Replicated linkage for eye color on 15q using comparative ratings of sibling pairs

The aim of the study was to perform a genetic linkage analysis for eye color, for comparative data. Similarity in eye color of mono- and dizygotic twins was rated by the twins' mother, their father and/or the twins themselves. For 4748 twin pairs the similarity in eye color was available on a three point scale (not at all alike-somewhat alike-completely alike), absolute eye color on individuals was not assessed. The probability that twins were alike for eye color was calculated as a weighted average of the different responses of all respondents on several different time points. The mean probability of being alike for eye color was 0.98 for MZ twins (2167 pairs), whereas the mean probability for DZ twins was 0.46 (2537 pairs), suggesting very high heritability for eye color. For 294 DZ twin pairs genome-wide marker data were available. The probability of being alike for eye color was regressed on the average amount of IBD sharing. We found a peak LOD-score of 2.9 at chromosome 15q, overlapping with the region recently implicated for absolute ratings of eye color in Australian twins [Zhu, G., Evans, D. M., Duffy, D. L., Montgomery, G. W., Medland, S. E., Gillespie, N. A., Ewen, K. R., Jewell, M., Liew, Y. W., Hayward, N. K., Sturm, R. A., Trent, J. M., and Martin, N. G. (2004). Twin Res. 7:197-210] and containing the OCA2 gene, which is the major candidate gene for eye color [Sturm, R. A. Teasdale, R. D, and Box, N. F. (2001). Gene 277:49-62]. Our results demonstrate that comparative measures on relatives can be used in genetic linkage analysis.

Pig eye trabeculectomy - a wet-lab teaching model

Purpose A teaching model for trabeculectomy is described using pig eyes prepared in formalin. Method The model enables trainee surgeons to practice various aspects of tissue handling required for successful trabeculectomy including the construction of a fornix-based conjunctival flap, scleral flap with buried releasable sutures, and water-tight conjunctival closure. Results Exposure to the necessary skills required to perform trabeculectomy surgery can be improved by the use of wet laboratory practice. Conclusions Trabeculectomy surgery experience is becoming more limited as fewer procedures are being performed due to the efficacy of recent medications. Wet laboratories will become an increasingly important aspect of a comprehensive ophthalmology training programme.

The temporal and spatial limits of compensation for fixational eye movements

High-fidelity eye tracking is combined with a perceptual grouping task to provide insight into the likely mechanisms underlying the compensation of retinal image motion caused by movement of the eyes. The experiments describe the covert detection of minute temporal and spatial offsets incorporated into a test stimulus. Analysis of eye motion on individual trials indicates that the temporal offset sensitivity is actually due to motion of the eye inducing artificial spatial offsets in the briefly presented stimuli. The results have strong implications for two popular models of compensation for fixational eye movements, namely efference copy and image-based models. If an efference copy model is assumed, the results place constraints on the spatial accuracy and source of compensation. If an image-based model is assumed then limitations are placed on the integration time window over which motion estimates are calculated. (c) 2006 Elsevier Ltd. All rights reserved.

Unraveling the molecular underpinnings of Philadelphia-negative myeloproliferative neoplasms: implications for future therapeutic strategies

The present thesis encompasses the two researches projects I conducted during my PhD program in Molecular Biology and Pathology. The common thread is represented by the analysis of the signaling pathways implicated in the pathophysiology of the two most aggressive Philadelphia-negative myeloproliferative neoplasms, namely, atypical chronic myeloid leukemia (aCML) and primary myelofibrosis (PMF). In the last decade, since the description of the JAK2V617F mutation in 2005, the field of the molecular characterization of Philadelphia-negative myeloproliferative neoplasms has experienced an astonishing implementation that led to the discovery of 16 new mutations involving signal transduction, epigenetic modifiers, cell cycle regulators. Nevertheless, their pathogenetic relevance and whether they could represent good “druggable” candidates have to be proved yet. In the first section I provide the first report of the signaling cascade down-stream the rare cytogenetic lesion t(8;9)(p22;p24)/PCM1-JAK2 associated with aCML, finding that it selectively activates the ERK1/2 signaling without affecting JAK/STAT phosphorylation. In the second part, I investigated the implication of the ε isoform of novel Protein kinase Cs (PKCs) in the pathophysiology of the aberrant megakaryocytopoiesis in PMF, concluding that the over-expression of PKCε detains a crucial relevance in the aberrant behavior of PMF megakaryocytes and its inhibition is capable to restore their normal differentiation and abrogate the anti-apoptotic signaling. Both results are discussed in the view of their therapeutic implications. In case PCM1/JAK2-related hematologic neoplasms, ERK-inhibitors rather than JAK-inhibitors (i.e. ruxolitinib) should be considered as a “tailored” drugs. In case of PMF, PKCε-inhibitors (i.e. εV1-2 peptide) configure as an appealing strategy to re-direct the megakaryocytic neoplastic clone.

Objective grading of the anterior eye

Purpose. To convert objective image analysis of anterior ocular surfaces into recognisable clinical grades, in order to provide a more sensitive and reliable equivalent to current subjective grading methods; a prospective, randomized study correlating clinical grading with digital image assessment. Methods. The possible range of clinical presentations Of bulbar and palpebral hyperaemia, palpebral roughness and corneal staining were represented by 4 sets of 10 images. The images were displayed in random order and graded by 50 clinicians using both subjective CCLRU and Efron grading scales. Previously validated objective image analysis was performed 3 times oil each of the 40 images. Digital measures included edge-detection and relative-coloration components. Step-wise regression analysis determined correlations between the average subjective grade and the objective image analysis measures. Results. Average subjective grades Could be predicted by a combination of the objective image analysis components. These digital ``grades'' accounted for between 69%, (for Efron scale-graded palpebral redness) and 98% (for Efron scale-graded bulbar hyperaemia) of the subjective variance. Conclusions. The results indicate that clinicians may use a combination of vessel areas and overall hue in their judgment of clinical severity for certain conditions. Objective grading call take these aspects into account, and be used to predict an average ``objective grade'' to be used by a clinician in describing the anterior eye. These measures are more sensitive and reliable than subjective grading while still utilizing familiar terminology, and can be applied in research or practice to improve the detection, and monitoring of ocular surface changes.

Eye infections caused by fungi (ocular mycoses)

Ocular mycoses are being reported with increasing frequency as a consequence of new medical practice and an increase in the number of immunosuppressed patients in the population, e.g.,, patients who are HIV positive and patients receiving radiation or chemotherapy. This article describes the ocular mycoses likely to be seen in such patients.