Microspectrophotometry of rod photoreceptors was used to follow variations in visual pigment vitamin A1/A2 ratio at various life history stages in coho salmon. Coho parr shifted their A1/A2 ratio seasonally with A2 increasing during winter and decreasing in summer. The cyclical pattern was statistically examined by a least-squares cosine model, fit to the 12-month data sets collected from different populations. A1/A2 ratio varied with temperature and day length. In 1+ (>12 month old) parr the A2 to A1 shift in spring coincided with smoltification, a metamorphic transition preceding seaward migration in salmonids. The coincidence of the shift from A2 to A1 with both the spring increase in temperature and day length, and with the timing of seaward migration presented a challenge for interpretation. Our data show a shift in A1/A2 ratio correlated with season, in both 0+ (<12 months old) coho parr that remained in fresh water for another year and in oceanic juvenile coho. These findings support the hypothesis that the A1/A2 pigment pair system in coho is an adaptation to seasonal variations in environmental variables rather than to a change associated with migration or metamorphosis.

SUMMARYA number of teleost fishes have photoreceptor mechanisms to detect linearly polarized light. We studied the neuronal mechanism underlying this ability. It was found that a polarized signal could be detected in rainbow trout (Oncorhynchus mykiss) both in the electroretinogram (ERG) and in the compound action potential (CAP) measured in the optic nerve, indicating a strong retinal contribution to the processing of polarized light. The CAP recordings showed a W-shaped sensitivity curve, with a peak at 0°, 90°a nd 180°, consistent with processes for both vertical and horizontal orientation. By contrast, the ERG recordings reveal a more complex pattern. In addition to the peaks at 0°, 90° and 180°, two additional peaks appeared at 45° and 135°. This result suggests a specialized contribution of the outer retina in the processing of polarized light. The spectral sensitivity of the mechanisms responsible for these intermediate peaks was studied using chromatic adaptation. Here we show that long wavelength-sensitive (LWS) cone mechanism adaptation shifted the intermediate peaks towards 90°, whereas ultraviolet-sensitive (UVS) cone mechanism adaptation shifted the peaks away from 90° towards either 0° or 180°. These results provide further confirmation that the 90° peak is dominated by the LWS cone mechanism and the 0° and 180° peaks are dominated by the UVS cone mechanism. In addition, a pharmacological approach was used to examine the retinal neural mechanisms underlying polarization sensitivity. The effect of blocking negative feedback from horizontal cells to cones on the ERG was studied by making intraocular injections of low doses of cobalt, known to block this feedback pathway. It was found that the intermediate peaks seen in the ERG polarization sensitivity curves were eliminated after application of cobalt, suggesting that these peaks are due to outer retinal inhibition derived from feedback of horizontal cells onto cones. A simple computational model was developed to evaluate these results. The model consists of opponent and non-opponent processing elements for the two polarization detectors. This model provides a first approximation analysis suggesting that opponent processing occurs in the outer retina for polarization vision. Although it seems that polarization vision uses a slightly more complicated coding scheme than colour vision, the results presented in this paper suggest that opponent and non-opponent channels process polarization information.

SUMMARYThe role of exogenous thyroid hormone on visual pigment content of rod and cone photoreceptors was investigated in coho salmon (Oncorhynchus kisutch). Coho vary the ratio of vitamin A 1 -and A 2 -based visual pigments in their eyes. This variability potentially alters spectral sensitivity and thermal stability of the visual pigments. We tested whether the direction of shift in the vitamin A 1 /A 2 ratio, resulting from application of exogenous thyroid hormone, varied in fish of different ages and held under different environmental conditions. Changes in the vitamin A 1 /A 2 visual pigment ratio were estimated by measuring the change in maximum absorbance (λ max ) of rods using microspectrophotometry (MSP). Exogenous thyroid hormone resulted in a longwavelength shift in rod, middle-wavelength-sensitive (MWS) and long-wavelength-sensitive (LWS) cone photoreceptors. Rod and LWS cone λ max values increased, consistent with an increase in vitamin A 2 . MWS cone λ max values increased more than predicted for a change in the vitamin A 1 /A 2 ratio. To account for this shift, we tested for the expression of multiple RH2 opsin subtypes. We isolated and sequenced a novel RH2 opsin subtype, which had 48 amino acid differences from the previously sequenced coho RH2 opsin. A substitution of glutamate for glutamine at position 122 could partially account for the greater than predicted shift in MWS cone λ max values. Our findings fit the hypothesis that a variable vitamin A 1 /A 2 ratio provides seasonality in spectral tuning and/or improved thermal stability of visual pigments in the face of seasonal environmental changes, and that multiple RH2 opsin subtypes can provide flexibility in spectral tuning associated with migration-metamorphic events.

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1999) hypothesized, based on molecular evidence, that Salmo and Oncorhynchus were not sister taxa. Recent reconstruction of the phylogenetic relationships among the Salmonidae, based on more complete mitochondrial and nuclear DNA data sets (Crespi and Fulton, 2004;Ishiguro et al., 2003), however, has revealed that Salvelinus and Oncorhynchus form sister taxa, with Salmo as the outgroup. This new relationship changes past interpretations of trait evolution within the Salmoninae. Therefore, the conclusion that the traits for spectral sensitivity and polarization sensitivity are ancestral to the clade containing Salmo, Oncorhynchus and Salvelinus (Parkyn Accepted 2 June 2010 SUMMARY We were interested in comparing the characteristics of polarization sensitivity in Atlantic salmon to those in Pacific salmon. Here we show that the common ancestor to the clade containing Salmo salar, Oncorhynchus mykiss, O. nerka, O. clarkii and Salvelinus fontinalis has the trait of ultraviolet polarization sensitivity. We examined spectral and polarization sensitivity of juvenile Atlantic salmon (Salmo salar) using both optic nerve compound action potential (CAP) and electroretinogram (ERG) recordings. Our experiments employed photic manipulation to adjust the sensitivity of the four cone mechanisms of Atlantic salmon. A spectrally broad background was used to ensure a contribution of all cone mechanisms to both spectral and polarization sensitivity. Chromatic adaptation was used to isolate the sensitivity of each of the four cone mechanisms for both spectral and polarization sensitivity. Under spectrally broad conditions, UV sensitive (UVS), mid wavelength sensitive (MWS) and long wavelength sensitive (LWS) cone mechanisms contributed to polarization sensitivity. CAP recordings produced the typical 'W' shaped polarization sensitivity curve reflecting two active polarization detectors with peaks at e-vector orientations of 0deg, 90deg and 180deg, and troughs at 30deg and 150deg. ERG recordings produced a four-peaked polarization sensitivity curve reflecting two active polarization detectors and negative feedback activity, with peaks at e-vectors 0deg, 45deg, 90deg, 135deg and 180deg, and troughs at 30deg, 60deg, 120deg and 150deg. Polarization-sensitivity measurements of isolated cone mechanisms revealed two orthogonal polarization detector mechanisms in Atlantic salmon, identical to that found in rainbow trout and other Pacific salmonid fishes. Moreover, under spectrally broad background conditions, CAP and ERG polarization sensitivity of Atlantic salmon did not differ significantly from that reported in Pacific salmonids.

IntroductionThe European Risk Management Plan (EU-RMP) is a proactive planning tool for identification, characterisation and management of important risks and missing information throughout the lifecycle of a medicinal product. Over the past 15 years the EU-RMP has been a part of the pharmacovigilance practice in Europe, but there are no published studies assessing impact of the growing experience and evolving regulatory framework on the content and focus of the EU-RMP. Objectives The objectives were to study the real-world impact of evolving pharmacovigilance guidelines on the proactive lifecycle management of important risks and missing information through EU-RMPs, and to further explore the impact of different resources on the management of the benefit-risk profile. Methods A retrospective study based on the review of 64 EU-RMPs dated between 01 January 2006 and 01 October 2020 for seven human medicinal products for which Boehringer Ingelheim holds the Marketing Authorisation in the European Union. Data on the timing and rational behind changes (i.e., inclusion, reclassification, removal) to the safety concerns (Important Identified Risks, Important Potential Risks, Missing Information) and associated additional Pharmacovigilance activities and/or Risk Minimisation measures were collected and assessed. ResultsThe analysed EU-RMPs included a total of 197 safety concerns, 129 of which were removed and 19 were reclassified during the observation period. The implementation of the Guidelines on Good Pharmacovigilance Practices Module V in 2012 and Revision 2 in 2017 resulted in a noticeable decrease in the number of safety concerns. Clinical trial, non-clinical and routine post-marketing data were common sources that influenced the safety concern dynamics, and results from dedicated post-authorisation studies lead to the removal of 21 important risks and missing information. Many safety concerns were related to pharmacological class effect (n = 55) and target population characteristics (n = 37). Conclusions This study demonstrated that the growing knowledge regarding benefit-risk of approved products and the introduction of new or revised regulatory guidelines influenced the EU-RMP lifecycle of safety concerns, and moreover, the results emphasise that exchange of knowledge about the pharmacological class and target population between stakeholders are important for keeping an up-to-date understanding of a medicinal product's safety profile. The aim of improving the efficiency of risk management has leveraged the accumulation of knowledge leading to revision of regulatory guidelines and increasingly, proactive Risk Management Plans focused on safety concerns that are important for patients and public health.

As the effects of climate change become more visible, extreme weather events are becoming more common. The effects of flooding on health are understood but the long-term impact on the well-being of those affected need to be considered. This mixed methods secondary analysis of a cross-sectional survey examined the extent to which being flooded in the past is associated with ongoing concerns about flooding. Survey data were collected from residents in Hull 11 years after the initial flooding event. Respondents were asked about the floods in 2007 and their current level of concern about flooding. Ordinal logistic regression explored the effect of age and tenancy status as predictors of current concern. Textual data were analyzed using thematic content analysis. Responses were received from 457 households, of whom 202 (48%) were affected by flooding in 2007. A fifth of respondents were very concerned about future flooding. Those who were not flooded were significantly less concerned about the risk of future flooding (U = 33391.0, z = 5.89, p < 0.001). Those who reported negative health and wellbeing effects from the floods were significantly more concerned about future flooding than those whose health was not affected (U = 7830.5, z = 4.43, p < 0.001). Whilst some residents were reassured by the introduction of new flood alleviation schemes, others did not feel these were adequate, and worried about the impact of climate change. The financial and emotional impacts of the floods still resonated with families 11 years after the event, with many fearing they would not cope if it happened again. Despite the 2007 floods in Hull happening over a decade ago, many of those affected continue to experience high levels of anxiety when storms are forecast. Residents feel powerless to protect themselves, and many remain unconvinced by the presence of new flood alleviation schemes. However, with the ongoing threat of climate change, it may be that other residents are unrealistic in their expectation to be ‘protected’ from flood events. Therefore, public health agencies need to be able to mobilize organizations to come together to pro-actively support families affected by flooding, to ensure those in need do not fall through the gaps of public healthcare delivery.

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