistochemistry. Nerves innervating EOMs were traced from the orbital apex toward the scleral insertion, and some were reconstructed in three dimensions.
Classical motor nn positive for ChAT entered rectus and SO EOMs and coursed anteriorly, without usually exhibiting recurrent branches. In every orbit, nonclassical (NC) nn entered each EOM well posterior to classical motor nn. These NC nn entered and arborized in the posterior EOMs, mainly within the orbital layer (OL), but often traveled into the global layer or entered an adjacent EOM. Other NC nn originated in the orbital apex and entered each EOM through its orbital surface, ultimately anastomosing with classical motor nn. Mixed sensory and motor nn interconnected EOM spindles.
EOMs exhibit a previously undescribed pattern of NC innervation originating in the proximal orbit that partially joins branches of the classical motor nn. This NC innervation appears preferential for the OL, and may have mixed supplemental motor and/or proprioceptive functions, perhaps depending upon species. The origin of the NC innervation is currently unknown.
PMCID: PMC3608520  PMID: 22559851
cranial nerve; eye movement; extra-ocular muscle; spindle
4.  The Molecular Basis for Recognition of CD1d/α-Galactosylceramide by a Human Non-Vα24 T Cell Receptor 
PLoS Biology  2012;10(10):e1001412.
Human Vα24− CD1d-restricted T cells use variation in their CDR1α loop to respond to lipid antigens presented by CD1d, altering their specificities from that of invariant natural killer T cells.
CD1d-mediated presentation of glycolipid antigens to T cells is capable of initiating powerful immune responses that can have a beneficial impact on many diseases. Molecular analyses have recently detailed the lipid antigen recognition strategies utilized by the invariant Vα24-Jα18 TCR rearrangements of iNKT cells, which comprise a subset of the human CD1d-restricted T cell population. In contrast, little is known about how lipid antigens are recognized by functionally distinct CD1d-restricted T cells bearing different TCRα chain rearrangements. Here we present crystallographic and biophysical analyses of α-galactosylceramide (α-GalCer) recognition by a human CD1d-restricted TCR that utilizes a Vα3.1-Jα18 rearrangement and displays a more restricted specificity for α-linked glycolipids than that of iNKT TCRs. Despite having sequence divergence in the CDR1α and CDR2α loops, this TCR employs a convergent recognition strategy to engage CD1d/αGalCer, with a binding affinity (∼2 µM) almost identical to that of an iNKT TCR used in this study. The CDR3α loop, similar in sequence to iNKT-TCRs, engages CD1d/αGalCer in a similar position as that seen with iNKT-TCRs, however fewer actual contacts are made. Instead, the CDR1α loop contributes important contacts to CD1d/αGalCer, with an emphasis on the 4′OH of the galactose headgroup. This is consistent with the inability of Vα24− T cells to respond to α-glucosylceramide, which differs from αGalCer in the position of the 4′OH. These data illustrate how fine specificity for a lipid containing α-linked galactose is achieved by a TCR structurally distinct from that of iNKT cells.
Author Summary
Certain lineages of T cells can recognize lipids as stimulatory antigens when presented in the context of CD1 molecules. We know how most Natural Killer T (NKT) cells react with this unusual ligand because they use a single invariant T cell receptor (TCR) alpha chain to do the job. NKT cells place particular emphasis on their CDR3α and CDR2β loops in recognition of antigen—these complementarity determining regions (CDRs) are the hypervariable parts of the TCR that “complement” an antigen's shape. How do these other T cells recognize closely related yet distinct lipid antigens? Here we show that human CD1d-restricted T cells, typically called Vα24− T cells due to their use of diverse Vα domains in their TCRs, use similar molecular strategies to respond to lipid antigens presented by CD1d. To this end we present a 2.5 Å complex structure of a Vα24− TCR complexed with CD1d presenting the protypical lipid, α-galactosylceramide (αGalCer). The TCR examined in this study notably shifts its binding slightly, placing more emphasis on the interaction with the CDR1α loop as revealed through alanine scanning mutagenesis. This shift explains the inability of these T cells to respond to lipids that vary at this site of contact (the 4'OH), like the related α-linked glucosylceramide. These results provide a molecular basis for the fine-specificity of different CD1d-restricted T cell lineages.
PMCID: PMC3479090  PMID: 23109910
5.  Expanding Repertoire In The Oculomotor Periphery: Selective Compartmental Function In Rectus Extraocular Muscles 
Since connective tissue pulleys implement Listing's law by systematically changing rectus extraocular muscle (EOM) pulling directions, non-Listing's law gaze-dependence of the vestibulo-ocular reflex is currently inexplicable. Differential activation of compartments within rectus EOMs may endow the ocular motor system with more behavioral diversity than previously supposed. Innervation to horizontal, but not vertical, rectus EOMs of mammals is segregated into superior and inferior compartments. Magnetic resonance imaging in normal subjects demonstrates contractile changes in the lateral rectus (LR) inferior, but not superior, compartment during ocular counter-rolling (OCR) induced by head tilt. In human orbits ipsilesional to unilateral superior oblique palsy, neither LR compartment exhibits contractile change during head tilt, although the inferior compartment contracts normally in contralesional orbits. This suggests that differential compartmental LR contraction assists normal OCR. Computational simulation suggests that differential compartmental action in horizontal rectus EOMs could achieve more force than required by vertical fusional vergence.
PMCID: PMC3286355  PMID: 21950970
extraocular muscles; magnetic resonance imaging; motor nerve; pulleys; vestibulo-ocular reflex
6.  Functional Imaging of Human Extraocular Muscles In Head Tilt Dependent Hypertropia 
High-resolution MRI shows heterogeneous extraocular muscle features in strabismus, typical of superior oblique palsy. Rectus pulley counterrotations in response to head tilt may be paradoxical and depend on the presence of superior oblique atrophy, which is detected in half of patients.
Although alteration in hypertropia induced by head tilt is considered a clinical criterion for diagnosis of superior oblique (SO) palsy, the mechanism of this head-tilt–dependent hypertropia (HTDHT) is unclear. In this study, magnetic resonance imaging (MRI) was used to study extraocular muscle (EOM) responses to head tilt in HTDHT.
Orbital MRI was used to study 16 normal subjects and 22 subjects with HTDT, of whom 12 had unilateral SO atrophy and 10 had “masquerading” SO palsy with normal SO size. Sizes and paths of all EOMs were compared in 90° roll tilts.
Normal subjects exhibited the expected 3° to 7° physiologic extorsion of all four rectus pulleys in the orbit up-versus-down roll positions, corresponding to ocular counterrolling. In orbits with SO atrophy, the lateral (LR) and inferior rectus (IR) pulleys paradoxically intorted by approximately 2°. Subjects with HTDHT but normal SO size exhibited reduced or reversed extorsion of the medial, superior, and LR pulleys, whereas pulley shift was normal in nonhypertropic fellow orbits in HTDHT. In normal subjects and in SO atrophy, the inferior oblique (IO) muscle contracted in the orbit up-versus-down roll position, but paradoxically relaxed in HTDHT without SO atrophy.
The ipsilesional IR and LR pulleys shift abnormally during head tilt in HTDHT with SO atrophy. In HTDHT without SO atrophy, the ipsilesional MR, SO, and LR pulleys shift abnormally, and the IO relaxes paradoxically during head tilt. These widespread alterations in EOM pulling directions suggest that complex neural adjustments to the otolith–ocular reflexes mediate HTDHT.
PMCID: PMC3109014  PMID: 21282574
7.  Characterization of Ocular Tissues Using Microindentation and Hertzian Viscoelastic Models 
Microindentation permits biomechanical characterization of small specimens of ocular tissues and demonstrates that although properties of periocular fatty tissues vary markedly by location, comparable bovine and human tissues behave similarly.
The authors applied a novel microindentation technique to characterize biomechanical properties of small ocular and orbital tissue specimens using the Hertzian viscoelastic formulation, which defines material viscoelasticity in terms of the contact pressure required to maintain deformation by a harder body.
They used a hard spherical indenter having 100 nm displacement and 100 μg force precision to impose small deformations on fresh bovine sclera, iris, crystalline lens, kidney fat, orbital pulley tissue, and orbital fatty tissue; normal human orbital fat, eyelid fat, and dermal fat; and orbital fat associated with thyroid eye disease. For each tissue, stress relaxation testing was performed using a range of ramp displacements. Results for single displacements were used to build quantitative Hertzian models that were, in turn, compared with behavior for other displacements. Findings in orbital tissues were correlated with quantitative histology.
Viscoelastic properties of small specimens of orbital and ocular tissues were reliably characterized over a wide range of rates and displacements by microindentation using the Hertzian formulation. Bovine and human orbital fatty tissues exhibited highly similar elastic and viscous behaviors, but all other orbital tissues exhibited a wide range of biomechanical properties. Stiffness of fatty tissues tissue depended strongly on the connective tissue content.
Relaxation testing by microindentation is a powerful method for characterization of time-dependent behaviors of a wide range of ocular and orbital tissues using small specimens, and provides data suitable to define finite element models of a wide range of tissue interactions.
PMCID: PMC3109037  PMID: 21310907
8.  Intramuscular Innervation of Primate Extraocular Muscles: Unique Compartmentalization in Horizontal Recti 
Segregation of intramuscular motor nerves indicates distinct superior and inferior zones within the horizontal but not vertical rectus extraocular muscles in humans and monkeys, supporting a potential functional role for differential innervation that might mediate oculorotary actions.
It has been proposed that the lateral rectus (LR), like many skeletal and craniofacial muscles, comprises multiple neuromuscular compartments subserving different physiological functions. To explore the anatomic potential of compartmentalization in all four rectus extraocular muscles (EOMs), evidence was sought of possible regional selectivity in intramuscular innervation of all rectus EOMs.
Whole orbits of two humans and one macaque monkey were serially sectioned at 10 μm thickness and stained with Masson's trichrome. Three-dimensional reconstruction was performed of the intramuscular courses of motor nerves from the deep orbit to the anterior extents of their arborizations within all four rectus EOMs in each orbit.
Findings concorded in monkey and human orbits. Externally to the global surface of the lateral (LR) and medial rectus (MR) EOMs, motor nerve trunks bifurcated into approximately equal-sized branches before entering the global layer and observing a segregation of subsequent arborization into superior zones that exhibited minimal overlap along the length of the LR and only modest overlap for MR. In contrast, intramuscular branches of the superior and the nasal portion of the inferior rectus were highly mixed.
Consistent segregation of intramuscular motor nerve arborization suggests functionally distinct superior and inferior zones within the horizontal rectus EOMs in both humans and monkeys. Reduced or absent compartmentalization in vertical rectus EOMs supports a potential functional role for differential innervation in horizontal rectus zones that could mediate previously unrecognized vertical oculorotary actions.
PMCID: PMC3088565  PMID: 21220556

Results 1-8 (8)