An update on intraocular lens power calculations in eyes with previous laser refractive surgery.

PURPOSE OF REVIEW: There is an ever-growing body of research regarding intraocular lens (IOL) power calculations following photorefractive keratectomy (PRK), laser-assisted in-situ keratomileusis (LASIK), and small-incision lenticule extraction (SMILE). This review intends to summarize recent data and offer updated recommendations. RECENT FINDINGS: Postmyopic LASIK/PRK eyes have the best refractive outcomes when multiple methods are averaged, or when Barrett True-K is used. Posthyperopic LASIK/PRK eyes also seem to do best when Barrett True-K is used, but with more variable results. With both aforementioned methods, using measured total corneal power incrementally improves results. For post-SMILE eyes, the first nontheoretical data favors raytracing. SUMMARY: Refractive outcomes after cataract surgery in eyes with prior laser refractive surgery are less accurate and more variable compared to virgin eyes. Surgeons may simplify their approach to IOL power calculations in postmyopic and posthyperopic LASIK/PRK by using Barrett True-K, and employing measured total corneal power when available. For post-SMILE eyes, ray tracing seems to work well, but lack of accessibility may hamper its adoption.

Prenatal Alcohol Exposure and Chorioamnionitis Results in Microstructural Brain Injury in a Preclinical Investigation.

BACKGROUND: Prenatal Alcohol Exposure (PAE) impacts 2% to 5% of infants born in the United States yearly. Women who consume alcohol during pregnancy have a five-fold increased rate of Chorioamnionitis (CHORIO). Both PAE and CHORIO cause microstructural injury to multiple brain regions including major white matter tracts. OBJECTIVE: Utilizing two previously established animal models, we hypothesized that the combination of PAE+CHORIO would result in greater deficits in myelination and structural integrity than PAE alone. MATERIAL AND METHODS: Pregnant Long-Evans rats voluntarily drank 5% ethanol or saccharin until Gestational Day 19 (GD). On GD19, CHORIO was induced in one group of PAE dams by a 30 min uterine artery occlusion and injection of Lipopolysaccharide (LPS) into each amniotic sac. The remaining PAE dams and saccharin controls underwent sham surgery. Pups were born on GD22 and weaned on Postnatal Day 24 (PD). On PD28, offspring were sacrificed, and their brains examined using ex-vivo Diffusion Tensor Imaging (DTI). RESULTS: Compared to control, PAE alone did not affect offspring birth weights, mortality or any DTI measures. In contrast, PAE+CHORIO significantly reduced offspring survival and, in surviving pups, increased Radial Diffusivity (RD) in medial frontal cortex and decreased Fractional Anisotropy (FA) in medial and ventral frontal cortex and within capsular regions. CONCLUSION: The combination of moderate PAE+CHORIO results in an increased mortality, concomitant with diffuse microstructural brain injury noted in young adolescent offspring at PD28. Future studies should examine the extent to which PAE exacerbates the damage caused by CHORIO alone and whether these deficits persist into adulthood.

Short-term, high-dose hydroxychloroquine corneal toxicity.

PURPOSE: To describe the corneal findings and management of a 61-year-old female with vortex keratopathy following short term, high dose hydroxychloroquine used in the setting of a clinical trial for recurrent breast cancer. OBSERVATIONS: The patient was found to have significant corneal vortex keratopathy without retinal pathology within 3 months of 1200 mg daily hydroxychloroquine treatment as an adjuvant medication for cancer therapy. Cessation of the medication led to the resolution of the corneal verticillata within 1 month yet the vision did not return to baseline. Ultimately, remaining irregular astigmatism and ocular surface disease required a scleral contact lens to achieve a BSCVA of 20/25 OU. CONCLUSIONS AND IMPORTANCE: Hydroxychloroquine-induced vortex keratopathy is largely considered dose and duration dependent and is uncommon with most standard treatment algorithms. However, with increasing use of high-dose hydroxychloroquine in adjunct cancer therapy, corneal findings are likely to become more frequent. Persistent visual impairment may occur, thus increased understanding of this pathology can aid in counseling patients and guiding treatment recommendations.

The LFA-1 antagonist BIRT377 reverses neuropathic pain in prenatal alcohol-exposed female rats via actions on peripheral and central neuroimmune function in discrete pain-relevant tissue regions.

Previous reports show that moderate prenatal alcohol exposure (PAE) poses a risk factor for developing neuropathic pain following adult-onset peripheral nerve injury in male rats. Recently, evidence suggests that immune-related mechanisms underlying neuropathic pain in females are different compared to males despite the fact that both sexes develop neuropathy of similar magnitude and duration following chronic constriction injury (CCI) of the sciatic nerve. Data suggest that the actions of peripheral T cells play a greater role in mediating neuropathy in females. The goal of the current study is to identify specificity of immune cell and cytokine changes between PAE and non-PAE neuropathic females by utilizing a well-characterized rodent model of sciatic nerve damage, in an effort to unmask unique signatures of immune-related factors underlying the risk of neuropathy from PAE. Cytokines typically associated with myeloid cell actions such as interleukin (IL)-1ß, tumor necrosis factor (TNF), IL-6, IL-4 and IL-10 as well as the neutrophil chemoattractant CXCL1, are examined. In addition, transcription factors and cytokines associated with various differentiated T cell subtypes are examined (anti-inflammatory FOXP3, proinflammatory IL-17A, IL-21, ROR-γt, interferon (IFN)-γ and T-bet). Lymphocyte function associated antigen 1 (LFA-1) is an adhesion molecule expressed on peripheral immune cells including T cells, and regulates T cell activation and extravasation into inflamed tissue regions. A potential therapeutic approach was explored with the goal of controlling proinflammatory responses in neuroanatomical regions critical for CCI-induced allodynia by blocking LFA-1 actions using BIRT377. The data show profound development of hindpaw allodynia in adult non-PAE control females following standard CCI, but not following minor CCI, while minor CCI generated allodynia in PAE females. The data also show substantial increases in T cell-associated proinflammatory cytokine mRNA and proteins, along with evidence of augmented myeloid/glial activation (mRNA) and induction of myeloid/glial-related proinflammatory cytokines, CCL2, IL-1ß and TNF in discrete regions along the pain pathway (damaged sciatic nerve, dorsal root ganglia; DRG, and spinal cord). Interestingly, the characteristic anti-inflammatory IL-10 protein response to nerve damage is blunted in neuropathic PAE females. Moreover, T cell profiles are predominantly proinflammatory in neuropathic Sac and PAE females, augmented levels of Th17-specific proinflammatory cytokines IL-17A and IL-21, as well as the Th1-specific factor, T-bet, are observed. Similarly, the expression of RORγt, a critical transcription factor for Th17 cells, is detected in the spinal cord of neuropathic females. Blocking peripheral LFA-1 actions with intravenous (i.v.) BIRT377 reverses allodynia in Sac and PAE rats, dampens myeloid (IL-1ß, TNF, CXCL1)- and T cell-associated proinflammatory factors (IL-17A and RORγt) and spinal glial activation. Moreover, i.v. BIRT377 treatment reverses the blunted IL-10 response to CCI observed only in neuropathic PAE rats and elevates FOXP3 in pain-reversed Sac rats. Unexpectedly, intrathecal BIRT377 treatment is unable to alter allodynia in either Sac or PAE neuropathic females. Together, these data provide evidence that: 1) fully differentiated proinflammatory Th17 cells recruited at the sciatic nerve, DRGs and lumbar spinal cord may interact with the local environment to shape the immune responses underlying neuropathy in female rats, and, 2) PAE primes peripheral and spinal immune responses in adult females. PAE is a risk factor in females for developing peripheral neuropathy after minor nerve injury.

Prenatal alcohol exposure is a risk factor for adult neuropathic pain via aberrant neuroimmune function.

BACKGROUND: Clinical studies show that prenatal alcohol exposure (PAE) results in effects that persist into adulthood. Experimental animal models of moderate PAE demonstrate that young adults with PAE display potentiated sensitivity to light touch, clinically termed allodynia, following sciatic nerve chronic constriction injury (CCI) that coincides with heightened spinal glial, spinal macrophage, and peripheral immune responses. However, basal touch sensitivity and corresponding glial and leukocyte activation are unaltered. Therefore, the current study explored whether the enduring pathological consequences of moderate PAE on sensory processing are unmasked only following secondary neural insult. METHODS: In middle-aged (1 year) Long Evans rats that underwent either prenatal saccharin exposure (control) or moderate PAE, we modified the well-characterized model of sciatic neuropathy, CCI, to study the effects of PAE on neuro-immune responses in adult offspring. Standard CCI manipulation required 4 chromic gut sutures, while a mild version applied a single suture loosely ligated around one sciatic nerve. Spinal glial immunoreactivity was examined using immunohistochemistry. The characterization and functional responses of leukocyte populations were studied using flow cytometry and cell stimulation assays followed by quantification of the proinflammatory cytokines interleukin-1beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α). Data were statistically analyzed by ANOVA and unpaired t tests. RESULTS: The current report demonstrates that mild CCI generates robust allodynia only in PAE rats, while the pathological effects of PAE following the application of a standard CCI are revealed by enhanced allodynia and elevated spinal glial activation. Additionally, mild CCI increases spinal astrocyte activation but not microglia, suggesting astrocytes play a larger role in PAE-induced susceptibility to aberrant sensory processing. Leukocyte populations from PAE are altered under basal conditions (i.e., prior to secondary insult), as the distribution of leukocyte populations in lymphoid organs and other regions are different from those of controls. Lastly, following in vitro leukocyte stimulation, only PAE augments the immune response to antigen stimulation as assessed by heightened production of TNF-α and IL-1ß. CONCLUSIONS: These studies demonstrate PAE may prime spinal astrocytes and peripheral leukocytes that contribute to enduring susceptibility to adult-onset neuropathic pain that is not apparent until a secondary insult later in life.

Contrasting cellular damage after Blue-IRIS and Femto-LASIK in cat cornea.

Blue-intra-tissue refractive index shaping (Blue-IRIS) is a new approach to laser refractive correction of optical aberrations in the eye, which alters the refractive index of the cornea rather than changing its shape. Before it can be implemented in humans, it is critical to establish whether and to what extent, Blue-IRIS damages the cornea. Here, we contrasted the impact of -1.5 D cylinder refractive corrections inscribed using either Blue-IRIS or femtosecond laser in-situ keratomileusis (femto-LASIK) on corneal cell viability. Blue-IRIS was used to write a -1.5 D cylinder gradient index (GRIN) lens over a 2.5 mm by 2.5 mm area into the mid-stromal region of the cornea in six freshly-enucleated feline eyes. The same correction (-1.5 D cylinder) was inscribed into another four cat eyes using femto-LASIK. Six hours later, all corneas were processed for histology and stained for terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) and p-γ-H2AX to label damaged cells. In Blue-IRIS-treated corneas, no tissue was removed and TUNEL-stained cells were confined to the laser focal zone in the stroma. In femto-LASIK, photoablation removed 14 µm of anterior stroma, but in addition, TUNEL-positive cells clustered across the femto-flap, the epithelium at the flap edges and the stroma below the ablation zone. Keratocytes positive for p-γ-H2AX were seen adjacent to all Blue-IRIS focal zones, but were completely absent from femto-LASIK-treated corneas. Unlike femto-LASIK, Blue-IRIS attains refractive correction in the cornea without tissue removal and only causes minimal, localized keratocyte death within the laser focal zones. In addition, Blue-IRIS induced DNA modifications associated with phosphorylation of γ-H2AX in keratocytes adjacent to the laser focal zones. We posit that this p-γ-H2AX response is related to alterations in chromatin structure caused by localized changes in osmolarity, a possible mechanism for the induced refractive index changes.

Comparable change in stromal refractive index of cat and human corneas following blue-IRIS.

Blue intratissue refractive index shaping (blue-IRIS) is a method with potential to correct ocular refraction noninvasively in humans. To date, blue-IRIS has only ever been applied to cat corneas and hydrogels. To test the comparability of refractive index change achievable in cat and human tissues, we used blue-IRIS to write identical phase gratings in ex vivo feline and human corneas. Femtosecond pulses (400 nm) were focused ? 300 ?? ? m below the epithelial surface of excised cat and human corneas and scanned to write phase gratings with lines ? 1 ?? ? m wide, spaced 5 ?? ? m apart, using a scan speed of 5 ?? mm / s . Additional cat corneas were used to test writing at 3 and 7 ?? mm / s in order to document speed dependence of the refractive index change magnitude. The first-order diffraction efficiency was immediately measured and used to calculate the refractive index change attained. Our data show that blue-IRIS induces comparable refractive index changes in feline and human corneas, an essential requirement for further developing its use as a clinical vision correction technique.

Prenatal alcohol exposure potentiates chronic neuropathic pain, spinal glial and immune cell activation and alters sciatic nerve and DRG cytokine levels.

A growing body of evidence indicates that prenatal alcohol exposure (PAE) may predispose individuals to secondary medical disabilities later in life. Animal models of PAE reveal neuroimmune sequelae such as elevated brain astrocyte and microglial activation with corresponding region-specific changes in immune signaling molecules such as cytokines and chemokines. The aim of this study was to evaluate the effects of moderate PAE on the development and maintenance of allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in adult male rat offspring. Because CCI allodynia requires the actions of glial cytokines, we analyzed lumbar spinal cord glial and immune cell surface markers indicative of their activation levels, as well as sciatic nerve and dorsal root ganglia (DRG) cytokines in PAE offspring in adulthood. While PAE did not alter basal sensory thresholds before or after sham manipulations, PAE significantly potentiated adult onset and maintenance of allodynia. Microscopic analysis revealed exaggerated astrocyte and microglial activation, while flow cytometry data demonstrated increased proportions of immune cells with cell surface major histocompatibility complex II (MHCII) and ß-integrin adhesion molecules, which are indicative of PAE-induced immune cell activation. Sciatic nerves from CCI rats revealed that PAE potentiated the proinflammatory cytokines interleukin (IL)-1ß, IL-6 and tumor necrosis factor-alpha (TNFα) protein levels with a simultaneous robust suppression of the anti-inflammatory cytokine, IL-10. A profound reduction in IL-10 expression in the DRG of PAE neuropathic rats was also observed. Taken together, our results provide novel insights into the vulnerability that PAE produces for adult-onset central nervous system (CNS) pathological conditions from peripheral nerve injury.

First demonstration of ocular refractive change using blue-IRIS in live cats.

PURPOSE: To determine the efficacy of intratissue refractive index shaping (IRIS) using 400-nm femtosecond laser pulses (blue light) for writing refractive structures directly into live cat corneas in vivo, and to assess the longevity of these structures in the eyes of living cats. METHODS: Four eyes from two adult cats underwent Blue-IRIS. Light at 400 nm with 100-femtosecond (fs) pulses were tightly focused into the corneal stroma of each eye at an 80-MHz repetition rate. These pulses locally increased the refractive index of the corneal stroma via an endogenous, two-photon absorption process and were used to inscribe three-layered, gradient index patterns into the cat corneas. The optical effects of the patterns were then tracked using optical coherence tomography (OCT) and Shack-Hartmann wavefront sensing. RESULTS: Blue-IRIS patterns locally changed ocular cylinder by -1.4 ± 0.3 diopters (D), defocus by -2.0 ± 0.5 D, and higher-order root mean square (HORMS) by 0.31 ± 0.04 µm at 1 month post-IRIS, without significant changes in corneal thickness or curvature. Refractive changes were maintained for the duration they were tracked, 12 months post-IRIS in one eye, and just more than 3 months in the remaining three eyes. CONCLUSIONS: Blue-IRIS can be used to inscribe refractive structures into live cat cornea in vivo that are stable for at least 12 months, and are not associated with significant alterations in corneal thicknesses or radii of curvature. This result is a critical step toward establishing Blue-IRIS as a promising technique for noninvasive vision correction.

The validity of phosphatidylethanol in dried blood spots of newborns for the identification of prenatal alcohol exposure.

BACKGROUND: Accurate identification of prenatal alcohol exposure (PAE) in the newborn period offers an opportunity for early identification of children at risk of future neurocognitive problems and the implementation of interventional approaches earlier in life. PAE newborn screening by measuring phosphatidylethanol in dried blood spot (PEth-DBS) cards is feasible, logistically easier, and more cost-efficient compared with other biomarkers. However, the sensitivity and specificity of this method have yet to be established. METHODS: This prospective cohort study examined validity of PEth-DBS among 28 infants with PAE and 32 controls relative to maternal self-report and other biomarkers. Pregnant women were recruited from a University of New Mexico clinic and followed to early postpartum period. The composite index, which was based on self-reported measures of alcohol use and allowed to classify subjects into PAE and control groups, was the criterion measure used to estimate sensitivity and specificity of PEth-DBS. RESULTS: The study included large proportions of patients representing ethnic minorities (7.4% American Indian, 81.7% Hispanic/Latina), low education (54.2%

Patterns of social-experience-related c-fos and Arc expression in the frontal cortices of rats exposed to saccharin or moderate levels of ethanol during prenatal brain development.

Recent findings from our laboratory indicate that alterations in frontal cortex function, structural plasticity, and related social behaviors are persistent consequences of exposure to moderate levels of ethanol during prenatal brain development [24]. Fetal-ethanol-related reductions in the expression of the immediate early genes (IEGs) c-fos and Arc and alterations in dendritic spine density in ventrolateral and medial aspects of frontal cortex suggest a dissociation reminiscent of that described by Kolb et al. [38] in which these aspects of frontal cortex undergo reciprocal experience-dependent changes. In addition to providing a brief review of the available data on social behavior and frontal cortex function in fetal-ethanol-exposed rats, the present paper presents novel data on social-experience-related IEG expression in four regions of frontal cortex (Zilles LO, VLO, Fr1, Fr2) that are evaluated alongside our prior data from AID and Cg3. Social experience in normal rats was related to a distinct pattern of IEG expression in ventrolateral and medial aspects of frontal cortex, with generally greater expression observed in ventrolateral frontal cortex. In contrast, weaker expression was observed in all aspects of frontal cortex in ethanol-exposed rats, with the exception of an experience-related increase in the medial agranular cortex. Behaviors related to social investigation and wrestling/boxing were differentially correlated with patterns of activity-related IEG expression in the regions under investigation for saccharin- and ethanol-exposed rats. These observations suggest that recruitment and expression of IEGs in frontal cortex following social experience are potentially important for understanding the long-term consequences of moderate prenatal ethanol exposure on frontal cortex function, synaptic plasticity, and related behaviors.

Moderate perinatal arsenic exposure alters neuroendocrine markers associated with depression and increases depressive-like behaviors in adult mouse offspring.

Arsenic is one of the most common heavy metal contaminants found in the environment, particularly in water. We examined the impact of perinatal exposure to relatively low levels of arsenic (50 parts per billion, ppb) on neuroendocrine markers associated with depression and depressive-like behaviors in affected adult C57BL/6J mouse offspring. Whereas most biomedical research on arsenic has focused on its carcinogenic potential, a few studies suggest that arsenic can adversely affect brain development and neural function. Compared to controls, offspring exposed to 50 parts per billion arsenic during the perinatal period had significantly elevated serum corticosterone levels, reduced whole hippocampal CRFR 1 protein level and elevated dorsal hippocampal serotonin 5HT 1A receptor binding and receptor-effector coupling. 5HT 1A receptor binding and receptor-effector coupling were not different in the ventral hippocampal formation, entorhinal or parietal cortices, or inferior colliculus. Perinatal arsenic exposure also significantly increased learned helplessness and measures of immobility in a forced swim task. Taken together, these results suggest that perinatal arsenic exposure may disrupt the regulatory interactions between the hypothalamic-pituitary-adrenal axis and the serotonergic system in the dorsal hippocampal formation in a manner that predisposes affected offspring to depressive-like behavior. These results are the first to demonstrate that relatively low levels of arsenic exposure during development can have long-lasting adverse effects on behavior and neurobiological markers associated with these behavioral changes.