Scavenging of retinoid cation radicals by urate, trolox, and α-, β-, γ-, and δ-tocopherols

Retinoids are present in human tissues exposed to light and under increased risk of oxidative stress, such as the retina and skin. Retinoid cation radicals can be formed as a result of the interaction between retinoids and other radicals or photoexcitation with light. It has been shown that such semi-oxidized retinoids can oxidize certain amino acids and proteins, and that α-tocopherol can scavenge the cation radicals of retinol and retinoic acid. The aim of this study was to determine (i) whether β-, γ-, and δ-tocopherols can also scavenge these radicals, and (ii) whether tocopherols can scavenge the cation radicals of another form of vitamin A-retinal. The retinoid cation radicals were generated by the pulse radiolysis of benzene or aqueous solution in the presence of a selected retinoid under oxidizing conditions, and the kinetics of retinoid cation radical decays were measured in the absence and presence of different tocopherols, Trolox or urate. The bimolecular rate constants are the highest for the scavenging of cation radicals of retinal, (7 to 8) × 109 M−1·s−1, followed by retinoic acid, (0.03 to 5.6) × 109 M−1·s−1, and retinol, (0.08 to 1.6) × 108 M−1·s−1. Delta-tocopherol is the least effective scavenger of semi-oxidized retinol and retinoic acid. The hydrophilic analogue of α-tocopherol, Trolox, is substantially less efficient at scavenging retinoid cation radicals than α-tocopherol and urate, but it is more efficient at scavenging the cation radicals of retinoic acid and retinol than δ-tocopherol. The scavenging rate constants indicate that tocopherols can effectively compete with amino acids and proteins for retinoid cation radicals, thereby protecting these important biomolecules from oxidation. Our results provide another mechanism by which tocopherols can diminish the oxidative damage to the skin and retina and thereby protect from skin photosensitivity and the development and/or progression of changes in blinding retinal diseases such as Stargardt’s disease and age-related macular degeneration (AMD)

Presence of a prothrombotic state in people with idiopathic pulmonary fibrosis: a population-based case-control study

BACKGROUND: Laboratory studies suggest that the clotting cascade is activated in fibrotic lungs. Since humans vary in their tendency to clot due to a variety of inherited or acquired defects, we investigated whether a prothrombotic state increases the chance of developing idiopathic pulmonary fibrosis (IPF) and/or worsens the prognosis of IPF. METHODS: We recruited 211 incident cases of IPF and 256 age-and sex-matched general population controls and collected data on medical history, medication, smoking habit, blood samples as well as lung function and high-resolution CT scans done as part of routine clinical care. A prothrombotic state was defined as the presence of at least one inherited or acquired clotting defect or marker of fibrinolytic dysfunction. We used logistic regression to quantify the association between a prothrombotic state and IPF adjusted for age, sex, smoking habit and highly sensitive C reactive protein. Cox regression was used to determine the influence of a prothrombotic state on survival. RESULTS: Cases were more than four times more likely than controls to have a prothrombotic state (OR 4.78, 95% CI 2.93 to 7.80; p<0.0001). Cases with a prothrombotic state were also likely to have more severe disease (forced vital capacity <70% predicted) at presentation (OR 10.79, 95% CI 2.43 to 47.91) and had a threefold increased risk of death (HR 3.26, 95% CI 1.09 to 9.75). CONCLUSIONS: People with IPF are more likely to have a prothrombotic state than general population controls and the presence of a prothrombotic state has an adverse impact on survival

Virtual Support for Real-World Movement:Using Chatbots to Overcome Barriers to Physical Activity

Conversational agents (CAs, aka chatbots) for behavioral interventions have great potential to improve patient engagement and provide solutions that can benefit human health. In this study, we examined the potential efficacy of chatbots in assisting with the resolution of specific barriers that people frequently encounter when doing behavioral interventions for the purpose of increasing physical activity (PA). To do this, six common barriers (i.e., things that stand in the way of increasing PA) were targeted (e.g., stress and fatigue), we adopted domain knowledge (i.e., psychological theories and behavioral change techniques) to design six interventions aimed at tackling each of these six barriers. These interventions were then incorporated into consultative conversations, which were subsequently integrated into a chatbot. A user study was conducted on non-clinical samples (n=77) where all participants were presented with three randomly but equally distributed chatbot interventions and a control condition. Each intervention conversation addressed a specific barrier to PA, while the control conversation did not address any barrier. The outcome variables were beliefs in PA engagement, attitudes toward the effectiveness of each intervention to resolve the barrier, and the overall chatbot experience. The results showed a significant increase in beliefs of PA engagement in most intervention groups compared to the control group, and positive attitudes toward the effectiveness of the interventions in reducing their respective barriers to PA, and positive chatbot experience. The results demonstrate that theory-grounded interventions delivered by chatbots can effectively help people overcome specific barriers to PA, thereby increasing their beliefs in PA engagement. These promising findings indicate that chatbot interventions can be an accessible and widely applicable solution for a larger population to promote PA.</p

Validation of the Baveno Vi Criteria to Identify Low Risk Cirrhotic Patients not Requiring Endoscopic Surveillance for Varices

BACKGROUND: The Baveno VI guidelines propose that cirrhotic patients with a liver stiffness measurement (LSM) 150000/μL can avoid screening endoscopy as their combination is highly specific for excluding clinically significant varices. The aim of the study was to validate these criteria. METHODS: Transient elastography data was collected from two institutions from 2006-2015. Inclusion criteria were a LSM ⩾10kPa and an upper gastrointestinal endoscopy within 12 months, with a diagnosis of compensated chronic liver disease. Exclusion criteria were porto-mesenteric-splenic vein thrombosis and non-cirrhotic portal hypertension. Varices were graded as low risk (grade 150) are at low risk of having varices and do not need a screening endoscopy. Varices are a complication of cirrhosis, confer a risk of serious bleeding, and can be diagnosed and treated by endoscopy. Our study reviewed the clinical records of patients who have had liver stiffness scans and endoscopy over a 9 year period at two hospitals. The results show that only about 2% of patients who meet the Baveno VI criteria will be miss classified as not having varices

Photochemistry and photopolymerisation of substituted 2-methylanthraquinones and novel 2-acryloxymethylanthraquinone in radiation curing

© 2018 Elsevier B.V. Anthraquinones have been the subject of numerous photochemical studies and their photopolymerization activities have been examined under various conditions to improve more efficient photochemical systems. This article involves further detailed investigations into the photophysical, photochemistry and photopolymerisation properties of 4 commercial derivatives of 2-substituted anthraquinone, namely, 2-Bromomethylanthraquinone (2BA), 2 Chloromethylanthraquinone (2CA), 2 Ethylanthraquinone (2EA), 2 Hydroxymethylanthraquinone (2HA) and one novel synthesized anthraquinone, 2 Acryloxymethylanthraquinone (2AA). 2AA is synthesized from 2HA. The results from both spectroscopic and analysis studies proved the 2AA to having the ester link. Absorption spectroscopy and solvent shift data are used to characterise their spectral activity. Luminescence studies involving fluorescence and phosphorescence analysis indicates efficient intersystem crossing to triplet state and n-π* nature of the lowest excited triplet state. The polymerisation activity was studied using methyl methacrylate (MMA) and analysis of the cure rate was measured using the gravimetric method. All the compounds are shown to be highly dependent on the structure. However, the rate of polymerisation (Rp) was reduced in the presence of amine. This is consistent with other results, proving the behaviour of derivatives with n-π* configuration. Hardness tests for all compounds took place using a different formula of acrylated resin/monomer systems. The excited state characteristics of the methyl derivatives have also been examined using micro and nanosecond flash photolysis. Triplet absorption spectra of all the anthraquinone derivatives show a significant red shift in the region of 340–370 nm with increasing solvent polarity due to stabilisation of the lowest triplet state by solvent reorganization. Hydrogen atom abstraction takes place in 2 propanol, forming a semiquinone radical. In the presence of the tertiary amine, triethylamine, all anthraquinone derivatives show the formation of intermediary species related to either the exciplex or the radical ion pair. Under aerobic conditions, the first decay rate for all anthraquinone derivatives increases and showed oxygen to be a good quencher with a bimolecular rate constant of around 2 × 10 8 mol. dm −3 s −1 . Relative to benzophenone, the molar absorption coefficient, ε, and quantum yield of intersystem crossing, Φisc were calculated, and it is summarised that the value for Φisc for all compound is less than 1.00 and controls to a major extent their photochemical activities

Diagnosis and assessment of dilated cardiomyopathy: a guideline protocol from the British Society of Echocardiography.

Heart failure (HF) is a debilitating and life-threatening condition, with 5-year survival rate lower than breast or prostate cancer. It is the leading cause of hospital admission in over 65s, and these admissions are projected to rise by more than 50% over the next 25 years. Transthoracic echocardiography (TTE) is the first-line step in diagnosis in acute and chronic HF and provides immediate information on chamber volumes, ventricular systolic and diastolic function, wall thickness, valve function and the presence of pericardial effusion, while contributing to information on aetiology. Dilated cardiomyopathy (DCM) is the third most common cause of HF and is the most common cardiomyopathy. It is defined by the presence of left ventricular dilatation and left ventricular systolic dysfunction in the absence of abnormal loading conditions (hypertension and valve disease) or coronary artery disease sufficient to cause global systolic impairment. This document provides a practical approach to diagnosis and assessment of dilated cardiomyopathy that is aimed at the practising sonographer

The novel choline kinase inhibitor ICL-CCIC-0019 reprograms cellular metabolism and inhibits cancer cell growth.

The glycerophospholipid phosphatidylcholine is the most abundant phospholipid species of eukaryotic membranes and essential for structural integrity and signaling function of cell membranes required for cancer cell growth. Inhibition of choline kinase alpha (CHKA), the first committed step to phosphatidylcholine synthesis, by the selective small-molecule ICL-CCIC-0019, potently suppressed growth of a panel of 60 cancer cell lines with median GI50 of 1.12 μM and inhibited tumor xenograft growth in mice. ICL-CCIC-0019 decreased phosphocholine levels and the fraction of labeled choline in lipids, and induced G1 arrest, endoplasmic reticulum stress and apoptosis. Changes in phosphocholine cellular levels following treatment could be detected non-invasively in tumor xenografts by [18F]-fluoromethyl-[1,2–2H4]-choline positron emission tomography. Herein, we reveal a previously unappreciated effect of choline metabolism on mitochondria function. Comparative metabolomics demonstrated that phosphatidylcholine pathway inhibition leads to a metabolically stressed phenotype analogous to mitochondria toxin treatment but without reactive oxygen species activation. Drug treatment decreased mitochondria function with associated reduction of citrate synthase expression and AMPK activation. Glucose and acetate uptake were increased in an attempt to overcome the metabolic stress. This study indicates that choline pathway pharmacological inhibition critically affects the metabolic function of the cell beyond reduced synthesis of phospholipids

Deprivation and exposure to public activities during the COVID-19 pandemic in England and Wales

BACKGROUND: Differential exposure to public activities may contribute to stark deprivation-related inequalities in SARS-CoV-2 infection and outcomes but has not been directly investigated. We set out to investigate whether participants in Virus Watch-a large community cohort study based in England and Wales-reported differential exposure to public activities and non-household contacts during the autumn-winter phase of the COVID-19 pandemic according to postcode-level socioeconomic deprivation. METHODS: Participants (n=20 120-25 228 across surveys) reported their daily activities during 3 weekly periods in late November 2020, late December 2020 and mid-February 2021. Deprivation was quantified based on participants' residential postcode using English or Welsh Index of Multiple Deprivation quintiles. We used Poisson mixed-effect models with robust standard errors to estimate the relationship between deprivation and risk of exposure to public activities during each survey period. RESULTS: Relative to participants in the least deprived areas, participants in the most deprived areas exhibited elevated risk of exposure to vehicle sharing (adjusted risk ratio (aRR) range across time points: 1.73-8.52), public transport (aRR: 3.13-5.73), work or education outside of the household (aRR: 1.09-1.21), essential shops (aRR: 1.09-1.13) and non-household contacts (aRR: 1.15-1.19) across multiple survey periods. CONCLUSION: Differential exposure to essential public activities-such as attending workplaces and visiting essential shops-is likely to contribute to inequalities in infection risk and outcomes. Public health interventions to reduce exposure during essential activities and financial and practical support to enable low-paid workers to stay at home during periods of intense transmission may reduce COVID-related inequalities

Household overcrowding and risk of SARS-CoV-2: analysis of the Virus Watch prospective community cohort study in England and Wales

Background: Household overcrowding is associated with increased risk of infectious diseases across contexts and countries. Limited data exist linking household overcrowding and risk of COVID-19. We used data collected from the Virus Watch cohort to examine the association between overcrowded households and SARS-CoV-2. // Methods: The Virus Watch study is a household community cohort of acute respiratory infections in England and Wales. We calculated overcrowding using the measure of persons per room for each household. We considered two primary outcomes: PCR-confirmed positive SARS-CoV-2 antigen tests and laboratory-confirmed SARS-CoV-2 antibodies. We used mixed-effects logistic regression models that accounted for household structure to estimate the association between household overcrowding and SARS-CoV-2 infection. // Results: 26,367 participants were included in our analyses. The proportion of participants with a positive SARS-CoV-2 PCR result was highest in the overcrowded group (9.0%; 99/1,100) and lowest in the under-occupied group (4.2%; 980/23,196). In a mixed-effects logistic regression model, we found strong evidence of an increased odds of a positive PCR SARS-CoV-2 antigen result (odds ratio 2.45; 95% CI:1.43–4.19; p-value=0.001) and increased odds of a positive SARS-CoV-2 antibody result in individuals living in overcrowded houses (3.32; 95% CI:1.54–7.15; p-value<0.001) compared with people living in under-occupied houses. // Conclusion: Public health interventions to prevent and stop the spread of SARS-CoV-2 should consider the risk of infection for people living in overcrowded households and pay greater attention to reducing household transmission