Reduced Retinal Function in the Absence of Nav1.6

Background: Mice with a function-blocking mutation in the Scn8a gene that encodes Nav1.6, a voltage-gated sodium channel (VGSC) isoform normally found in several types of retinal neurons, have previously been found to display a profoundly abnormal dark adapted flash electroretinogram. However the retinal function of these mice in light adapted conditions has not been studied. Methodology/Principal Findings: In the present report we reveal that during light adaptation these animals are shown to have electroretinograms with significant decreases in the amplitude of the a- and b-waves. The percent decrease in the a-and b-waves substantially exceeds the acute effect of VGSC block by tetrodotoxin in control littermates. Intravitreal injection of CoCl 2 or CNQX to isolate the a-wave contributions of the photoreceptors in littermates revealed that at high background luminance the cone-isolated component of the a-wave is of the same amplitude as the a-wave of mutants. Conclusions/Significance: Our results indicate that Scn8a mutant mice have reduced function in both rod and the cone retinal pathways. The extent of the reduction in the cone pathway, as quantified using the ERG b-wave, exceeds the reduction seen in control littermates after application of TTX, suggesting that a defect in cone photoreceptors contributes to the reduction. Unless the postreceptoral component of the a-wave is increased in Scn8a mutant mice, the reduction in the b-wave is larger than can be accounted for by reduced photoreceptor function alone. Our data suggests that th

Stroke genetics: prospects for personalized medicine.

Epidemiologic evidence supports a genetic predisposition to stroke. Recent advances, primarily using the genome-wide association study approach, are transforming what we know about the genetics of multifactorial stroke, and are identifying novel stroke genes. The current findings are consistent with different stroke subtypes having different genetic architecture. These discoveries may identify novel pathways involved in stroke pathogenesis, and suggest new treatment approaches. However, the already identified genetic variants explain only a small proportion of overall stroke risk, and therefore are not currently useful in predicting risk for the individual patient. Such risk prediction may become a reality as identification of a greater number of stroke risk variants that explain the majority of genetic risk proceeds, and perhaps when information on rare variants, identified by whole-genome sequencing, is also incorporated into risk algorithms. Pharmacogenomics may offer the potential for earlier implementation of 'personalized genetic' medicine. Genetic variants affecting clopidogrel and warfarin metabolism may identify non-responders and reduce side-effects, but these approaches have not yet been widely adopted in clinical practice

Snakebite and its socio-economic impact on the rural population of Tamil Nadu, India

BACKGROUND: Snakebite represents a significant health issue worldwide, affecting several million people each year with as many as 95,000 deaths. India is considered to be the country most affected, but much remains unknown about snakebite incidence in this country, its socio-economic impact and how snakebite management could be improved. METHODS/PRINCIPAL FINDINGS: We conducted a study within rural villages in Tamil Nadu, India, which combines a household survey (28,494 people) of snakebite incidence with a more detailed survey of victims in order to understand the health and socio-economic effects of the bite, the treatments obtained and their views about future improvements. Our survey suggests that snakebite incidence is higher than previously reported. 3.9% of those surveyed had suffered from snakebite and the number of deaths corresponds to 0.45% of the population. The socio-economic impact of this is very considerable in terms of the treatment costs and the long-term effects on the health and ability of survivors to work. To reduce this, the victims recommended improvements to the accessibility and affordability of antivenom treatment. CONCLUSIONS: Snakebite has a considerable and disproportionate impact on rural populations, particularly in South Asia. This study provides an incentive for researchers and the public to work together to reduce the incidence and improve the outcomes for snake bite victims and their families

Circadian Rhythms of Fetal Liver Transcription Persist in the Absence of Canonical Circadian Clock Gene Expression Rhythms In Vivo

The cellular circadian clock and systemic cues drive rhythmicity in the transcriptome of adult peripheral tissues. However, the oscillating status of the circadian clocks in fetal tissues, and their response to maternal cues, are less clear. Most clock genes do not cycle in fetal livers from mice and rats, although tissue level rhythms rapidly emerge when fetal mouse liver explants are cultured in vitro. Thus, in the fetal mouse liver, the circadian clock does not oscillate at the cellular level (but is induced to oscillate in culture). To gain a comprehensive overview of the clock status in the fetal liver during late gestation, we performed microarray analyses on fetal liver tissues. In the fetal liver we did not observe circadian rhythms of clock gene expression or many other transcripts known to be rhythmically expressed in the adult liver. Nevertheless, JTK_CYCLE analysis identified some transcripts in the fetal liver that were rhythmically expressed, albeit at low amplitudes. Upon data filtering by coefficient of variation, the expression levels for transcripts related to pancreatic exocrine enzymes and zymogen secretion were found to undergo synchronized daily fluctuations at high amplitudes. These results suggest that maternal cues influence the fetal liver, despite the fact that we did not detect circadian rhythms of canonical clock gene expression in the fetal liver. These results raise important questions on the role of the circadian clock, or lack thereof, during ontogeny

The effects of spatially heterogeneous prey distributions on detection patterns in foraging seabirds

Many attempts to relate animal foraging patterns to landscape heterogeneity are focused on the analysis of foragers movements. Resource detection patterns in space and time are not commonly studied, yet they are tightly coupled to landscape properties and add relevant information on foraging behavior. By exploring simple foraging models in unpredictable environments we show that the distribution of intervals between detected prey (detection statistics)is mostly determined by the spatial structure of the prey field and essentially distinct from predator displacement statistics. Detections are expected to be Poissonian in uniform random environments for markedly different foraging movements (e.g. L\'evy and ballistic). This prediction is supported by data on the time intervals between diving events on short-range foraging seabirds such as the thick-billed murre ({\it Uria lomvia}). However, Poissonian detection statistics is not observed in long-range seabirds such as the wandering albatross ({\it Diomedea exulans}) due to the fractal nature of the prey field, covering a wide range of spatial scales. For this scenario, models of fractal prey fields induce non-Poissonian patterns of detection in good agreement with two albatross data sets. We find that the specific shape of the distribution of time intervals between prey detection is mainly driven by meso and submeso-scale landscape structures and depends little on the forager strategy or behavioral responses.Comment: Submitted first to PLoS-ONE on 26/9/2011. Final version published on 14/04/201

The Spatial Association of Gene Expression Evolves from Synchrony to Asynchrony and Stochasticity with Age

For multicellular organisms, different tissues coordinate to integrate physiological functions, although this systematically and gradually declines in the aging process. Therefore, an association exists between tissue coordination and aging, and investigating the evolution of tissue coordination with age is of interest. In the past decade, both common and heterogeneous aging processes among tissues were extensively investigated. The results on spatial association of gene changes that determine lifespan appear complex and paradoxical. To reconcile observed commonality and heterogeneity of gene changes among tissues and to address evolution feature of tissue coordination with age, we introduced a new analytical strategy to systematically analyze genome-wide spatio-temporal gene expression profiles. We first applied the approach to natural aging process in three species (Rat, Mouse and Drosophila) and then to anti-aging process in Mouse. The results demonstrated that temporal gene expression alteration in different tissues experiences a progressive association evolution from spatial synchrony to asynchrony and stochasticity with age. This implies that tissue coordination gradually declines with age. Male mice showed earlier spatial asynchrony in gene expression than females, suggesting that male animals are more prone to aging than females. The confirmed anti-aging interventions (resveratrol and caloric restriction) enhanced tissue coordination, indicating their underlying anti-aging mechanism on multiple tissue levels. Further, functional analysis suggested asynchronous DNA/protein damage accumulation as well as asynchronous repair, modification and degradation of DNA/protein in tissues possibly contributes to asynchronous and stochastic changes of tissue microenvironment. This increased risk for a variety of age-related diseases such as neurodegeneration and cancer that eventually accelerate organismal aging and death. Our study suggests a novel molecular event occurring in aging process of multicellular species that may represent an intrinsic molecular mechanism of aging

The direction of research into visual disability and quality of life in glaucoma

<p>Abstract</p> <p>Background</p> <p>Glaucoma will undoubtedly impact on a person's ability to function as they go about their day-to-day life. The purpose of this study is to investigate the amount of published knowledge in quality of life (QoL) and visual disability studies for glaucoma, and make comparisons with similar research in other chronic conditions.</p> <p>Methods</p> <p>A systematic literature search of the Global Health, EMBASE Psychiatry and MEDLINE databases. Title searches for glaucoma and six other example chronic diseases were entered alongside a selection of keywords chosen to capture studies focusing on QoL and everyday task ability. These results were further filtered during a manual search of resulting abstracts. Outcomes were the number of publications per year for each disease, number relating to QoL and type of glaucoma QoL research.</p> <p>Results</p> <p>Fifteen years ago there were no published studies relating to the impact of glaucoma on QoL but by 2009 this had risen to 1.2% of all glaucoma articles. The number of papers relating to QoL as a proportion of all papers in glaucoma in the past 10 years (0.6%) is smaller than for AMD and some other disabling chronic diseases. Most QoL studies in glaucoma (82%) involve questionnaires.</p> <p>Conclusion</p> <p>QoL studies in glaucoma are increasing in number but represent a tiny minority of the total publications in glaucoma research. There are fewer QoL articles in glaucoma compared to some other disabling chronic conditions. The majority of QoL articles in glaucoma research use questionnaires; performance-based measures of visual disability may offer an additional method of determining how the disease impacts on QoL.</p

Rd9 Is a Naturally Occurring Mouse Model of a Common Form of Retinitis Pigmentosa Caused by Mutations in RPGR-ORF15

Animal models of human disease are an invaluable component of studies aimed at understanding disease pathogenesis and therapeutic possibilities. Mutations in the gene encoding retinitis pigmentosa GTPase regulator (RPGR) are the most common cause of X-linked retinitis pigmentosa (XLRP) and are estimated to cause 20% of all retinal dystrophy cases. A majority of RPGR mutations are present in ORF15, the purine-rich terminal exon of the predominant splice-variant expressed in retina. Here we describe the genetic and phenotypic characterization of the retinal degeneration 9 (Rd9) strain of mice, a naturally occurring animal model of XLRP. Rd9 mice were found to carry a 32-base-pair duplication within ORF15 that causes a shift in the reading frame that introduces a premature-stop codon. Rpgr ORF15 transcripts, but not protein, were detected in retinas from Rd9/Y male mice that exhibited retinal pathology, including pigment loss and slowly progressing decrease in outer nuclear layer thickness. The levels of rhodopsin and transducin in rod outer segments were also decreased, and M-cone opsin appeared mislocalized within cone photoreceptors. In addition, electroretinogram (ERG) a- and b-wave amplitudes of both Rd9/Y male and Rd9/Rd9 female mice showed moderate gradual reduction that continued to 24 months of age. The presence of multiple retinal features that correlate with findings in individuals with XLRP identifies Rd9 as a valuable model for use in gaining insight into ORF15-associated disease progression and pathogenesis, as well as accelerating the development and testing of therapeutic strategies for this common form of retinal dystrophy