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 \ud 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 \ud 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

Hydrological Cycle Changes Explain Weak Snowball Earth Storm Track Despite Increased Surface Baroclinicity

Simulations show that storm tracks were weaker during past cold, icy climates relative to the modern climate despite increased surface baroclinicity. Previous work explained the weak North Atlantic storm track during the Last Glacial Maximum using dry zonally asymmetric mechanisms associated with orographic forcing. Here we show that zonally symmetric mechanisms associated with the hydrological cycle explain the weak Snowball Earth storm track. The weak storm track is consistent with the decreased meridional gradient of evaporation and atmospheric shortwave absorption and can be predicted following global mean cooling and the Clausius-Clapeyron relation. The weak storm track is also consistent with decreased latent heat release aloft in the tropics, which decreases upper tropospheric baroclinicity and mean available potential energy. Overall, both hydrological cycle mechanisms are reflected in the significant correlation between storm track intensity and the meridional surface moist static energy gradient across a range of simulated climates between modern and Snowball Earth

An Excess of Jupiter Analogs in Super-Earth Systems

We use radial velocity observations to search for long-period gas giant companions in systems hosting inner super-Earth (1-4 R_Earth, 1-10 M_Earth) planets to constrain formation and migration scenarios for this population. We consistently re-fit published RV datasets for 65 stars and find 9 systems with statistically significant trends indicating the presence of an outer companion. We combine these RV data with AO images to constrain the masses and semi-major axes of these companions. We quantify our sensitivity to the presence of long-period companions by fitting the sample with a power law distribution and find an occurrence rate of 39+/-7% for companions 0.5-20 M_Jup and 1-20 AU. Half of our systems were discovered by the transit method and half were discovered by the RV method. While differences in RV baselines and number of data points between the two samples lead to different sensitivities to distant companions, we find that occurrence rates of gas giant companions in each sample are consistent at the 0.5$\sigma$ level. We compare the frequency of Jupiter analogs in these systems to the equivalent rate from field star surveys and find that Jupiter analogs are more common around stars hosting super-Earths. We conclude that the presence of outer gas giants does not suppress the formation of inner super-Earths, and that these two populations of planets instead appear to be correlated. We also find that the stellar metallicities of systems with gas giant companions are higher than those without companions, in agreement with the well-established metallicity correlation from RV surveys of field stars.Comment: published in A

Profound vision loss impairs psychological well-being in young and middle-aged individuals.

PurposeThe aim of this study was to evaluate the effects of profound vision loss on psychological well-being in adolescents, young adults, and middle-aged adults with regard to mood, interpersonal interactions, and career-related goals. In addition, we assessed the significance of the resources that may be used to enhance psychological well-being in cases of profound vision loss, and in particular, examined the utility of low vision aids and the role of the ophthalmologist as a provider of emotional support.MethodsA questionnaire was issued to individuals aged 13-65 years with profound vision loss resulting from Leber's hereditary optic neuropathy (LHON). Depression prevalence was evaluated with questions regarding major depressive disorder symptomatology. Participants appraised the effects of vision loss on their interpersonal interactions and career goals by providing an impact rating (IR) on a 21-point psychometric scale from -10 to +10. Social well-being index was defined as the average of interpersonal IR and career IR. Subjects were additionally asked about the use of low vision aids and sources of emotional support.ResultsA total of 103 participants (mean age =26.4±11.2 years at LHON diagnosis; mean ± standard deviation) completed the questionnaire. Nearly half (49.5%) met the depression criteria after vision loss. Negative impacts on interpersonal interactions (median IR = -5) and career goals (median IR = -6) were observed; both ratings were worse (P<0.001) for depressed versus nondepressed subjects. Older age at diagnosis corresponded to higher depression prevalence and increased incidence of negative interpersonal IR and career IR. Sixty-eight percent of subjects used electronic vision aids; controlling for age, social well-being index was higher among these individuals than for those who did not use electronic aids (P=0.03). Over half of the participants (52.4%) asserted that they derived emotional support from their ophthalmologist.ConclusionProfound vision loss in adolescents, young adults, and middle-aged adults is associated with significant negative psychological and psychosocial effects, which are influenced by age and use of electronic vision aids. Ophthalmologists, in addition to managing vision loss, may serve an important role in the emotional adaptation of these patients

Enteric nervous system development in avian and zebrafish models

AbstractOur current understanding of the developmental biology of the enteric nervous system (ENS) and the genesis of ENS diseases is founded almost entirely on studies using model systems. Although genetic studies in the mouse have been at the forefront of this field over the last 20 years or so, historically it was the easy accessibility of the chick embryo for experimental manipulations that allowed the first descriptions of the neural crest origins of the ENS in the 1950s. More recently, studies in the chick and other non-mammalian model systems, notably zebrafish, have continued to advance our understanding of the basic biology of ENS development, with each animal model providing unique experimental advantages. Here we review the basic biology of ENS development in chick and zebrafish, highlighting conserved and unique features, and emphasising novel contributions to our general understanding of ENS development due to technical or biological features

Determining Predictor Importance In Multiple Regression Under Varied Correlational And Distributional Conditions

This study examines the performance of eight methods of predictor importance under varied correlational and distributional conditions. The proportion of times a method correctly identified the dominant predictor was recorded. Results indicated that the new methods of importance proposed by Budescu (1993) and Johnson (2000) outperformed commonly used importance methods

The Probability Distribution of Binary Pulsar Coalescence Rate Estimates. II. Neutron Star-White Dwarf Binaries

We consider the statistics of pulsar binaries with white dwarf companions (NS-WD). Using the statistical analysis method developed by Kim et al. (2003) we calculate the Galactic coalescence rate of NS-WD binaries due to gravitational-wave emission. We find that the most likely values for the total Galactic coalescence rate (R_tot) of NS-WD binaries lie in the range 0.2--10 per Myr depending on different assumed pulsar population models. For our reference model, we obtain R_tot=4.11_(-2.56)^(+5.25) per Myr at a 68% statistical confidence level. These rate estimates are not corrected for pulsar beaming and as such they are found to be about a factor of 20 smaller than the Galactic coalescence rate estimates for double neutron star systems. Based on our rate estimates, we calculate the gravitational-wave background due to coalescing NS-WD binaries out to extragalactic distances within the frequency band of the Laser Interferometer Space Antenna. We find the contribution from NS-WD binaries to the gravitational-wave background to be negligible.Comment: 20 pages, 2 figures, 2 tables, Accepted for publication in Ap

Genome analysis of a highly virulent serotype 1 strain of streptococcus pneumoniae from West Africa

Streptococcus pneumoniae is a leading cause of pneumonia, meningitis, and bacteremia, estimated to cause 2 million deaths annually. The majority of pneumococcal mortality occurs in developing countries, with serotype 1 a leading cause in these areas. To begin to better understand the larger impact that serotype 1 strains have in developing countries, we characterized virulence and genetic content of PNI0373, a serotype 1 strain from a diseased patient in The Gambia. PNI0373 and another African serotype 1 strain showed high virulence in a mouse intraperitoneal challenge model, with 20% survival at a dose of 1 cfu. The PNI0373 genome sequence was similar in structure to other pneumococci, with the exception of a 100 kb inversion. PNI0373 showed only15 lineage specific CDS when compared to the pan-genome of pneumococcus. However analysis of non-core orthologs of pneumococcal genomes, showed serotype 1 strains to be closely related. Three regions were found to be serotype 1 associated and likely products of horizontal gene transfer. A detailed inventory of known virulence factors showed that some functions associated with colonization were absent, consistent with the observation that carriage of this highly virulent serotype is unusual. The African serotype 1 strains thus appear to be closely related to each other and different from other pneumococci despite similar genetic content