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Reconstruction of facial defects can be an intimidating endeavor, especially to resident physicians. When local flap reconstruction is preferred, design of the optimal flap can be a difficult choice. Poor selection can lead to unsightly scarring as well as increased morbidity. A low-cost, easy-to-fabricate gelatin prosthetic facial skin simulator is presented to offer training experience in wound closure, local tissue rearrangement, and facial defect reconstruction for resident instruction. In conjunction with a didactic lecture, 10 participants were asked to perform a Z-plasty, bilobed, rhomboid, and paramedian forehead flap, followed by an 18-question survey. While initial impressions are favorable, further validation studies are warranted., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.)

This study reports the synthesis, [(123)I]radiolabeling, and biological profile of a new series of iodinated compounds for potential translation to the corresponding [(131)I]radiolabeled compounds for radionuclide therapy of melanoma. Radiolabeling was achieved via standard electrophilic iododestannylation in 60-90% radiochemical yield. Preliminary SPECT imaging demonstrated high and distinct tumor uptake of all compounds, as well as high tumor-to-background ratios compared to the literature compound [(123)I]4 (ICF01012). The most favorable compounds ([(123)I]20, [(123)I]23, [(123)I]41, and [(123)I]53) were selected for further biological investigation. Biodistribution studies indicated that all four compounds bound to melanin containing tissue with low in vivo deiodination; [(123)I]20 and [(123)I]53 in particular displayed high and prolonged tumor uptake (13% ID/g at 48 h). [(123)I]53 had the most favorable overall profile of the cumulative uptake over time of radiosensitive organs. Metabolite analysis of the four radiotracers found [(123)I]41 and [(123)I]53 to be the most favorable, displaying high and prolonged amounts of intact tracer in melanin containing tissues, suggesting melanin specific binding. Results herein suggest that compound [(123)I]53 displays favorable in vivo pharmacokinetics and stability and hence is an ideal candidate to proceed with further preclinical [(131)I] therapeutic evaluation.

The prevalence of type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) has increased in the United States over the past 40 years. These conditions, long linked with many cardiovascular complications, have recently been linked with androgen or testosterone deficiency in men. Several pathophysiologic hypotheses exist regarding this association, with the most widely reported a relationship to obesity and insulin resistance. Several randomized trials have confirmed that when testosterone replacement therapy is given to patients with T2DM, MetS, or both, metabolic parameters such as waist circumference, hemoglobin A1c , and systolic blood pressure are significantly reduced by up to 11 cm, 1.9%, and 23 mm Hg, respectively. This has not, however, resulted in improved cardiovascular outcomes, as evidenced in studies that found increased rates of cardiovascular events following testosterone replacement therapy. In this review, we summarize the relevant literature regarding the pathophysiology and management of androgen deficiency in men with T2DM, MetS, or both., (© 2015 Pharmacotherapy Publications, Inc.)

The paucity of observed supermassive black hole binaries (SMBHBs) may imply that the gravitational wave background (GWB) from this population is anisotropic, rendering existing analyses suboptimal. We present the first constraints on the angular distribution of a nanohertz stochastic GWB from circular, inspiral-driven SMBHBs using the 2015 European Pulsar Timing Array data. Our analysis of the GWB in the ~2-90 nHz band shows consistency with isotropy, with the strain amplitude in l>0 spherical harmonic multipoles ≲40% of the monopole value. We expect that these more general techniques will become standard tools to probe the angular distribution of source populations.

Objective: To describe a novel use of fluorescent angiography in assessing donor limb perfusion prior to free tissue harvest in microvascular free tissue transfer., Study Design: Retrospective case series., Methods: From January 2012 to June 2013, 59 patients underwent head-and-neck microvascular free tissue reconstruction. Evaluation of donor site perfusion via indocyanine green (ICG) fluorescent angiography was utilized in 12 patients and 13 free flaps. Eleven cases were radial forearm free flaps (RFFF) and two were fibula free flaps (FFF). Preoperatively, RFFF patients were evaluated with Allen's testing, Doppler ultrasound, or both. FFF patients underwent magnetic resonance angiography. ICG was used intraoperatively to evaluate donor limb perfusion prior to free flap harvest. Intraoperative and postoperative complications of the donor limb were evaluated with cost analysis., Results: Average follow-up was 5.3 months. Preoperative Allen's testing was normal in six patients and ultrasound was performed in eight patients. One patient had a normal ultrasound, three showed minimal dampening, and four exhibited severe waveform flattening. There were no intraoperative complications using ICG. All 12 patients displayed adequate donor limb perfusion via fluorescent angiography. No digital or acute ischemic events were identified intraoperatively or postoperatively. There was no significant decrease in functionality or mobility of the donor limb. One patient noted mild arm pain with use., Conclusion: Fluorescent angiography is another method to evaluate donor site perfusion prior to free tissue harvest. Larger prospective analysis would be helpful to more thoroughly evaluate safety, although this is limited by the overall low risk of ischemic complications., Level of Evidence: 4., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: To evaluate the long-term outcomes of rituximab (RTX) treatment in patients with ocular granulomatosis with polyangiitis (GPA) with localized or generalized disease., Design: Retrospective cohort., Participants: Thirty-seven patients with ocular GPA receiving RTX in a multidisciplinary vasculitis clinic between 2004 and 2013., Methods: A total of 100 patients who received a course of RTX were identified, and notes were reviewed. Baseline demographic details, clinical characteristics (including organ involvement), drugs used, and outcome measures were recorded., Main Outcome Measures: The percentage in remission (inactive disease with prednisolone ≤7.5 mg with or without maintenance treatment) at 6 months, time to remission, percentage relapsing, side effects, B-cell count, antineutrophil cytoplasm antibody titers, induction, and maintenance regimens., Results: The median follow-up time after the first RTX course was 36.5 months. Twenty patients had scleritis, and 17 patients had orbital disease; 86% achieved remission at 6 months. The percentage in remission versus partial remission was not statistically significant between patients with scleritis and patients with orbital disease (85% vs. 15% with scleritis and 82% vs. 18% with orbital disease; P = 1.00). The percentage relapsing was not statistically significant (P = 0.33) between scleritis (60%) and orbital disease (41%). Localized disease (ocular ± ear-nose-throat/lung) was observed in 57%, and generalized disease (ocular plus other organs) was observed in 43%, the former having a median duration of disease of 40 months. There was no statistically significant difference (P = 0.37) in the percentage in remission between localized and generalized ocular disease. Relapses occurred in 51%, with localized disease being a significant risk factor for relapse. Fifty percent of patients with generalized disease versus none with localized disease received cyclophosphamide (CYP) as part of the induction regimen. Patients who received CYP during induction had significantly (P = 0.027) lower ratios of baseline 12-month proteinase 3 titers than patients who did not have CYP. Infections were observed in 16% of patients, with 8% requiring hospital admission., Conclusions: Our long-term data suggest that RTX is effective for inducing disease remission in localized and generalized ocular GPA. Localized disease is a significant risk factor for relapse, which may be related to less use of CYP in the induction regimen., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether the addition of 26 weeks of subcutaneous peginterferon-α-2b could reduce the requirement for systemic corticosteroids and conventional immunosuppressive medication in patients with Behçet's disease (BD)., Methods: We conducted a multicentre randomised trial in patients with BD requiring systemic therapy. Patients were randomised to 26 weeks of peginterferon-α-2b in addition to their standard care or to standard care only and followed 6-monthly for 3 years with BD activity scores and quality of life questionnaires. Patients at one centre had blood taken to measure regulatory T cells (Tregs) and Th17 cells., Results: 72 patients were included. At months 10-12, while among the entire patient population there was no difference in the corticosteroid dose or immunosuppression use between the treatment groups (adjusted OR 1.04, 95% CI 0.34 to 3.19), post hoc analysis revealed that in patients who were on corticosteroids at baseline the corticosteroid requirement was significantly lower in the peginterferon-α-2b (6.5 (5-15) mg/day) compared with the non-interferon group (10 (8.25-16.5) mg/day, p=0.039). Furthermore, there was a trend towards an improved quality of life that became significant by 36 months (p=0.008). This was associated with a significant rise in Tregs and a decrease in Th17 cells which was still present at 1 year and 6 months after the interferon was stopped. The safety profile was similar with adverse events in 10% in both groups., Conclusions: The addition of peginterferon-α-2b to the drug regime of BD patients did not significantly reduce their corticosteroid dose required at 1 year. However, in those on corticosteroids at baseline post hoc analysis demonstrated that the addition of peginterferon-α-2b did result in a significant reduction in corticosteroid dose with a significantly improved quality of life and trend to reduce other required immunosuppressive agents. This effect was seen at 1 year and associated with a rise in Tregs suggesting a possible mode for interferon action., Trial Registration Number: ISRCTN 36354474; EudraCT 2004-004301-18., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: The relative lengths of the index finger to the ring finger (2D:4D) is sexually dimorphic and is thought to be a correlate of prenatal sex steroids (low 2D:4D=high prenatal testosterone and low prenatal oestrogen). In adults there have been reports that low 2D:4D is consistently associated with high sports performance., Aims: To investigate correlations between 2D:4D and fitness levels in children., Study Design: Right 2D:4D and body size were measured, in addition to flexibility, speed, endurance and strength (Eurofit tests)., Subjects: 922 boys and 835 girls (mean ages (years): 10.8 ± 1.01 and 10.07 ± 1.00 respectively)., Outcome Measures: height, mass, BMI, triceps and subscapular skinfolds, 20 m shuttle run, sit and reach, standing broad jump, hand grip strength, 10 × 5m sprint, and the sit and reach test., Results: Boys significantly outperformed the girls in the 10 × 5m sprints, the 20 m shuttle run, standing broad jump, and hand grip strength. In boys but not girls, 2D:4D was significantly negatively correlated with scores in all these tests except the standing broad jump. In girls but not boys, 2D:4D was significantly positively correlated to stature, mass, BMI and waist circumference., Conclusions: It is suggested that high prenatal testosterone and low prenatal oestrogen (low 2D:4D) is implicated in high sprinting speed, endurance and hand grip strength in boys. In girls low prenatal testosterone and high prenatal oestrogen is associated with large body size., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To investigate whether intravitreal ranibizumab injections administered to a child alter systemic plasma levels of total and free VEGF 165., Methods: A 9-year-old child sustained a choroidal rupture from blunt trauma. He subsequently developed a secondary choroidal neovascular membrane, which was treated with five ranibizumab injections over a period of 8 months. Peripheral venous blood samples were taken at each visit over a period of 12 months and plasma was extracted. Plasma VEGF 165 levels were determined using enzyme-linked immunosorbent assay and were assayed both pre- and post-immunodepletion to remove complexed VEGF., Results: Plasma VEGF 165 levels proved labile following intravitreal injection of ranibizumab. Levels increased by 30% above baseline following the first intravitreal ranibizumab injection, but then returned to baseline despite two subsequent injections. There was then a rebound increase of 67% in total plasma VEGF levels following a further injection, which remained above baseline for 12 weeks despite two further intravitreal ranibizumab injections. Baseline levels were re-attained 26 weeks after the final injection., Conclusions: These results suggest intravitreal ranibizumab injections can cause significant, multiphasic changes in systemic VEGF levels. This may be of particular clinical significance in children as VEGF is known to be vital in the development of major organs, in addition to its role in the maintenance of normal organ function in adults.

Stimulation of postnatal neurogenesis in the subventricular zone (SVZ) and robust migration of neuroblasts to the lesion site in response to traumatic brain injury (TBI) is well established in rodent species; however, it is not yet known whether postnatal neurogenesis plays a role in repair after TBI in gyrencephalic species. Here we describe the anatomy of the SVZ in the piglet for the first time and initiate an investigation into the effect of TBI on the SVZ architecture and the number of neuroblasts in the white matter. Among all ages of immaturity examined the SVZ contained a dense mesh network of neurogenic precursor cells (doublecortin+) positioned directly adjacent to the ependymal cells (ventricular SVZ, Vsvz) and neuroblasts organized into chains that were distinct from the Vsvz (abventricular SVZ, Asvz). Though the architecture of the SVZ was similar among ages, the areas of Vsvz and Asvz neuroblast chains declined with age. At postnatal day (PND) 14 the white matter tracts have a tremendous number of individual neuroblasts. In our scaled cortical impact model, lesion size increased with age. Similarly, the response of the SVZ to injury was also age dependent. The younger age groups that sustained the proportionately smallest lesions had the largest SVZ areas, which further increased in response to injury. In piglets that were injured at 4 months of age and had the largest lesions, the SVZ did not increase in response to injury. Similar to humans, swine have abundant gyri and gyral white matter, providing a unique platform to study neuroblasts potentially migrating from the SVZ to the lesioned cortex along these white matter tracts. In piglets injured at PND 7, TBI did not increase the total number of neuroblasts in the white matter compared to uninjured piglets, but redistribution occurred with a greater number of neuroblasts in the white matter of the hemisphere ipsilateral to the injury compared to the contralateral hemisphere. At 7 days after injury, less than 1% of neuroblasts in the white matter were born in the 2 days following injury. These data show that the SVZ in the piglet shares many anatomical similarities with the SVZ in the human infant, and that TBI had only modest effects on the SVZ and the number of neuroblasts in the white matter. Piglets at an equivalent developmental stage to human infants were equipped with the largest SVZ and a tremendous number of neuroblasts in the white matter, which may be sufficient in lesion repair without the dramatic stimulation of neurogenic machinery. It has yet to be determined whether neurogenesis and migrating neuroblasts play a role in repair after TBI and/or whether an alteration of normal migration during active postnatal population of brain regions is beneficial in species with gyrencephalic brains., (© 2015 S. Karger AG, Basel.)

Diabetic maculopathy is an important cause of severe sight impairment. There has been a significant evolution in its treatment over the past decade and laser treatment is now largely being superseded by intravitreal injections of anti-vascular endothelial growth factor agents or corticosteroids.

Circadian clocks are biological oscillators that regulate daily behaviors in organisms across the kingdoms of life. Their rhythms are generated by complex systems, generally involving interlocked regulatory feedback loops. These rhythms are entrained by the daily light/dark cycle, ensuring that the internal clock time is coordinated with the environment. Mathematical models play an important role in understanding how the components work together to function as a clock which can be entrained by light. For a clock to entrain, it must be possible for it to be sped up or slowed down at appropriate times. To understand how biophysical processes affect the speed of the clock, one can compute velocity response curves (VRCs). Here, in a case study involving the fruit fly clock, we demonstrate that VRC analysis provides insight into a clock׳s response to light. We also show that biochemical mechanisms and parameters together determine a model׳s ability to respond realistically to light. The implication is that, if one is developing a model and its current form has an unrealistic response to light, then one must reexamine one׳s model structure, because searching for better parameter values is unlikely to lead to a realistic response to light., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Bioluminescence rhythms from cellular reporters have become the most common method used to quantify oscillations in circadian gene expression. These experimental systems can reveal phase and amplitude change resulting from circadian disturbances, and can be used in conjunction with mathematical models to lend further insight into the mechanistic basis of clock amplitude regulation. However, bioluminescence experiments track the mean output from thousands of noisy, uncoupled oscillators, obscuring the direct effect of a given stimulus on the genetic regulatory network. In many cases, it is unclear whether changes in amplitude are due to individual changes in gene expression level or to a change in coherence of the population. Although such systems can be modeled using explicit stochastic simulations, these models are computationally cumbersome and limit analytical insight into the mechanisms of amplitude change. We therefore develop theoretical and computational tools to approximate the mean expression level in large populations of noninteracting oscillators, and further define computationally efficient amplitude response calculations to describe phase-dependent amplitude change. At the single-cell level, a mechanistic nonlinear ordinary differential equation model is used to calculate the transient response of each cell to a perturbation, whereas population-level dynamics are captured by coupling this detailed model to a phase density function. Our analysis reveals that amplitude changes mediated at either the individual-cell or the population level can be distinguished in tissue-level bioluminescence data without the need for single-cell measurements. We demonstrate the effectiveness of the method by modeling experimental bioluminescence profiles of light-sensitive fibroblasts, reconciling the conclusions of two seemingly contradictory studies. This modeling framework allows a direct comparison between in vitro bioluminescence experiments and in silico ordinary differential equation models, and will lead to a better quantitative understanding of the factors that affect clock amplitude., (Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the long-term clinical and functional outcome, risks, and causes of vision loss and burden of disease among patients with uveitis., Design: Cross-sectional study., Participants: The study included 1076 patients diagnosed with uveitis who attended the uveitis clinic at Moorfields Eye Hospital, London, United Kingdom, between 2011 and 2013., Methods: Information was gathered from the notes of all patients who were examined in the clinic., Main Outcome Measures: Best-corrected visual acuity (BCVA), causes of moderate vision loss (MVL; 20/50-20/120), and severe vision loss (SVL; ≤ 20/200)., Results: The study included 1799 eyes of 1076 patients with an average follow-up of 7.97 ± 0.17 years (median, 5.6 years; range, 1 month-54 years; 8159 patient-years; 14 226 eye-years). Average BCVA remained stable for patients with anterior uveitis (20/30 at baseline to 20/33 at 10 years), as well as for those with nonanterior uveitis (20/50 at baseline to 20/47 at 10 years). Vision loss was noted in 19.2% of eyes, with an incidence for MVL of 0.01 per eye-year or 0.02 per patient-year and for SVL of 0.01 per eye-year or 0.02 per patient-year. Patients were more at risk of vision loss if they had non-anterior uveitis disease, vitreous opacities, retinal detachment, cystoid macular edema (CME), macular scarring, macular hole, optic neuropathy, or macular ischemia. Chronic CME was the most common cause of MVL (3.55%), and macular scarring was the most common cause for irreversible SVL (4%). Among 525 patients (48.7%) who received oral prednisolone, 320 (61%) required a dose of more than 40 mg/day and 130 (24.8%) also required 1 or more second-line agents. Patients were reviewed on average 33.7 ± 0.7 times or 5.9 ± 0.46 times/year., Conclusions: Long-term functional outcome among uveitis patients is good, with BCVA remaining stable for more than 10 years of follow-up. In cases when vision loss occurs, it is related mainly to retinal changes. The burden on clinical services is similar regardless of the severity of disease or the risk of vision loss., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Birdshot chorioretinopathy remains incompletely understood, but new insights into its pathogenesis have been reported recently, and treatment and monitoring options have also expanded. Central visual acuity may remain good until the late stages of the disease, but loss of visual field and peripheral retinal function is common., Recent Findings: The underlying pathogenesis of the disease has long been believed to be T-cell driven, but examination of the IL-17 pathway has now further refined the potential underlying mechanism. New imaging techniques, including extended depth imaging of the choroid with optical coherence tomography, have demonstrated promise in detecting disease activity earlier, enabling targeted treatment to be given. Treatment options have expanded with the advent of the biological agents, and these may yet improve outcomes, particularly in refractory patients., Summary: Laboratory research continues to investigate the underlying mechanisms of disease, but our understanding remains frustratingly incomplete for a disease with such a clear HLA association. Clinical research is increasingly being driven to improve the phenotyping of affected patients so that those at risk of visual loss can be identified early and treated more aggressively with individually targeted therapies such as the newer biological agents, but how successful this approach will ultimately prove to be remains to be seen.

This study examined the safety, pharmacodynamic (PD), and pharmacokinetic (PK) biosimilarity of the human recombinant erythropoietin (EPO) products ior(®) EPOCIM and Eprex(®) following a 28-day repeated intravenous dose administration in male and female Sprague-Dawley rats with a 14-day recovery period. Safety profiling was based on clinical observations, clinical pathology, and pathology findings for control rats dosed with vehicle and rats dosed either with 30, 300, and 600 I.U./kg of ior(®) EPOCIM or 600 I.U. of Eprex(®) . Adverse findings for both ior(®) EPOCIM and Eprex(®) were similar and were a consequence of thrombotic events (ulcerative skin lesions, swollen hock joints/lameness, stomach ulcers) and decreased body weight gains, all known adverse reactions to this class of drug in rats. With the exception of stomach ulcers, all other adverse findings were fully reversible. Neither drug stimulated the production of antidrug antibodies. As expected, ior(®) EPOCIM and Eprex(®) both increased reticulocyte, red blood cell, hemoglobin, and hematocrit levels in rats. The PK of EPO following dosing with ior(®) EPOCIM was well behaved and consistent with the literature. The results of this study imply that ior(®) EPOCIM and Eprex(®) had safety profiles, PD responses, and toxicokinetic profiles that were biosimilar., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

The role of dopaminergic (DA) projections from the ventral tegmental area (VTA) in appetitive and rewarding behavior has been widely studied, but the VTA also has documented DA-independent functions. Several drugs of abuse, act on VTA GABAergic neurons, and most studies have focused on local inhibitory connections. Relatively little is known about VTA GABA projection neurons and their connections to brain sites outside the VTA. This study employed viral-vector-mediated cell-type-specific anterograde tracing, classical retrograde tracing, and immunohistochemistry to characterize VTA GABA efferents throughout the brain. We found that VTA GABA neurons project widely to forebrain and brainstem targets, including the ventral pallidum, lateral and magnocellular preoptic nuclei, lateral hypothalamus, and lateral habenula. Minor projections also go to central amygdala, mediodorsal thalamus, dorsal raphe, and deep mesencephalic nuclei, and sparse projections go to prefrontal cortical regions and to nucleus accumbens shell and core. These projections differ from the major VTA DA target regions. Retrograde tracing studies confirmed results from the anterograde experiments and differences in projections from VTA subnuclei. Retrogradely labeled GABA neurons were not numerous, and most non-tyrosine hydroxylase/retrogradely labeled cells lacked GABAergic markers. Many non-TH/retrogradely labeled cells projecting to several areas expressed VGluT2. VTA GABA and glutamate neurons project throughout the brain, most prominently to regions with reciprocal connections to the VTA. These data indicate that VTA GABA and glutamate neurons may have more DA-independent functions than previously recognized., (© 2014 Wiley Periodicals, Inc.)

Background: Two-thirds of Americans who are prescribed antihypertensive medications are not at a blood pressure (BP) goal of <140/90 mmHg, and low adherence is identified as a primary cause of inadequate control. Improved adherence to antihypertensive medications has been shown to enhance BP control and reduce the risk of cardiovascular complications. This study investigated the effectiveness of a pill box clinic to improve BP in veterans with uncontrolled hypertension taking 3 or more antihypertensive medications., Objectives: To (a) investigate the reduction of systolic BP by 10 mmHg from pre-intervention to post-intervention (primary outcome) and (b) investigate the percentage of patients meeting goal blood pressure--as defined by The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7)--and percentage of patient adherence to antihypertensive medications (secondary outcomes)., Methods: Patients with uncontrolled hypertension currently taking at least 3 antihypertensive medications were enrolled in this prospective pre/post study. Under the supervision of a pharmacist, each patient was provided two 7-day pill boxes to organize all antihypertensive medications. In addition, baseline BP and previous history of nonadherence were documented. Following the initial encounter, patients attended 2 follow-up appointments, at 2 and 4 weeks, for refill of pill boxes, BP measurement, and adherence assessment. A chi-square test was used for categorical outcomes and logistic regression for nominal outcomes as well as descriptive statistics, as appropriate., Results: Sixty patients were enrolled, with 50 completing appointments 1 and 2, and 45 completing all 3 appointments. Of those, 24% and 31% achieved at least a 10 mmHg reduction in systolic BP from baseline to appointments 2 and 3, respectively (P = 0.438). Systolic BP readings for appointments 1, 2, and 3 were not statistically significant (mean [SD]: 134.1 [11.8], 131.9 [9.4], and 130.6 [11.4], respectively). Goal BP per JNC7 was achieved by 44% and 51% of patients at appointments 2 and 3, respectively, compared with baseline (P = 0.201). All patients had ≥ 80% adherence to antihypertensive medications, assessed via pill counts at the second and third appointments., Conclusion: Although results were not statistically significant, the pill box clinic resulted in clinically significant reductions in systolic BP by 10 mmHg, as well as an increased number of patients meeting prescribed BP goals.

Purpose: To describe the long-term outcome of eyes with uveitis after repeated treatment with dexamethasone implants (Ozurdex; Allergan, Inc., Irvine, CA)., Design: Retrospective, observational case series., Participants: Thirty-eight eyes of 27 patients with uveitis that were treated with 61 dexamethasone implants., Methods: All eyes underwent dexamethasone pellet implantation. Anatomic and functional outcomes, as well as ocular complications, were noted., Main Outcome Measures: Best-corrected visual acuity (BCVA), central retinal thickness (CRT), vitreous haze score, and presence of increased intraocular pressure or cataract., Results: Average follow-up was 17.3 ± 1.8 months after the first implant (median, 13.3 months; range, 3-54.5 months; 54.65 eye-years), with 14 eyes (36.9%) receiving a single implant and 24 eyes (63.1%) receiving multiple implantations. After the first implantation, average BCVA improved significantly from 0.47 ± 0.05 logarithm of the minimum angle of resolution (logMAR) units (Snellen equivalent, 20/60) to 0.27 ± 0.07 logMAR (Snellen equivalent, 20/37; P<0.001); CRT decreased by 263 ± 44.22 μm (P = 0.003), although macular edema persisted in 50% of eyes, and the percentage of eyes achieving a vitreous haze score of 0 increased from 58% to 83% (P = 0.03). The median duration of therapeutic effect after the first injection was 6 months (range, 2-42 months), with a similar response achieved after each repeat implantation. The accumulated effect of repeat dexamethasone implants resulted in a continued improvement in BCVA (R(2) = 0.91; P<0.0001), with significant improvement and stabilization of CRT. After repeated implantations, 2 eyes had progression of posterior subcapsular opacities, although neither required surgery. There were 7 instances of increased intraocular pressure of more than 21 mmHg at a rate of 0.13 per eye-year, all of which responded to pharmacologic treatment., Conclusions: The accumulated effect of repeat dexamethasone pellet implantations improves retinal thickness and resolves ocular inflammation, resulting in restoration of ocular function. Ocular complications were minimal, with no eyes requiring surgery for increased ocular pressure or progression of cataract., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Importance: Uveitic glaucoma is among the most common causes of irreversible visual loss in uveitis. However, glaucoma detection can be obscured by inflammatory changes., Objective: To determine whether retinal nerve fiber layer (RNFL) measurement can be used to detect glaucoma in uveitic eyes with elevated intraocular pressure (IOP)., Design, Setting, and Participants: Comparative case series of RNFL measurement using optical coherence tomography performed from May 1, 2010, through October 31, 2012, at a tertiary referral center. We assigned 536 eyes with uveitis (309 patients) in the following groups: normal contralateral eyes with unilateral uveitis (n = 72), normotensive uveitis (Uv-N) (n = 143), raised IOP and normal optic disc and/or visual field (Uv-H) (n = 233), and raised IOP and glaucomatous disc and/or visual field (Uv-G) (n = 88)., Exposures: Eyes with uveitis and elevated IOP (>21 mm Hg) on at least 2 occasions., Main Outcomes and Measures: Comparison of RNFL values between groups of eyes and correlation with clinical data; risk factors for raised IOP, glaucoma, and RNFL thinning., Results: Mean (SD) global RNFL was thicker in Uv-N (106.4 [21.4] µm) compared with control (96.0 [9.0] µm; P < .001) eyes and was thicker in Uv-N eyes with active (119.6 [23.2] µm) compared with quiescent (102.3 [20.8] µm; P = .001) uveitis, which in turn was not significantly different from control eyes (P = .07). Compared with Uv-N eyes, significant RNFL thinning was seen in all quadrants except the temporal in Uv-G eyes and significant thinning in the inferior quadrant of Uv-H eyes with no evidence of disc or visual field changes (P = .03). Risk factors for elevated IOP were male sex and anterior uveitis. Age, higher peak IOP, longer duration of follow-up, and uveitis-induced elevation of IOP were risk factors for glaucoma and RNFL defect., Conclusions and Relevance: Screening for glaucomatous RNFL changes in uveitis must be performed during quiescent periods. Thinning of the inferior quadrant suggests that glaucomatous damage, more than uveitic ocular hypertension, is in fact occurring. Measurement of RNFL may detect signs of damage before disc or visual field changes and therefore identifies a subgroup that should receive more aggressive treatment.

The management of peritonsillar abscesses is a skill developed early in residency training. Although drainage is not technically complicated, the procedure is intimidating to the neophyte. Task simulators have become increasingly common to provide training opportunities in a controlled environment. The authors designed a peritonsillar abscess simulator using a latex moulage of the oral cavity and other common materials. Twelve medical professionals of various levels of experience were instructed to expose, anesthetize, aspirate, and drain the simulated abscess. After completion, a questionnaire was completed by each volunteer. Initial impressions were positive that the model adequately replicated the tasks requisite for abscess drainage and was suitable as an instructional device. The initial construct cost was approximately 10 dollars, with disposables costing roughly 25 cents. Further research is under way to formally assess the simulator for face, content, and construct validity., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014.)

Background: The calcium-dependent phosphatase calcineurin is highly expressed in the amygdala, a brain area important for behaviors related to mood disorders and anxiety. Organ transplant patients are administered the calcineurin inhibitor cyclosporine A (CsA) chronically and demonstrate an increased incidence of anxiety and mood disorders. It is therefore important to determine whether chronic blockade of calcineurin may contribute to symptoms of anxiety and depression in these patients., Methods: Pharmacological (CSA) and viral-mediated gene transfer (adeno-associated viral expression of short hairpin RNA [shRNA]) approaches were used to inhibit calcineurin activity systemically or selectively in the amygdala of the mouse brain to determine the role of calcineurin in behaviors related to anxiety and depression., Results: Systemic inhibition of calcineurin activity with CsA or local downregulation of calcineurin levels in the amygdala using adeno-associated viral-delivered shRNAs targeting calcineurin B increased measures of anxiety-like behavior in the elevated plus maze, the light/dark box, and the open field test. A decrease in locomotor activity was also observed in mice treated systemically with CsA. In the forced swim model of depression-like behavior, both systemic CsA treatment and shRNA-mediated calcineurin blockade in the amygdala significantly increased immobility., Conclusions: Taken together, these data demonstrate that decreasing calcineurin activity in the amygdala increases anxiety-like behaviors and to some extent depression-like behaviors. These studies suggest that chronic administration of CsA to organ transplant patients could have significant effects on anxiety and mood and this should be recognized as a potential clinical consequence of treatment to prevent transplant rejection., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Granulomatosis with polyangiitis (GPA), previously Wegener's granulomatosis, requires prompt diagnosis and systemic review to exclude life-threatening disease. However, early diagnosis of orbital GPA may be difficult because anti-neutrophil cytoplasmic antibody (ANCA) and anti-PR3 antibody screening can be negative at presentation and orbital biopsies taken for diagnosis may not show the classic features of GPA. This study was designed to compare GPA with other causes of orbital inflammation and to identify the presenting clinical and imaging features most likely to predict GPA and its systemic spread., Design: Retrospective noninterventional comparative case series., Participants: A total of 247 patients who had undergone orbital biopsies for clinical presentations with orbital inflammation were identified from the Institute of Ophthalmology pathology database., Methods: Patients were divided into GPA and non-GPA groups on the basis of their final clinical diagnosis. Clinical and imaging features of these 2 groups were compared to determine those predictive of GPA, and patients with GPA also had long-term evaluation for systemic involvement., Main Outcome Measures: A diagnosis of orbital GPA and development of systemic GPA were the main outcome measures., Results: Features highly suggestive of GPA were sinonasal symptoms, sinonasal changes, or paranasal bone erosion on imaging (P < 0.001). Bony erosion was independent of ANCA status or systemic involvement. Twenty-two percent of patients (8/37) with GPA had evidence of systemic involvement at presentation, and no patient presenting with solely orbital GPA developed later systemic disease over a median follow-up of 2.7 years., Conclusions: A high index of suspicion should be maintained for GPA when a patient presents with an orbital mass and sinonasal symptoms or imaging shows sinonasal involvement or paranasal bone erosion. No patient with solely orbital GPA involvement at presentation developed systemic disease, suggesting that orbital GPA can remain localized in the long-term., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the outcomes of changing immunosuppressive therapy for noninfectious uveitis after failure., Design: Retrospective cohort study., Participants: Patients with noninfectious uveitis managed at 2 tertiary uveitis clinics in the United Kingdom and Australia., Methods: Participants with a history of using immunosuppressive therapy were identified in clinics, and notes were reviewed by doctors trained in uveitis therapy. Each treatment episode/course (starting or changing a therapy) was identified, and demographic details, clinical characteristics, drug used (second-line immunosuppressive agent [ISA] or biologicals), and drug doses were obtained., Main Outcome Measures: For each treatment episode, the reasons for changing therapy, corticosteroid-sparing effects, and control of inflammation were determined., Results: A total of 147 patients were identified who underwent 309 different treatment episodes. Fifty-five percent of patients eventually required a change in treatment after their first treatment episode/course. Forty-five episodes involved switching from one ISA to another, with 50% to 100% of these patients achieving "success" (prednisolone ≤10 mg and sustained control) with the new ISA. A combination of ISAs were used in 53 episodes, with "success" being achieved in 50% to 71% of these patients. Biological agents were used in 45 episodes, the most common one being infliximab, which achieved success in 80% of patients., Conclusions: Our data suggest that control of inflammation can be achieved after switching or combining ISAs., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Our previous observations show that chronic opiate administration, including self-administration, decrease the soma size of dopamine (DA) neurons in the ventral tegmental area (VTA) of rodents and humans, a morphological change correlated with increased firing rate and reward tolerance. Given that a general hallmark of drugs of abuse is to increase activity of the mesolimbic DA circuit, we sought to determine whether additional drug classes produced a similar morphological change. Sections containing VTA were obtained from rats that self-administered cocaine or ethanol and from mice that consumed nicotine. In contrast to opiates, we found no change in VTA DA soma size induced by any of these other drugs. These data suggest that VTA morphological changes are induced in a drug-specific manner and reinforce recent findings that some changes in mesolimbic signaling and neuroplasticity are drug-class dependent.

HB-EGF is a member of the EGF family of ligands that is initially synthesized as a membrane-bound growth factor termed, proHB-EGF. The membrane bound proHB-EGF undergoes extensive proteolytic processing by several metalloproteinases capable of stimulating cellular proliferation. Soluble, mature HB-EGF binds to and activates EGF receptors. HB-EGF is a critical molecular component to a number of normal physiological processes including but not limited to tissue injury and wound healing, reproduction, angiogenesis and recently, adipogenesis. Misexpression of HB-EGF is linked to tumor formation and cancer including hepatocellular, pancreatic, gastric, breast, colon and melanoma, gliomas and glioblastomas. HB-EGF is a likely tool for therapeutic approaches to enhance treatment of injuries as well as a target for prevention of several cancers and obesity., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Streptococcus pneumoniae (SP) and nontypeable Haemophilus influenzae (NTHi) are common commensals of the human airway and major bacterial pathogens of otitis media (OM) and other upper airway infections. The interaction between them may play an important role in the pathogenesis of polymicrobial infections. Although previous studies suggested NTHi could promote pneumococcal survival and biofilm formation, how NTHi affects pneumococcal activities has not been defined. Our data in the present studies indicated that the outcome of the interaction between SP and NTHi was in a cell-density-dependent manner and the enhancement of pneumococcal survival happened at the later stages of culturing. Using quantitative PCR, we found that the expression of pneumococcal genes regulating autolysis and fratricide, lytA and cbpD, were significantly down-regulated in co-culture with NTHi. We further observed that influence of NTHi was not on direct cell-to-cell contact, but that this contact may contribute to the interaction between these two microorganisms. These results suggest that pneumococcal survival and biofilm formation can be enhanced by down-regulating pneumococcal cell wall hydrolase production thereby inhibiting pneumococcal autolysis and fratricide in the presence of NTHi., (Copyright © 2013. Published by Elsevier Masson SAS.)

Importance: Birdshot chorioretinopathy is a chronic intraocular inflammatory disease with no uniform method to document long-term disease progression or response to treatment., Objective: To examine the long-term visual, clinical, and anatomic outcomes of patients with birdshot chorioretinopathy., Design, Setting, and Participants: A retrospective evaluation of 46 patients with birdshot chorioretinopathy treated at Moorfields Eye Hospital, London, England, was conducted. Medical records for a 19-year period (1993-2012) were reviewed., Exposures: Patients received no treatment, short-term (≤1 year) treatment including local or systemic corticosteroids, or long-term (>1 year) treatment including systemic corticosteroids and second-line immunosuppressive agents., Main Outcomes and Measures: Details regarding clinical and anatomic outcome, including best-corrected visual acuity, and visual field indices were evaluated., Results: Ninety-two eyes of 46 patients were monitored for a mean (SE) of 57.2 (5.8) months (445 eye-years, 17% follow-up of ≥10 years). Patients maintained a steady best-corrected visual acuity throughout the follow-up period. Some clinical indices correlated with transient worse best-corrected visual acuity, including presence of cataract (P = .05), foveal leakage on fluorescein angiography (P = .04), and increased central retinal thickness (P = .02). Serial visual field studies demonstrated that patients who received only short-term treatment had a worsening of their pattern standard deviation with time (Spearman correlation, 0.57; P = .003); for those who received long-term treatment, the pattern standard deviation remained stable (Spearman correlation, -0.24; P = .26)., Conclusions and Relevance: Our results suggest that central visual acuity can be maintained long term in patients with birdshot chorioretinopathy. Those who receive long-term immunosuppression appear to maintain better peripheral visual fields compared with patients who receive short-term treatment.

Birdshot chorioretinopathy is a relatively uncommon subtype of idiopathic posterior uveitis with distinct clinical characteristics and a strong genetic association with the Human Leukocyte Antigen (HLA)-A29 allele. The diagnosis remains clinical and is based on the presence of typical clinical features, including multiple, distinctive, hypopigmented choroidal lesions throughout the fundus. The long-term visual prognosis of this disorder, however, remains guarded - central visual acuity can be preserved until late in the disease and it is not uncommon for patients to receive inadequate immunosuppressive treatment, leading to a poor long-term outcome in which peripheral retinal damage eventually leads to visual deterioration. Birdshot chorioretinopathy has proven a particularly attractive area of study within the field of uveitis, as it is a relatively easily defined disease with an associated human leukocyte antigen haplotype. Despite this, however, the immune mechanisms involved in its pathogenesis remain unclear, and some patients continue to lose retinal function despite therapy with corticosteroids and conventional immunosuppressive agents. Laboratory research continues to investigate the underlying mechanisms of disease, and clinical research is now being driven to improve the phenotyping and monitoring of this condition as, in the era of so-called personalized medicine, it is becoming increasingly important to identify patients at risk of visual loss early so that they can be treated more aggressively with targeted therapies such as the newer biological agents. This approach requires the formation of collaborative groups, as the relative rarity of the condition makes it difficult for one center to accumulate enough patients for worthwhile studies. Nevertheless, results obtained with newer therapies, such as biological agents directed against particular cytokines or cell-surface receptors, demonstrate ever improving control of the inflammation in refractory cases, providing hope that the outlook for visual function in this condition can only improve.

H2O2 can cause oxidative damage associated with age-related diseases such as diabetes and cancer but is also used to initiate diverse responses, including increased antioxidant gene expression. Despite significant interest, H2O2-signaling mechanisms remain poorly understood. Here, we present a mechanism for the propagation of an H2O2 signal that is vital for the adaptation of the model yeast, Schizosaccharomyces pombe, to oxidative stress. Peroxiredoxins are abundant peroxidases with conserved antiaging and anticancer activities. Remarkably, we find that the only essential function for the thioredoxin peroxidase activity of the Prx Tpx1(hPrx1/2) in resistance to H2O2 is to inhibit a conserved thioredoxin family protein Txl1(hTxnl1/TRP32). Thioredoxins regulate many enzymes and signaling proteins. Thus, our discovery that a Prx amplifies an H2O2 signal by driving the oxidation of a thioredoxin-like protein has important implications, both for Prx function in oxidative stress resistance and for responses to H2O2., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent genetic studies have linked mental illness to alterations in disrupted in schizophrenia 1 (DISC1), a multifunctional scaffolding protein that regulates cyclic adenosine monophosphate (cAMP) signaling via interactions with phosphodiesterase 4 (PDE4). High levels of cAMP during stress exposure impair function of the prefrontal cortex (PFC), a region gravely afflicted in mental illness. As stress can aggravate mental illness, genetic insults to DISC1 may worsen symptoms by increasing cAMP levels. The current study examined whether viral knockdown (KD) of the Disc1 gene in rat PFC increases susceptibility to stress-induced PFC dysfunction. Rats were trained in a spatial working memory task before receiving infusions of (a) an active viral construct that knocked down Disc1 in PFC (DISC1 KD group), (b) a 'scrambled' construct that had no effect on Disc1 (Scrambled group), or (c) an active construct that reduced DISC1 expression dorsal to PFC (Anatomical Control group). Data were compared with an unoperated Control group. Cognitive performance was assessed following mild restraint stress that had no effect on normal animals. DISC1 KD rats were impaired by 1  h restraint stress, whereas Scrambled, Control, and Anatomical Control groups were unaffected. Thus, knocking down Disc1 in PFC reduced the threshold for stress-induced cognitive dysfunction, possibly through disinhibited cAMP signaling at neuronal network synapses. These findings may explain why patients with DISC1 mutations may be especially vulnerable to the effects of stress.

Abnormal adipogenesis leads to excessive fat accumulation and several health disorders. Mouse fibroblasts (MLC) transfected with ADAM 12S and HB-EGF promoted lipid accumulation. Addition of KBR-7785, an ADAM 12S inhibitor, to HB-EGF/ADAM 12S expressing cells suppressed adipogenesis. BrdU incorporation was attenuated and enhanced mitotracker staining was observed in HB-EGF/ADAM 12S cells. Quantitative real time RT-PCR resulted in elevated levels of expression of three brown adipose tissue (BAT) genes (PRDM16, PGC-1α, and UCP-1), while expression levels of the three white adipose tissue (WAT) genes (PPARγ, C/EBPα, and AKT-1) were unaltered in HB-EGF/ADAM 12S cells. Amino- or carboxy-terminal deletions of HB-EGF (HB-EGFΔN and HB-EGFΔC) co-expressed with ADAM 12S stimulated lipid accumulation. Human epidermoid carcinoma cells (A431) also exhibited lipid accumulation by HB-EGF/ADAM 12S co-expression. These studies suggest ADAM 12S and HB-EGF are involved in cellular plasticity resulting in the production of BAT-like cells and offers insight into novel therapeutic approaches for fighting obesity.

Object: Traumatic brain injury (TBI) is the leading cause of acquired disability in children, yet innate repair mechanisms are incompletely understood. Given data from animal studies documenting neurogenesis in response to trauma and other insults, the authors investigated whether similar responses could be found in children of different ages after TBI., Methods: Immunohistochemistry was used to label doublecortin (DCX), a protein expressed by immature migrating neuroblasts (newborn neurons), in specimens from patients ranging in age from 3 weeks to 10 years who had died either after TBI or from other causes. Doublecortin-positive (DCX+) cells were examined in the subventricular zone (SVZ) and periventricular white matter (PWM) and were quantified within the granule cell layer (GCL) and subgranular zone (SGZ) of the dentate gyrus to determine if age and/or injury affect the number of DCX+ cells in these regions., Results: The DCX+ cells decreased in the SVZ as patient age increased and were found in abundance around a focal subacute infarct in a 1-month-old non-TBI patient, but were scarce in all other patients regardless of age or history of trauma. The DCX+ cells in the PWM and dentate gyrus demonstrated a migratory morphology and did not co-localize with markers for astrocytes, microglia, or macrophages. In addition, there were significantly more DCX+ cells in the GCL and SGZ of the dentate gyrus in children younger than 1 year old than in older children. The density of immature migrating neuroblasts in infants (under 1 year of age) was significantly greater than in young children (2-6 years of age, p = 0.006) and older children (7-10 years of age, p = 0.007)., Conclusions: The main variable influencing the number of migrating neuroblasts observed in the SVZ, PWM, and hippocampus was patient age. Trauma had no discernible effect on the number of migrating neuroblasts in this cohort of patients in whom death typically occurred within hours to days after TBI.

Purpose: To assess the outcomes of the intravitreal administration of methotrexate in uveitis., Methods: Multicenter, retrospective interventional case series of patients with noninfectious uveitis. Thirty-eight eyes of 30 patients were enrolled, including a total of 54 intravitreal injections of methotrexate at a dose of 400 µg in 0.1 mL. The primary outcome measure was visual acuity. Secondary outcome measures included control of intraocular inflammation and cystoid macular edema, time to relapse, development of adverse events, and levels of systemic corticosteroid and immunosuppressive therapy., Results: Methotrexate proved effective in controlling intraocular inflammation and improving vision in 30 of 38 eyes (79%). The side effect profile was good, with no reported serious ocular adverse events and only one patient having an intraocular pressure of >21 mmHg. Of the 30 eyes that responded to treatment, 8 relapsed, but 22 (73%) entered an extended period of remission, with the Kaplan-Meier estimate of median time to relapse for the whole group being 17 months. The eight eyes that relapsed were reinjected and all responded to treatment. One eye relapsed at 3 months, but 7 eyes again entered extended remission. Of the 14 patients on systemic therapy at the start of the study, 8 (57%) were able to significantly reduce this following intravitreal methotrexate injection., Conclusion: In patients with uveitis and uveitic cystoid macular edema, intravitreal MTX can effectively improve visual acuity and reduce cystoid macular edema and, in some patients, allows the reduction of immunosuppressive therapy. Some patients relapse at 3 to 4 months, but a large proportion (73%) enter an extended period of remission of up to 18 months. This larger study extends the results obtained from previous smaller studies suggesting the viability of intravitreal methotrexate as a treatment option in uveitis.

Despite their side-effects and the advent of systemic immunosuppressives and biologics, the use of corticosteroids remains in the management of patients with uveitis, particularly when inflammation is associated with systemic disease or when bilateral ocular disease is present. The use of topical corticosteroids as local therapy for anterior uveitis is well-established, but periocular injections of corticosteroid can also be used to control mild or moderate intraocular inflammation. More recently, intraocular corticosteroids such as triamcinolone and steroid-loaded vitreal inserts and implants have been found to be effective, including in refractory cases. Additional benefits are noted when ocular inflammation is unilateral or asymmetric, when local therapy may preclude the need to increase the systemic medication.Implants in particular have gained prominence with evidence of efficacy including both dexamethasone and fluocinolone loaded devices. However, an appealing avenue of research lies in the development of non-corticosteroid drugs in order to avoid the side-effects that limit the appeal of injected corticosteroids. Several existing drugs are being assessed, including anti-VEGF compounds such as ranibizumab and bevacizumab, anti-tumour necrosis factor alpha antibodies such as infliximab, as well as older cytotoxic medications such as methotrexate and cyclosporine, with varying degrees of success. Intravitreal sirolimus is currently undergoing phase 3 trials in uveitis and other inflammatory pathways have also been proposed as suitable therapeutic targets. Furthermore, the advent of biotechnology is seeing advances in generation of new therapeutic molecules such as high affinity binding peptides or modified high affinity or bivalent single chain Fab fragments, offering higher specificity and possibility of topical delivery.

Objective: To report the 12-month outcomes of the dexamethasone intravitreal implant in retinal vein occlusion (RVO), using an as-needed repeat injection protocol., Design: Retrospective consecutive case series of 51 eyes of 49 patients with macular oedema as a result of RVO that received an intravitreal dexamethasone implant and were followed up for at least 12 months., Results: 70% of patients responded to dexamethasone implant injection with an improvement in visual acuity (VA) and macular oedema within 3 months of injection, but only 30% of eyes gained ≥15 letters. The mean change in VA letter score at 12 months compared with baseline for branch RVO (BRVO) and central RVO (CRVO) was 5.7±2.3 and 11.5±11.0 EDTRS letters, respectively. 56% of patients relapsed, with the median time to relapse being 17 weeks for patients with branch RVO and 18 weeks for patients with CRVO. Repeat injections achieved similar VA gains, but the duration of effect of repeat dexamethasone implants was much shorter at 10 weeks. 14 eyes (27%) developed a significant rise in intraocular pressure, and three of these required treatment with oral acetazolamide. Four eyes with CRVO developed neovascular glaucoma during the study., Conclusions: The intravitreal dexamethasone implant does not last the 6 months implied by the retreatment protocol in the GENEVA trial, and improved results can be achieved with an as-needed retreatment protocol, particularly in CRVO. However, visual outcomes remain similar to those previously seen with triamcinolone in the SCORE study and neovascular complications remain a feature of CRVO.

Background: There is limited literature on the relationship between second to fourth finger digit ratio (2D:4D) and health- and skill-related fitness in children. To examine this relationship it is important to establish a reliable method of assessing 2D:4D for use with large groups of children., Aim: The aim of the study was to examine the reliability of a field-based 2D:4D measure in children. METHODS/RESEARCH DESIGN: Fifty 8-11 year olds had 2D:4D of the right hand measured using a Perspex table top, a digital camera, and Adobe Photoshop software. Second to fourth finger digit ratio (and 2D and 4D) intra-observer and inter-observer reliabilities were assessed on the same day and intraobserver reliability was measured between days. Limits of agreement (LoA), coefficient of variation (CV) and Pearson's correlation coefficient were used for statistical analysis., Results: High correlation coefficients (r=0.95-0.99) and low CV's (0.4-1.2%) were reported for intra- and inter-observer reliabilities on the same day and between days. LoA revealed negligible systematic bias with random error ranging from 0.02 to 0.12., Conclusion: These findings suggest that 2D:4D (and 2D and 4D) assessment in children using digital photography provides a reliable measure of 2D:4D that can be used during field-based testing., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A method for acoustic detection of small explosions at local distances is presented combining a matched filter with a p-value representing the conditional probability of detection. Because the physics of signal generation and propagation for small, locally recorded acoustic signals from small explosions is well understood, the single hypothesis to be tested is a signal corrupted by additive noise. A simple analytical signal representation is used where a known signal is assumed with parameters to be determined. The advantage of the approach is that the detector can be combined with other detectors that measure different signal characteristics all under the same unifying hypothesis.

A methodology for the combined acoustic detection and discrimination of explosions, which uses three discriminants, is developed for the purpose of identifying weak explosion signals embedded in complex background noise. By utilizing physical models for simple explosions that are formulated as statistical hypothesis tests, the detection/discrimination approach does not require a model for the background noise, which can be highly complex and variable in practice. Fisher's Combined Probability Test is used to combine the p-values from all multivariate discriminants. This framework is applied to acoustic data from a 400 g explosion conducted at Los Alamos National Laboratory.

Objective: A novel mouse model with a specific genetic mutation in a G protein coupled receptor (GPCR) encoded by the Oxgr1 gene results in a predisposition to spontaneous otitis media with effusion. As a primary component of interest in OME, mucin expression was examined in this model to assess expression as compared to wild type animals and suitability as a murine model of OME., Method: Mutant (Oxgr1(-/-)) and wild-type (Oxgr1(+/+)) mice between ages of 2 and 5 months were examined by otoscopy and auditory brainstem response (ABR). Histology changes in the middle ear were evaluated. Expression of mucin genes in the middle ear epithelium was determined using RT-PCR and quantitative PCR., Result: Otoscopic exam showed signs of inflammation in 82% of mutant mice. Significant elevated ABR thresholds were detected in mutant mice indicating hearing loss. Histology analysis of the middle ears demonstrated the presence of inflammatory cells, changes in the mucosal epithelium, and middle ear fluid. RT PCR using universal primers for bacterial 18s rRNA suggested the absence of bacteria in the middle ear. The knockout mice demonstrated expression of Muc1, Muc2, Muc3, Muc4, Muc5AC, Muc5B, Muc9, Muc10, Muc13, Muc15, Muc16, Muc18, Muc19 and Muc20. There was a trend of increase in Muc5B and Muc19 expression in the middle ear of the knockout mice compared to that of wild-type. There was no significant change in the level of Muc2, and Muc5AC was expressed at a level below the detection limit of quantification., Conclusion: Development of a murine model with genetic defect has several attractive features. The rate of OME in these animals is high at 82%. It is clear that this OME is related to histopathologic changes in the middle ear epithelium of these knock-out mice. Induction of mucus effusion is evident though the viation in dysregulation of GFM does exist in this non-challenge study condition. The underlying cause of these differences between individual animal requires further investigation. Given this, the Oxgr1(-/-) model is likely to be an ideal model to examine mucin regulation in MEE and potentially develop novel GPCR-specific targeted interventions to regulate these processes., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Treatment of non-infectious uveitis is based primarily on the use of systemic corticosteroids and second-line immunosuppressive drugs. However, their extensive side effect profile, particularly for steroids, has led to the increased use of other immunosuppressive drugs, as sparing capacity agents. Rituximab is an anti-CD20 chimeric antibody, often given as a single course of 2 infusions, resulting in complete depletion of peripheral mature B cells. While it is licensed to treat refractory systemic lymphoma patients, it has also shown promising results in systemic auto-immune diseases, where a single course of treatment is able to achieve long-term clinical remission. Treatment with rituximab has been reported for various ocular conditions, suggesting it may be effective in inducing long-term disease control and other systemic immunosuppressive agents can be reduced or discontinued. When disease relapse occurs, a further course or courses can be given with good results. This review summarizes the current evidence regarding the role of rituximab in treating non-infectious uveitis., (© 2013 S. Karger AG, Basel.)