Topical rosiglitazone is an effective anti-scarring agent in the cornea

Corneal scarring remains a major cause of blindness world-wide, with limited treatment options, all of which have side-effects. Here, we tested the hypothesis that topical application of Rosiglitazone, a Thiazolidinedione and ligand of peroxisome proliferator activated receptor gamma (PPARγ), can effectively block scar formation in a cat model of corneal damage. Adult cats underwent bilateral epithelial debridement followed by excimer laser ablation of the central corneal stroma to a depth of ~160 µm as a means of experimentally inducing a reproducible wound. Eyes were then left untreated, or received 50 µl of either 10 µM Rosiglitazone in DMSO/Celluvisc, DMSO/Celluvisc vehicle or Celluvisc vehicle twice daily for 2 weeks. Cellular aspects of corneal wound healing were evaluated with in vivo confocal imaging and post-mortem immunohistochemistry for alpha smooth muscle actin (αSMA). Impacts of the wound and treatments on optical quality were assessed using wavefront sensing and optical coherence tomography at 2, 4, 8 and 12 weeks post-operatively. In parallel, cat corneal fibroblasts were cultured to assess the effects of Rosiglitazone on TGFβ-induced αSMA expression. Topical application of Rosiglitazone to cat eyes after injury decreased αSMA expression and haze, as well as the induction of lower-order and residual, higher-order wavefront aberrations compared to vehicle-treated eyes. Rosiglitazone also inhibited TGFβ-induced αSMA expression in cultured corneal fibroblasts. In conclusion, Rosiglitazone effectively controlled corneal fibrosis in vivo and in vitro, while restoring corneal thickness and optics. Its topical application may represent an effective, new avenue for the prevention of corneal scarring with distinct advantages for pathologically thin corneas

On the Perception of Religious Group Membership from Faces

BACKGROUND: The study of social categorization has largely been confined to examining groups distinguished by perceptually obvious cues. Yet many ecologically important group distinctions are less clear, permitting insights into the general processes involved in person perception. Although religious group membership is thought to be perceptually ambiguous, folk beliefs suggest that Mormons and non-Mormons can be categorized from their appearance. We tested whether Mormons could be distinguished from non-Mormons and investigated the basis for this effect to gain insight to how subtle perceptual cues can support complex social categorizations. METHODOLOGY/PRINCIPAL FINDINGS: Participants categorized Mormons' and non-Mormons' faces or facial features according to their group membership. Individuals could distinguish between the two groups significantly better than chance guessing from their full faces and faces without hair, with eyes and mouth covered, without outer face shape, and inverted 180°; but not from isolated features (i.e., eyes, nose, or mouth). Perceivers' estimations of their accuracy did not match their actual accuracy. Exploration of the remaining features showed that Mormons and non-Mormons significantly differed in perceived health and that these perceptions were related to perceptions of skin quality, as demonstrated in a structural equation model representing the contributions of skin color and skin texture. Other judgments related to health (facial attractiveness, facial symmetry, and structural aspects related to body weight) did not differ between the two groups. Perceptions of health were also responsible for differences in perceived spirituality, explaining folk hypotheses that Mormons are distinct because they appear more spiritual than non-Mormons. CONCLUSIONS/SIGNIFICANCE: Subtle markers of group membership can influence how others are perceived and categorized. Perceptions of health from non-obvious and minimal cues distinguished individuals according to their religious group membership. These data illustrate how the non-conscious detection of very subtle differences in others' appearances supports cognitively complex judgments such as social categorization

Understanding non-compliance to colorectal cancer screening: a case control study, nested in a randomised trial [ISRCTN83029072]

BACKGROUND: The major limit to colorectal cancer screening effectiveness is often low compliance. We studied the reasons for non compliance and determinants of compliance to faecal occult blood tests in Lazio, Italy. METHODS: This is a case-control study nested within a trial that tested the effect of type of test and provider on colorectal cancer screening compliance. Non compliant trial subjects were classified as cases, and compliant subjects were classified as controls. We sampled 600 cases and 600 controls matched by their general practitioner, half were invited for screening at the hospital, and the other half directly at their general practitioner's office. Cases and controls answered questions on: distance from test provider, logistical problems, perception of colorectal cancer risk, confidence in screening efficacy, fear of results, presence of colorectal cancer in the family, and gastrointestinal symptoms. RESULTS: About 31% of cases never received the letter offering free screening, and 17% of the sampled population had already been screened. The first reported reason for non-compliance was "lack of time" (30%); the major determinant of compliance was the distance from the test provider: odds ratio >30 minutes vs <15 minutes 0.3 (95%CI = 0.2–0.7). The odds ratio for lack of time was 0.16 (95% IC 0.1–0.26). The effect was stronger if the hospital (0.03 95%CI = 0.01–0.1) rather than the general practitioner (0.3 95%CI = 0.2–0.6) was the provider. Twenty-two percent of controls were accompanied by someone to the test. CONCLUSION: To increase compliance, screening programmes must involve test providers who are geographically close to the target population

Endothelin-1 as a neuropeptide: neurotransmitter or neurovascular effects?

Endothelin-1 (ET-1) is an endothelium-derived peptide that also possesses potent mitogenic activity. There is also a suggestion the ET-1 is a neuropeptide, based mainly on its histological identification in both the central and peripheral nervous system in a number of species, including man. A neuropeptide role for ET-1 is supported by studies showing a variety of effects caused following its administration into different regions of the brain and by application to peripheral nerves. In addition there are studies proposing that ET-1 is implicated in a number of neural circuits where its transmitter affects range from a role in pain and temperature control to its action on the hypothalamo-neurosecretory system. While the effect of ET-1 on nerve tissue is beyond doubt, its action on nerve blood flow is often ignored. Here, we review data generated in a number of species and using a variety of experimental models. Studies range from those showing the distribution of ET-1 and its receptors in nerve tissue to those describing numerous neurally-mediated effects of ET-1

Pathways to a cancer-free future: a protocol for modelled evaluations to minimise the future burden of colorectal cancer in Australia.

INTRODUCTION:With almost 50% of cases preventable and the Australian National Bowel Cancer Screening Program in place, colorectal cancer (CRC) is a prime candidate for investment to reduce the cancer burden. The challenge is determining effective ways to reduce morbidity and mortality and their implementation through policy and practice. Pathways-Bowel is a multistage programme that aims to identify best-value investment in CRC control by integrating expert and end-user engagement; relevant evidence; modelled interventions to guide future investment; and policy-driven implementation of interventions using evidence-based methods. METHODS AND ANALYSIS: Pathways-Bowel is an iterative work programme incorporating a calibrated and validated CRC natural history model for Australia (Policy1-Bowel) and assessing the health and cost outcomes and resource use of targeted interventions. Experts help identify and prioritise modelled evaluations of changing trends and interventions and critically assess results to advise on their real-world applicability. Where appropriate the results are used to support public policy change and make the case for optimal investment in specific CRC control interventions. Fourteen high-priority evaluations have been modelled or planned, including evaluations of CRC outcomes from the changing prevalence of modifiable exposures, including smoking and body fatness; potential benefits of daily aspirin intake as chemoprevention; increasing CRC incidence in people aged <50 years; increasing screening participation in the general and Aboriginal and Torres Strait Islander populations; alternative screening technologies and modalities; and changes to follow-up surveillance protocols. Pathways-Bowel is a unique, comprehensive approach to evaluating CRC control; no prior body of work has assessed the relative benefits of a variety of interventions across CRC development and progression to produce a list of best-value investments. ETHICS AND DISSEMINATION:Ethics approval was not required as human participants were not involved. Findings are reported in a series of papers in peer-reviewed journals and presented at fora to engage the community and policymakers

Photochemical activation of TRPA1 channels in neurons and animals

Optogenetics is a powerful research tool because it enables high-resolution optical control of neuronal activity. However, current optogenetic approaches are limited to transgenic systems expressing microbial opsins and other exogenous photoreceptors. Here, we identify optovin, a small molecule that enables repeated photoactivation of motor behaviors in wild type animals. Surprisingly, optovin's behavioral effects are not visually mediated. Rather, photodetection is performed by sensory neurons expressing the cation channel TRPA1. TRPA1 is both necessary and sufficient for the optovin response. Optovin activates human TRPA1 via structure-dependent photochemical reactions with redox-sensitive cysteine residues. In animals with severed spinal cords, optovin treatment enables control of motor activity in the paralyzed extremities by localized illumination. These studies identify a light-based strategy for controlling endogenous TRPA1 receptors in vivo, with potential clinical and research applications in non-transgenic animals, including humans

Animal models of focal brain ischemia

Stroke is a leading cause of disability and death in many countries. Understanding the pathophysiology of ischemic injury and developing therapies is an important endeavor that requires much additional research. Animal stroke models provide an important mechanism for these activities. A large number of stroke models have been developed and are currently used in laboratories around the world. These models are overviewed as are approaches for measuring infarct size and functional outcome

A systems analysis of the chemosensitivity of breast cancer cells to the polyamine analogue PG-11047

<p>Abstract</p> <p>Background</p> <p>Polyamines regulate important cellular functions and polyamine dysregulation frequently occurs in cancer. The objective of this study was to use a systems approach to study the relative effects of PG-11047, a polyamine analogue, across breast cancer cells derived from different patients and to identify genetic markers associated with differential cytotoxicity.</p> <p>Methods</p> <p>A panel of 48 breast cell lines that mirror many transcriptional and genomic features present in primary human breast tumours were used to study the antiproliferative activity of PG-11047. Sensitive cell lines were further examined for cell cycle distribution and apoptotic response. Cell line responses, quantified by the GI₅₀(dose required for 50% relative growth inhibition) were correlated with the omic profiles of the cell lines to identify markers that predict response and cellular functions associated with drug sensitivity.</p> <p>Results</p> <p>The concentrations of PG-11047 needed to inhibit growth of members of the panel of breast cell lines varied over a wide range, with basal-like cell lines being inhibited at lower concentrations than the luminal cell lines. Sensitive cell lines showed a significant decrease in S phase fraction at doses that produced little apoptosis. Correlation of the GI₅₀values with the omic profiles of the cell lines identified genomic, transcriptional and proteomic variables associated with response.</p> <p>Conclusions</p> <p>A 13-gene transcriptional marker set was developed as a predictor of response to PG-11047 that warrants clinical evaluation. Analyses of the pathways, networks and genes associated with response to PG-11047 suggest that response may be influenced by interferon signalling and differential inhibition of aspects of motility and epithelial to mesenchymal transition.</p> <p>See the related commentary by Benes and Settleman: <url>http://www.biomedcentral.com/1741-7015/7/78</url></p

Germline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the colon cancer family registry cohort

Objectives: Immunohistochemistry for DNA mismatch repair proteins is used to screen for Lynch syndrome in individuals with colorectal carcinoma (CRC). Although solitary loss of PMS2 expression is indicative of carrying a germline mutation in PMS2, previous studies reported MLH1 mutation in some cases. We determined the prevalence of MLH1 germline mutations in a large cohort of individuals with a CRC demonstrating solitary loss of PMS2 expression. Design: This cohort study included 88 individuals affected with a PMS2-deficient CRC from the Colon Cancer Family Registry Cohort. Germline PMS2 mutation analysis (long-range PCR and multiplex ligation-dependent probe amplification) was followed by MLH1 mutation testing (Sanger sequencing and multiplex ligation-dependent probe amplification). Results: Of the 66 individuals with complete mutation screening, we identified a pathogenic PMS2 mutation in 49 (74%), a pathogenic MLH1 mutation in 8 (12%) and a MLH1 variant of uncertain clinical significance predicted to be damaging by in silico analysis in 3 (4%); 6 (9%) carried variants likely to have no clinical significance. Missense point mutations accounted for most alterations (83%; 9/11) in MLH1. The MLH1 c.113A> G p.Asn38Ser mutation was found in 2 related individuals. One individual who carried the MLH1 intronic mutation c.677+3A>G p.Gln197Argfs*8 leading to the skipping of exon 8, developed 2 tumours, both of which retained MLH1 expression. Conclusions: A substantial proportion of CRCs with solitary loss of PMS2 expression are associated with a deleterious MLH1 germline mutation supporting the screening for MLH1 in individuals with tumours of this immunophenotype, when no PMS2 mutation has been identified.Christophe Rosty, Mark Clendenning, Michael D Walsh, Stine V Eriksen … Nicola Poplawski … Joanne Young … et al