Toxic effects of indocyanine green, infracyanine green, and trypan blue on the human retinal pigmented epithelium

Background: Indocyanine green, infracyanine green, and trypan blue are frequently used as aids to visualize structures removed during vitreoretinal surgery. But they may have toxic effects on the retina. We therefore compared the acute and chronic toxicities of these stains on cultured human retinal pigmented epithelial (RPE) cells using clinically relevant concentrations and an identical experimental setup for each agent. Methods: Monolayers of RPE cells were incubated with various concentrations of indocyanine green, infracyanine green (each at 0.005%, 0.05%, and 0.5%) or trypan blue (0.05%, 0.06%, 0.1%, 0.15%, and 0.5%) for 5min (acute exposure) or 6 days (chronic exposure). Using the propidium iodide assay, acute cytotoxicity was monitored at 15-min intervals for up to 3h. Chronic cytotoxicity was assessed by monitoring cell calcein esterase activity, cell proliferation, and cell morphology (viability) after 6 days of exposure. Results: Indocyanine and infracyanine green induced acute and chronic toxicities at a concentration above 0.05%. Trypan blue evoked no acute toxicity, but it was chronically cytotoxic at all tested concentrations. Conclusions: Despite thorough rinsing after application, significant amounts of the not sufficiently water soluble indocyanine and infracyanine green are retained after surgery by the eye. Trypan blue, being more water-soluble than ICG, is probably retained to the least degree. This circumstance is fortunate given that trypan blue exhibits a chronic cytotoxicity comparable to ICG at all clinically relevant concentrations. During vitrectomy, surgeons should aim to expose retinal tissue to only low concentrations of these stains and for as short a period as possibl

Grateful parents raising grateful children: Niche selection and the socialization of child gratitude

Given that children’s exposure to gratitude-related activities may be one way that parents can socialize gratitude in their children, we examined whether parents’ niche selection (i.e., tendency to choose perceived gratitude-inducing activities for their children) mediates the association between parents’ reports of their own and their children's gratitude. Parent-child dyads (N =101; children aged 6-9; 52% girls; 80% Caucasian; 85% mothers) participated in a laboratory visit and parents also completed a seven-day online diary regarding children’s gratitude. Decomposing specific indirect effects within a structural equation model, we found that parents high in gratitude were more likely to set goals to use niche selection as a gratitude socialization strategy, and thereby more likely to place their children in gratitude-related activities. Placement in these activities, in turn, was associated with more frequent expression of gratitude in children. We describe future directions for research on parents’ role in socializing gratitude in their children

Scoping literature review and focus groups with healthcare professionals on psychosocial and lifestyle assessments for childhood obesity care

Background: Childhood obesity is a complex disease resulting from the interaction of multiple factors. The effective management of childhood obesity requires assessing the psychosocial and lifestyle factors that may play a role in the development and maintenance of obesity. This study centers on available scientific literature on psychosocial and lifestyle assessments for childhood obesity, and experiences and views of healthcare professionals with regard to assessing psychosocial and lifestyle factors within Dutch integrated care. Methods: Two methods were used. First, a scoping review (in PubMed, Embase, PsycInfo, IBSS, Scopus and Web of Science) was performed by systematically searching for scientific literature on psychosocial and lifestyle assessments for childhood obesity. Data were analysed by extracting data in Microsoft Excel. Second, focus group discussions were held with healthcare professionals from a variety of disciplines and domains to explore their experiences and views about assessing psychosocial and lifestyle factors within Dutch integrated care. Data were analysed using template analysis, complemented with open coding in MAXQDA. Results: The results provide an overview of relevant psychosocial and lifestyle factors that should be assessed and were classified as child, family, parental and lifestyle (e.g. nutrition, physical activity and sleep factors) and structured into psychological and social aspects. Insights into how to assess psychosocial and lifestyle factors were identified as well, including talking about psychosocial factors, lifestyle and weight; the professional-patient relationship; and attitudes of healthcare professionals. Conclusions: This study provides an overview of psychosocial and lifestyle factors that should be identified within the context of childhood obesity care, as they may contribute to the development and maintenance of obesity. The results highlight the importance of both what is assessed and how it is assessed. The results of this study can be used to develop practical tools for facilitating healthcare professionals in conducting a psychosocial and lifestyle assessment.</p

Elliptic Curves over Real Quadratic Fields are Modular

We prove that all elliptic curves defined over real quadratic fields are modular.Comment: 38 pages. Magma scripts available as ancillary files with this arXiv versio

Pharmacological and biotransformation studies of 1-acyl-substituted derivatives of d-lysergic acid diethylamide (LSD)

The ergoline d-lysergic acid diethylamide (LSD) is one of the most potent psychedelic drugs. 1-Acetyl-LSD (ALD-52), a derivative of LSD containing an acetyl group on the indole nitrogen, also produces psychedelic effects in humans and has about the same potency as LSD. Recently, several other 1-acyl-substitued LSD derivatives, including 1-propanoyl-LSD (1P-LSD) and 1-butanoyl-LSD (1B-LSD), have appeared as designer drugs. Although these compounds are assumed to act as prodrugs for LSD, studies have not specifically tested this prediction. The present investigation was conducted to address the gap of information about the pharmacological effects and mechanism-of-action of 1-acyl-substituted LSD derivatives. Competitive binding studies and calcium mobilization assays were performed to assess the interaction of ALD-52, 1P-LSD, and 1B-LSD with serotonin 5-HT2 receptor subtypes. A receptorome screening was performed with 1B-LSD to assess its binding to other potential targets. Head twitch response (HTR) studies were performed in C57BL/6J mice to assess in vivo activation of 5-HT2A (the receptor thought to be primarily responsible for hallucinogenesis). Finally, liquid chromatography/ion-trap mass spectrometry (LC/MS) was used to quantify plasma levels of LSD in Sprague-Dawley rats treated with ALD-52 and 1P-LSD. 1-Acyl-substitution reduced the affinity of LSD for most monoamine receptors, including 5-HT2A sites, by one to two orders of magnitude. Although LSD acts as an agonist at 5-HT2 subtypes, ALD-52, 1P-LSD and 1B-LSD had weak efficacy or acted as antagonists in Ca2+-mobilization assays. Despite the detrimental effect of 1-acyl substitution on 5-HT2A affinity and efficacy, 1-acyl-substitued LSD derivatives induce head twitches in mice with relatively high potency. High levels of LSD were detected in the plasma of rats after subcutaneous administration of ALD-52 and 1P-LSD, demonstrating these compounds are rapidly and efficiently deacylated in vivo. These findings are consistent with the prediction that ALD-52, 1P-LSD and 1B-LSD serve as pro-drugs for LSD

N -Benzyl-5-methoxytryptamines as Potent Serotonin 5-HT 2 Receptor Family Agonists and Comparison with a Series of Phenethylamine Analogues

A series of N-benzylated-5-methoxytryptamine analogues was prepared and investigated, with special emphasis on substituents in the meta position of the benzyl group. A parallel series of several N-benzylated analogues of 2,5-dimethoxy-4-iodophenethylamine (2C-I) also was included for comparison of the two major templates (i.e., tryptamine and phenethylamine). A broad affinity screen at serotonin receptors showed that most of the compounds had the highest affinity at the 5-HT2 family receptors. Substitution at the para position of the benzyl group resulted in reduced affinity, whereas substitution in either the ortho or the meta position enhanced affinity. In general, introduction of a large lipophilic group improved affinity, whereas functional activity often followed the opposite trend. Tests of the compounds for functional activity utilized intracellular Ca2+ mobilization. Function was measured at the human 5-HT2A, 5-HT2B, and 5-HT2C receptors, as well as at the rat 5-HT2A and 5-HT2C receptors. There was no general correlation between affinity and function. Several of the tryptamine congeners were very potent functionally (EC50 values from 7.6 to 63 nM), but most were partial agonists. Tests in the mouse head twitch assay revealed that many of the compounds induced the head twitch and that there was a significant correlation between this behavior and functional potency at the rat 5-HT2A receptor

Ecological and cultural factors underlying the global distribution of prejudice

Prejudiced attitudes and political nationalism vary widely around the world, but there has been little research on what predicts this variation. Here we examine the ecological and cultural factors underlying the worldwide distribution of prejudice. We suggest that cultures grow more prejudiced when they tighten cultural norms in response to destabilizing ecological threats. A set of seven archival analyses, surveys, and experiments (∑N = 3,986,402) find that nations, American states, and pre-industrial societies with tighter cultural norms show the most prejudice based on skin color, religion, nationality, and sexuality, and that tightness predicts why prejudice is often highest in areas of the world with histories of ecological threat. People’s support for cultural tightness also mediates the link between perceived ecological threat and intentions to vote for nationalist politicians. Results replicate when controlling for economic development, inequality, conservatism, residential mobility, and shared cultural heritage. These findings offer a cultural evolutionary perspective on prejudice, with implications for immigration, intercultural conflict, and radicalization.publishedVersio

Development of an action programme tackling obesity-related behaviours in adolescents:a participatory system dynamics approach

System dynamics approaches are increasingly addressing the complexity of public health problems such as childhood overweight and obesity. These approaches often use system mapping methods, such as the construction of causal loop diagrams, to gain an understanding of the system of interest. However, there is limited practical guidance on how such a system understanding can inform the development of an action programme that can facilitate systems changes. The Lifestyle Innovations Based on Youth Knowledge and Experience (LIKE) programme combines system dynamics and participatory action research to improve obesity-related behaviours, including diet, physical activity, sleep and sedentary behaviour, in 10–14-year-old adolescents in Amsterdam, the Netherlands. This paper illustrates how we used a previously obtained understanding of the system of obesity-related behaviours in adolescents to develop an action programme to facilitate systems changes. A team of evaluation researchers guided interdisciplinary action-groups throughout the process of identifying mechanisms, applying the Intervention Level Framework to identify leverage points and arriving at action ideas with aligning theories of change. The LIKE action programme consisted of 8 mechanisms, 9 leverage points and 14 action ideas which targeted the system’s structure and function within multiple subsystems. This illustrates the feasibility of developing actions targeting higher system levels within the confines of a research project timeframe when sufficient and dedicated effort in this process is invested. Furthermore, the system dynamics action programme presented in this study contributes towards the development and implementation of public health programmes that aim to facilitate systems changes in practice.</p