Menthol reduces phototoxicity pain in a mouse model of photodynamic therapy

Phototoxicity-induced pain is a major clinical problem triggered by light acting on photosensitising drugs or endogenous porphyrins, notably protoporphyrin IX (PpIX), an intermediary in heme biosynthesis. PpIX accumulates in individuals with erythropoietic protoporphyria and is elevated during photodynamic therapy subsequent to application of 5- aminolevulinic acid (ALA). Pain occurs during irradiation of PpIX and responds poorly to conventional analgesics. Our objective was to develop a model of PpIX phototoxicity pain and investigate the potential of menthol as an analgesic. Application of ALA to the tails of C57 black and SWISS white mice caused PpIX accumulation and nociception during irradiation (630 nm at 3.7 J/cm2 ). Despite similar PpIX accumulation, C57 mice exhibited less pain behavior compared to SWISS mice due to light absorption by pigmentation. Irradiation of ALA-treated dorsal root ganglion neurons caused phototoxicity-evoked action potentials (APs) in both mouse strains. The antioxidant L-tryptophan increased the light dose required to elicit such APs. By contrast, the addition of keratinocytes to neuronal cultures decreased the threshold for APs, suggesting a requirement for proliferating cells. Inhibition of fatty acid amide hydrolase, selective antagonism of TRPV1 or the application of lidocaine or its quaternary derivative QX-314, reduced AP frequency, while antagonism of TRPA1 had no effect. These results suggest that products of singlet O2-mediated lipid peroxidation trigger nociceptor activation via TRPV1. Menthol inhibited phototoxicity-evoked APs and reduced pain behavior when applied topically to mice. These findings suggest that menthol might provide pain relief in patients experiencing PpIXphototoxicity pain caused by photodynamic therapy or erythropoietic protoporphyria

Sparse coding on the spot: Spontaneous retinal waves suffice for orientation selectivity

Ohshiro, Hussain, and Weliky (2011) recently showed that ferrets reared with exposure to flickering spot stimuli, in the absence of oriented visual experience, develop oriented receptive fields. They interpreted this as refutation of efficient coding models, which require oriented input in order to develop oriented receptive fields. Here we show that these data are compatible with the efficient coding hypothesis if the influence of spontaneous retinal waves is considered. We demonstrate that independent component analysis learns predominantly oriented receptive fields when trained on a mixture of spot stimuli and spontaneous retinal waves. Further, we show that the efficient coding hypothesis provides a compelling explanation for the contrast between the lack of receptive field changes seen in animals reared with spot stimuli and the significant cortical reorganisation observed in stripe-reared animals

The influence of restricted orientation rearing on map structure in primary visual cortex

Visual experience is critical to the development of the structure of the primary visual cortex and, in turn, normal functional vision. The primary visual cortex contains maps of multiple features of the visual input, and these maps are characterised by specific types of geometric relationships. Manipulations of the visual environment during development in animals such as ferrets, cats and monkeys provide an opportunity to probe the rules governing map formation via their effect on these relationships. Here we use a computational model of map formation based on dimension-reduction principles to predict the effect on map relationships of presenting only a single orientation to one eye and the orthogonal orientation to the other eye. Since orientation preference and ocular dominance are now tightly coupled one might expect orientation and ocular dominance contours to lose their normally orthogonal relationship and instead run parallel to each other. However, surprisingly, the model predicts that orthogonal intersection can sometimes be preserved in this case. The model also predicts that orientation pinwheels can migrate from the centre to the borders of ocular dominance columns, and that the wavelengths of the ocular dominance and orientation maps can become coupled. These predictions provide a way to further test the adequacy of dimension reduction principles for explaining map structure under perturbed as well as normal rearing conditions, and thus allow us to deepen our understanding of the effect of the visual environment on visual cortical development

Bond graph modelling of chemoelectrical energy transduction

Energy-based bond graph modelling of biomolecular systems is extended to include chemoelectrical transduction thus enabling integrated thermodynamically-compliant modelling of chemoelectrical systems in general and excitable membranes in particular. Our general approach is illustrated by recreating a well-known model of an excitable membrane. This model is used to investigate the energy consumed during a membrane action potential thus contributing to the current debate on the trade-off between the speed of an action potential event and energy consumption. The influx of Na+ is often taken as a proxy for energy consumption; in contrast, this paper presents an energy based model of action potentials. As the energy based approach avoids the assumptions underlying the proxy approach it can be directly used to compute energy consumption in both healthy and diseased neurons. These results are illustrated by comparing the energy consumption of healthy and degenerative retinal ganglion cells using both simulated and in vitro data

Ultraviolet radiation exposure during daylight Photodynamic Therapy

Background: Daylight photodynamic therapy (dPDT) is an effective treatment for field-change actinic keratoses (AK), with similar efficacy to conventional PDT but lower patient pain scores. Whilst AK occur consequent to chronic solar ultraviolet (UV) exposure, paradoxically solar visible radiation is used during PDT.Objectives: To investigate the nature and levels of UV exposure, both erythemal UV and UVA, occurring during dPDT.Methods: Four years of solar erythemally effective UV (UVE) irradiance, UVA irradiance and illuminance data were obtained from Pubic Health England for 12 locations. For a standard 2 h treatment period, the data were converted into standard erythemal doses (SEDs), UVA dose and protoporphyrin-IX (PpIX)-weighted dose from UVE irradiance, UVA irradiance and illuminance respectively. These three parameters were compared ascertaining the UV exposure received during dPDT.Results: Analysis of UV exposure during dPDT showed a UK maximum average UVE exposure of 8.2 SED at Camborne (PpIX dose 23.4 J cm−2). Treatment earlier in the day reduces average UV exposure (Camborne 5.2 SED, PpIX dose 18.2 J cm−2), whilst PpIX dose achieves threshold during winter months (Camborne, November, 0.8 SED, PpIX dose 7.1 J cm−2). Cyprus and Gibraltar (with high UV exposure during dPDT) experience a maximum of 14.3 SED and 12.9 SED, with respective PpIX doses of 36.1 J cm−2 and 35.1 J cm−2, in June. UVA exposure is also presented for comparison.Conclusion: Therapeutically effective dPDT doses can be achieved at times of the day and year when UV exposure is minimal. </p

Edge Detection in Landing Budgerigars (Melopsittacus undulatus)

Background: While considerable scientific effort has been devoted to studying how birds navigate over long distances, relatively little is known about how targets are detected, obstacles are avoided and smooth landings are orchestrated. Here we examine how visual features in the environment, such as contrasting edges, determine where a bird will land. Methodology/Principal Findings: Landing in budgerigars (Melopsittacus undulatus) was investigated by training them to fly from a perch to a feeder, and video-filming their landings. The feeder was placed on a grey disc that produced a contrasting edge against a uniformly blue background. We found that the birds tended to land primarily at the edge of the disc and walk to the feeder, even though the feeder was in the middle of the disc. This suggests that the birds were using the visual contrast at the boundary of the disc to target their landings. When the grey level of the disc was varied systematically, whilst keeping the blue background constant, there was one intermediate grey level at which the budgerigar's preference for the disc boundary disappeared. The budgerigars then landed randomly all over the test surface. Even though this disc is (for humans) clearly distinguishable from the blue background, it offers very little contrast against the background, in the red and green regions of the spectrum. Conclusions: We conclude that budgerigars use visual edges to target and guide landings. Calculations of photoreceptor excitation reveal that edge detection in landing budgerigars is performed by a color-blind luminance channel that sums the signals from the red and green photoreceptors, or, alternatively, receives input from the red double-cones. This finding has close parallels to vision in honeybees and primates, where edge detection and motion perception are also largely color-blind

Prototype constructions in early language acquisition

In this paper we bring together several lines of cross-linguistic research to demonstrate the role of prototypicality in young children’s acquisition of the transitive construction. Much research has shown that young children are slow to form abstract constructions because they fail to see the more general applicability of syntactic markers such as word order and case marking. Here we attempt to explain this fact by investigating the nature of the language children do and do not hear, specifically, the reliability and availability of the linguistic cues they are exposed to. We suggest that constructions redundantly marked with multiple cues could have a special status as a nucleus around which the prototype forms—which makes it difficult for them to isolate the functional significance of each cue. The implications of this view for language acquisition are discussed within a usage-based framework

A Three-Dimensional Atlas of the Honeybee Neck

Three-dimensional digital atlases are rapidly becoming indispensible in modern biology. We used serial sectioning combined with manual registration and segmentation of images to develop a comprehensive and detailed three-dimensional atlas of the honeybee head-neck system. This interactive atlas includes skeletal structures of the head and prothorax, the neck musculature, and the nervous system. The scope and resolution of the model exceeds atlases previously developed on similar sized animals, and the interactive nature of the model provides a far more accessible means of interpreting and comprehending insect anatomy and neuroanatomy