Kinematics of the Upper Eyelid and the Globe During Downward Excursion With Comparative Analysis in Patients With Thyroid Eye Disease.

PURPOSE: To analyze the kinematics of the upper eyelid and the globe on downward excursion for potential use in monitoring thyroid eye disease (TED) progression in an objective manner. METHODS: Ten normal volunteers and 10 patients with TED were studied. A high-speed (240 fps) digital camera with a coaxial light source set at a constant distance from the subjects' eyes was used to record the excursion of the upper eyelid and the globe from extreme upgaze to extreme downgaze. Clinical data, including age, gender, race, thyroid function tests, Vision, Inflammation/Congestion, Strabismus/motility restriction, Appearance/exposure score (primary surgeons' preference of TED grading system), exophthalmometry, and eyelid measurements were collected for all patients with TED. Frame-by-frame analyses of the videos were performed using Python software (version 3.6) and the Open Source Computer Vision Library. Temporal resolution was obtained by measuring the number of frames from initiation of eyelid and globe movement from extreme upgaze (t 0 ) to extreme downgaze (t f ). Spatial resolution was obtained by measuring the number of pixels the eyelid margin and the globe traversed from t 0 to t f . The data were then plotted on a graph to calculate the velocity of the upper eyelid and the globe during downward excursion. RESULTS: Velocimetric calculations using high-speed photography suggests that downward excursion of the upper eyelid, and the globe occurs in 2 phases: the acceleration phase and the deceleration phase. Comparative analysis of slow-motion videography demonstrates that patients with TED were found to have attenuation in the early acceleration phase of upper eyelid excursion compared with normal subjects. In patients with TED, the difference in velocity between the eyelid and the globe occurs in the early deceleration phase. CONCLUSIONS: The upper eyelid normally synchronizes intimately with the globe during downward eye movement. Data from this study reveal that attenuation mostly in the early deceleration phase of eyelid movement relative to the globe accounts for the dynamic eyelid lag seen on clinical examination. Further analysis is needed to show if a quantified von Graefe sign can be used as an objective means of monitoring progression in TED.

Structural and Functional Characterization of Dynamic Oligomerization in Burkholderia cenocepacia HMG-CoA Reductase.

The enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR), in most organisms, catalyzes the four-electron reduction of the thioester (S)-HMG-CoA to the primary alcohol (R)-mevalonate, utilizing NADPH as the hydride donor. In some organisms, including the opportunistic lung pathogen Burkholderia cenocepacia, it catalyzes the reverse reaction, utilizing NAD+ as a hydride acceptor in the oxidation of mevalonate. B. cenocepacia HMGR has been previously shown to exist as an ensemble of multiple non-additive oligomeric states, each with different levels of enzymatic activity, suggesting that the enzyme exhibits characteristics of the morpheein model of allostery. We have characterized a number of factors, including pH, substrate concentration, and enzyme concentration, that modulate the structural transitions that influence the interconversion among the multiple oligomers. We have also determined the crystal structure of B. cenocepacia HMGR in the hexameric state bound to coenzyme A and ADP. This hexameric assembly provides important clues about how the transition among oligomers might occur, and why B. cenocepacia HMGR, unique among characterized HMGRs, exhibits morpheein-like behavior.

Prospective External Validation of Three Preoperative Risk Scores for Prediction of New Onset Atrial Fibrillation After Cardiac Surgery.

BACKGROUND: Postoperative atrial fibrillation (POAF) is associated with early and late morbidity and mortality of cardiac surgical patients. Prophylactic treatment of atrial fibrillation (AF) has been recommended to improve outcome in cardiac surgical patients at high risk of developing POAF. Reliable models for prediction of POAF are needed to achieve that goal. This study attempted to externally validate 3 risk models proposed for preoperative prediction of POAF in cardiac surgical patients: the POAF score, the CHA2DS2-VASc score, and the Atrial Fibrillation Risk Index. METHODS: This was a prospective cohort study of 1416 adult patients who underwent nonemergent coronary artery bypass graft and/or valve surgery in a single cardiac surgical center between February 2014 and September 2015. A risk score for each of the 3 prediction models was calculated in each patient. All patients were followed for up to 2 weeks, or until hospital discharge, to observe the primary outcome of new onset AF requiring treatment. Discrimination was assessed using receiver operating characteristic curves. Calibration was assessed using the Pearson χ goodness-of-fit test and calibration plots. Utility of the score to implement AF prophylaxis based on the risk of POAF, in comparison to strategies of treating all patients, or not treating any patients, was assessed via a net benefit analysis. RESULTS: Of the 1416 patients included in this study, 478 had the primary outcome (33.8%). The areas under the receiver operating characteristic curve for prediction of POAF in the population subsets for which the scores were validated were as follows: 0.651 (95% confidence interval [CI], 0.621-0.681) for the POAF score, 0.593 (95% CI, 0.557-0.629) for the CHA2DS2-VASc score (P < .001 versus POAF score, P < .222 versus Atrial Fibrillation Risk Index), and 0.563 (95% CI, 0.522-0.604) for the Atrial Fibrillation Risk Index (P < .001 versus POAF score). The calibration analysis showed that the predictive models had a poor fit between the observed and expected rates of POAF. Net benefit analysis showed that AF preventive strategies based on these scores, and targeting patients with moderate or high risk of POAF, improve decision-making in comparison to preventive strategies of treating all patients. CONCLUSIONS: The 3 prediction scores evaluated in this study have limited ability to predict POAF in cardiac surgical patients. Despite this, they may be useful in preventive strategies targeting patients with moderate or high risk of PAOF in comparison with preventive strategies applied to all patients.

Apremilast Use in a Case of Cicatricial Ectropion Secondary to Severe Lamellar Ichthyosis.

Ichthyosis is a cutaneous disorder characterized by excessive amounts of dry thickened skin surface scales. Ocular manifestations of ichthyosis include cicatricial ectropion, which may cause exposure keratoconjunctivitis and rarely corneal perforation. Topical emollients, anti-inflammatory ointments, and systemic retinoids have been used to control the disease process, while surgical correction with donor graft has been reserved for severe cases involving corneal exposure. The authors report a case of a Caucasian male with lamellar ichthyosis with severe bilateral upper and lower eyelid cicatricial ectropion and corneal ulceration requiring surgical correction. Treatment with apremilast, a novel phosphodiesterase-4 inhibitor, for the treatment of a concomitant plaque psoriasis achieved good control of his skin diseases and minimized the recurrence of eyelid ectropion.

The diagnosis and management of the Spitz nevus in the pediatric population: a systematic review and meta-analysis protocol.

BACKGROUND: Spitz nevi are uncommon melanocytic neoplasms found in children. Historically, the diagnosis and management of these tumors has lacked consensus among oncologists, pathologists, plastic surgeons, and dermatologists. Once interpreted and treated as a "juvenile melanoma", many have argued for the benignancy of such tumors in certain patient age groups, encouraging a conservative approach. The lack of consensus surrounding the diagnosis and perceived malignant potential of these tumors has led physicians to approach them on a case-by-case basis and institutional protocols. To date, no evidence-based management guideline exists. The objective of this systematic review is to both collect and appraise the evidence on the diagnosis and management of these tumors. METHODS: A comprehensive electronic literature search will be conducted in PubMed, MEDLINE, Embase, and the Cochrane Library from inception to December 2016. Our search involved collaborating with a healthcare librarian to create a strategy for the OVID/MEDLINE databases. A search of electronic databases for oncology, pathology, plastic surgery, and dermatology abstracts will be performed. Key search terms will include, among several others, "Spitz nevi," "Spitzoid melanoma," "juvenile tumor," and "pediatric". The language of publication will be restricted to English and French. Wherever data allows, meta-analyses will be used to assess differences between Spitz nevi and the tumor of comparison. Additionally, data extraction and summarization using tables will be performed. This review has been registered with PROSPERO (CRD42016034045). CONCLUSIONS: This review will systematically and comprehensively review diagnostic and management practices associated with the Spitz nevus. This overview of current literature will hopefully provide the foundation for future standardization of clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016034045.

Orbital and Orbitocranial Trauma From Pencil Fragments: Role of Timely Diagnosis and Management.

PURPOSE: To emphasize the importance of early detection and radiologic evaluation of retained organic foreign bodies (FBs) in orbital or orbitocranial penetrating injuries by pencil. DESIGN: Retrospective case series. METHODS: A retrospective chart review of patients who had penetrating orbital or orbitocranial trauma at 2 tertiary hospitals was conducted. Patients whose mechanism of injury was penetrating trauma by pencil were included. The patients' demographics, time between initial trauma and detection of foreign body, radiologic images, and resulting sequelae were reviewed. RESULTS: Four patients were included in this study. All patients were male; 3 were less than 2 years of age and 1 was 34 years old. Accidents were witnessed in 2 cases, and initial detections of FBs were delayed in 3 cases, from 2 days to 7 weeks. Three cases involved the right orbit. Computed tomography (CT) imaging of the head demonstrated penetration of the orbital walls in 3 cases. Three-dimensional CT scans were used to differentiate the penetrating graphite pencil fragments from the orbital wall, and catheter angiography was used in 1 case of suspected orbital apex penetration. Vision was lost in 1 patient while other severe neurologic deficits were fully recovered after removal of FB. CONCLUSIONS: Penetrating injury by pencils to the periorbital structures and delayed detection of retained pencil fragments can result in threat to life and vision. Radiologic examinations are essential to the detection of these retained FBs. Prompt detection and removal of the FBs within 48 hours and treatment with antibiotics can save vision and life.

p16INK4A expression is frequently increased in periorbital and ocular squamous lesions.

BACKGROUND: p16 expression is a well established biomarker of cervical dysplasia and carcinoma arising from high risk human papilloma virus infection. Increased p16 expression is also seen in squamous neoplasms arising at other sites, including head, neck, and oropharyngeal tract. Squamous lesions are also frequently encountered at ocular surface and peri-orbital skin sites, but the prevalence of increased p16 expression in these lesions has been poorly studied. METHODS: We retrospectively surveyed 13 ocular surface and 16 orbital squamous lesions biopsied at UC San Diego Healthcare System and VA San Diego Healthcare System for p16 expression by immunohistochemistry. These cases included ocular surface lesions with diagnoses of conjunctival intraepithelial neoplasm (CIN) and squamous cell carcinoma in situ. Peri-orbital eyelid biopsies included lesions with diagnoses of SCCis and invasive squamous cell carcinoma. We performed multivariate logistic regression, followed by student's T-test or Fisher's exact test to determine if there were statistically significant associations between p16 immunoreactivity and patient age, gender, diagnosis, and ethnicity. Statistical significance was defined as p < 0.05. RESULTS: We found an unexpectedly large prevalence of strong nuclear and cytoplasmic p16 immunoreactivity in our cases. Almost all of the ocular surface squamous lesions were diffusely positive for p16 expression (12/13). All of the periorbital lesions showed diffuse p16 immunoreactivity (16/16). Altogether, 28/29 lesions tested showed strong and diffuse p16 expression. We found no statistically significant correlation between p16 expression and patient age, gender, ethnicity, or diagnosis. In 6 of the peri-orbital biopsies, we had sufficient tissue to assess high-risk HPV expression by in situ hybridization. Interestingly, all of these cases were negative for HPV, despite strong p16 expression. CONCLUSION: Strong p16 expression was observed in virtually all of the ocular surface and peri-orbital squamous neoplasms in our study. The relationship between p16 expression and HPV infection in ocular surface and peri-orbital sites requires further investigation.

Novel control of lactate dehydrogenase from the freeze tolerant wood frog: role of posttranslational modifications.

Lactate dehydrogenase (LDH), the terminal enzyme of anaerobic glycolysis, plays a crucial role both in sustaining glycolytic ATP production under oxygen-limiting conditions and in facilitating the catabolism of accumulated lactate when stress conditions are relieved. In this study, the effects on LDH of in vivo freezing and dehydration stresses (both of which impose hypoxia/anoxia stress on tissues) were examined in skeletal muscle of the freeze-tolerant wood frog, Rana sylvatica. LDH from muscle of control, frozen and dehydrated wood frogs was purified to homogeneity in a two-step process. The kinetic properties and stability of purified LDH were analyzed, revealing no significant differences in V max, K m and I 50 values between control and frozen LDH. However, control and dehydrated LDH differed significantly in K m values for pyruvate, lactate, and NAD, I 50 urea, and in temperature, glucose, and urea effects on these parameters. The possibility that posttranslational modification of LDH was responsible for the stable differences in enzyme behavior between control and dehydrated states was assessed using ProQ diamond staining to detect phosphorylation and immunoblotting to detect acetylation, methylation, ubiquitination, SUMOylation and nitrosylation of the enzyme. LDH from muscle of dehydrated wood frogs showed significantly lower levels of acetylation, providing one of the first demonstrations of a potential role for protein acetylation in the stress-responsive control of a metabolic enzyme.

Inhibition of apoptosis prevents shear-induced detachment of endothelial cells.

BACKGROUND: Biomaterials placed into the vasculature in man fail to develop an endothelial lining. Attempts to seed endothelial cells (ECs) on prosthetic vascular grafts have failed due to flow-induced detachment. The mechanism of flow-induced detachment of ECs from biomaterials is undefined. We hypothesize that endothelial detachment from biomaterials is caused by flow-induced apoptosis related to the inability of human ECs to adapt to and withstand mechanical loading. MATERIALS AND METHODS: Human aortic endothelial cells were cultured on Dacron membranes, incubated in the presence or absence of a caspase inhibitor (Z-VAD-FMK), and exposed to 0, 1, 10, 20, or 30 dynes/cm(2) of shear stress for 2, 6, 12, and 24 h in a parallel plate bioreactor. The percent of ECs detached was determined and compared with no-flow controls. Apoptosis was determined by analyzing nuclear morphology and identifying cells with caspase activity using FAM-VAD-FMK. The actin cytoskeleton of cells was visualized with fluorescein phalloidin. RESULTS: Increasing shear stress resulted in detachment of ECs from the Dacron membranes, which was associated with increased apoptosis of the residual cells adherent to the membrane determined by both nuclear morphology and caspase activity. Significantly, treatment with the caspase inhibitor Z-VAD-FMK resulted in improved EC retention following exposure to high shear stress (20 and 30 dynes/cm(2)). The majority of apoptosis and detachment were determined to occur after 6 h. CONCLUSIONS: We have demonstrated that high shear stress-induced EC detachment from Dacron is an apoptosis-dependent phenomenon that can be pharmacologically inhibited by a pan-caspase inhibitor.