2,217 research outputs found
A solute gradient in the tear meniscus I. A hypothesis to explain Marx's line
Marx's line is a line of mucosal staining behind the mucocutaneous junction. It can be demonstrated throughout life in all normal lids by staining with lissamine green and related dyes. Of all the body orifices, only the mucosae of the eye and mouth are directly exposed to the atmosphere. In this paper, we suggest that for the eye, this exposure leads to the formation of Marx's line. The tear meniscus thins progressively toward its apex, where it is pinned at the mucocutaneous junction of the lid. It also thins toward the black line, which segregates the meniscus from the tear film after the blink. We predict that, because of the geometry of the tear meniscus, evaporation generates a solute gradient across the meniscus profile in the anteroposterior plane, which peaks at the meniscus apices at the end of the interblink. One outcome would be to amplify the level of tear molarity at these sites so that they reach hyperosmolar proportions. Preliminary mathematical modeling suggests that dilution of this effect by advection and diffusion of solute away from the meniscus apex at the mucocutaneous junction will be restricted by spatial constraints, the presence of tear and surface mucins at this site, and limited fluid flow. We conclude that evaporative water loss from the tear meniscus may result in a physiological zone of hyperosmolar and related stresses to the occlusal conjunctiva, directly behind the mucocutaneous junction. We hypothesize that this stimulates a high epithelial cell turnover at this site, incomplete epithelial maturation, and a failure to express key molecules such as MUC 16 and galectin-3, which, with the tight junctions between surface epithelial cells, are necessary to seal the ocular surface and prevent penetration of dyes and other molecules into the epithelium. This is proposed as the basis for Marx's line. In Part II of this paper (also published in this issue of The Ocular Surface), we address additional pathophysiological consequences of this mechanism, affecting lid margins
A solute gradient in the tear meniscus II. implications for lid margin disease, including meibomian gland dysfunction
We have hypothesized previously that evaporation from the tears generates a solute gradient across the tear meniscus, which delivers hyperosmolar stress to the mucocutaneous junction (MCJ) of the lid margin. This is proposed as the basis for Marx's line, a line of staining with topically applied dyes that lies directly behind the MCJ. In this article, we consider the implications of this hypothesis for progressive damage to the lid margin as an age-related phenomenon, its amplification in dry eye states, and its possible role in the etiology of meibomian gland dysfunction (MGD). It is suggested that a hyperosmolar or related stimulus, acting behind the MCJ over a lifetime, promotes the anterior migration of the MCJ, which is a feature of the aging lid margin. This mechanism would be amplified in dry eye states, not only by reason of increased tear molarity at the meniscus apex but also by raising the concentration of inflammatory peptides at this site. This could explain the increased width and irregularity of Marx's line in dry eye. While the presence of stem cells at the lid margin may equip this region to respond to such stress, their depletion could be the basis of irreversible lid margin damage. It is further proposed, given the proximity of the MCJ to the meibomian gland orifices, that the solute gradient mechanism could play a role in the initiation of MGD by delivering hyperosmolar and inflammatory stresses to the terminal ducts and orifices of the glands. By the same token, the presence of a zone of increased epithelial permeability in this region may provide a back door route for the delivery of drugs in the treatment of MGD
A mass and solute balance model for tear volume & osmolarity in the normal and the dry eye
Tear hyperosmolarity is thought to play a key role in the mechanism of dry eye, a common symptomatic condition accompanied by visual disturbance, tear film instability, inflammation and damage to the ocular surface. We have constructed a model for the mass and solute balance of the tears, with parameter estimation based on extensive data from the literature which permits the influence of tear evaporation, lacrimal flux and blink rate on tear osmolarity to be explored. In particular the nature of compensatory events has been estimated in aqueous-deficient (ADDE) and evaporative (EDE) dry eye.\ud
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The model reproduces observed osmolarities of the tear meniscus for the healthy eye and predicts a higher concentration in the tear film than meniscus in normal and dry eye states. The differential is small in the normal eye, but is significantly increased in dry eye, especially for the simultaneous presence of high meniscus concentration and low meniscus radius. This may influence the interpretation of osmolarity values obtained from meniscus samples since they need not fully reflect potential damage to the ocular surface caused by tear film hyperosmolarity.\ud
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Interrogation of the model suggests that increases in blink rate may play a limited role in compensating for a rise in tear osmolarity in ADDE but that an increase in lacrimal flux, together with an increase in blink rate, may delay the development of hyperosmolarity in EDE. Nonetheless, it is predicted that tear osmolarity may rise to much higher levels in EDE than ADDE before the onset of tear film breakup, in the absence of events at the ocular surface which would independently compromise tear film stability. Differences in the predicted responses of the pre-ocular tears in ADDE compared to EDE or hybrid disease to defined conditions suggest that no single, empirically-accessible variable can act as a surrogate for tear film concentration and the potential for ocular surface damage. This emphasises the need to measure and integrate multiple diagnostic indicators to determine outcomes and prognosis. Modelling predictions in addition show that further studies concerning the possibility of a high lacrimal flux phenotype in EDE are likely to be profitable
Standardized evaluation of algorithms for computer-aided diagnosis of dementia based on structural MRI: The CADDementia challenge
Algorithms for computer-aided diagnosis of dementia based on structural MRI have demonstrated high performance in the literature, but are difficult to compare as different data sets and methodology were used for evaluation. In addition, it is unclear how the algorithms would perform on previously unseen data, and thus, how they would perform in clinical practice when there is no real opportunity to adapt the algorithm to the data at hand. To address these comparability, generalizability and clinical applicability issues, we organized a grand challenge that aimed to objectively compare algorithms based on a clinically representative multi-center data set. Using clinical practice as the starting point, the goal was to reproduce the clinical diagnosis. Therefore, we evaluated algorithms for multi-class classification of three diagnostic groups: patients with probable Alzheimer's disease, patients with mild cognitive impairment and healthy controls. The diagnosis based on clinical criteria was used as reference standard, as it was the best available reference despite its known limitations. For evaluation, a previously unseen test set was used consisting of 354 T1-weighted MRI scans with the diagnoses blinded. Fifteen research teams participated with a total of 29 algorithms. The algorithms were trained on a small training set (n = 30) and optionally on data from other sources (e.g., the Alzheimer's Disease Neuroimaging Initiative, the Australian Imaging Biomarkers and Lifestyle flagship study of aging). The best performing algorithm yielded an accuracy of 63.0% and an area under the receiver-operating-characteristic curve (AUC) of 78.8%. In general, the best performances were achieved using feature extraction based on voxel-based morphometry or a combination of features that included volume, cortical thickness, shape and intensity. The challenge is open for new submissions via the web-based framework: http://caddementia.grand-challenge.org
Direct Measurements of the Transport of Nonequilibrium Electrons in Gold Films with Different Crystal Structures
The transport of femtosecond-laser-excited nonequilibrium electrons across polycrystalline and single-crystalline gold films has been investigated through time-of-flight measurements. The thicknesses of the films range from 25 to 400 nm. Ballistic electrons as well as electrons interacting with other electrons and/or with the lattice have been observed. The ballistic component dominates the transport in the thinner films, whereas the interactive transport mechanism is dominant at the upper end of the thickness range. A slower effective velocity of the interactive component is observed in the polycrystalline samples, and is assumed to arise from the presence of grain boundaries. The reflection coefficient of excited electrons at the grain boundaries is extracted from the experiment and is estimated to be r=0.12. The experiment also suggests that thermal equilibrium among the excited electrons is not fully established in the first 500 fs after excitation. © 1993 The American Physical Society
Disease Progression Timeline Estimation for Alzheimer's Disease using Discriminative Event Based Modeling
Alzheimer's Disease (AD) is characterized by a cascade of biomarkers becoming
abnormal, the pathophysiology of which is very complex and largely unknown.
Event-based modeling (EBM) is a data-driven technique to estimate the sequence
in which biomarkers for a disease become abnormal based on cross-sectional
data. It can help in understanding the dynamics of disease progression and
facilitate early diagnosis and prognosis. In this work we propose a novel
discriminative approach to EBM, which is shown to be more accurate than
existing state-of-the-art EBM methods. The method first estimates for each
subject an approximate ordering of events. Subsequently, the central ordering
over all subjects is estimated by fitting a generalized Mallows model to these
approximate subject-specific orderings. We also introduce the concept of
relative distance between events which helps in creating a disease progression
timeline. Subsequently, we propose a method to stage subjects by placing them
on the estimated disease progression timeline. We evaluated the proposed method
on Alzheimer's Disease Neuroimaging Initiative (ADNI) data and compared the
results with existing state-of-the-art EBM methods. We also performed extensive
experiments on synthetic data simulating the progression of Alzheimer's
disease. The event orderings obtained on ADNI data seem plausible and are in
agreement with the current understanding of progression of AD. The proposed
patient staging algorithm performed consistently better than that of
state-of-the-art EBM methods. Event orderings obtained in simulation
experiments were more accurate than those of other EBM methods and the
estimated disease progression timeline was observed to correlate with the
timeline of actual disease progression. The results of these experiments are
encouraging and suggest that discriminative EBM is a promising approach to
disease progression modeling
Transcriptomic comparison of communally reared wild, domesticated and hybrid Atlantic salmon fry under stress and control conditions
Background Domestication is the process by which organisms become adapted to the human-controlled environment. Since the selection pressures that act upon cultured and natural populations differ, adaptations that favour life in the domesticated environment are unlikely to be advantageous in the wild. Elucidation of the differences between wild and domesticated Atlantic salmon may provide insights into some of the genomic changes occurring during domestication, and, help to predict the evolutionary consequences of farmed salmon escapees interbreeding with wild conspecifics. In this study the transcriptome of the offspring of wild and domesticated Atlantic salmon were compared using a common-garden experiment under standard hatchery conditions and in response to an applied crowding stressor. Results Transcriptomic differences between wild and domesticated crosses were largely consistent between the control and stress conditions, and included down-regulation of environmental information processing, immune and nervous system pathways and up-regulation of genetic information processing, carbohydrate metabolism, lipid metabolism and digestive and endocrine system pathways in the domesticated fish relative to their wild counterparts, likely reflective of different selection pressures acting in wild and cultured populations. Many stress responsive functions were also shared between crosses and included down-regulation of cellular processes and genetic information processing and up-regulation of some metabolic pathways, lipid and energy in particular. The latter may be indicative of mobilization and reallocation of energy resources in response to stress. However, functional analysis indicated that a number of pathways behave differently between domesticated and wild salmon in response to stress. Reciprocal F1 hybrids permitted investigation of inheritance patterns that govern transcriptomic differences between these genetically divergent crosses. Additivity and maternal dominance accounted for approximately 42 and 25% of all differences under control conditions for both hybrids respectively. However, the inheritance of genes differentially expressed between crosses under stress was less consistent between reciprocal hybrids, potentially reflecting maternal environmental effects. Conclusion We conclude that there are transcriptomic differences between the domesticated and wild salmon strains studied here, reflecting the different selection pressures operating on them. Our results indicate that stress may affect certain biological functions differently in wild, domesticated and hybrid crosses and these should be further investigated
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