Residual erythropoiesis protects against myocardial hemosiderosis in transfusion-dependent thalassemia by lowering labile plasma iron via transient generation of apotransferrin

Cardiosiderosis is a leading cause of mortality in transfusion-dependent thalassemias. Plasma non-transferrin-bound iron and its redox-active component, labile plasma iron, are key sources of iron loading in cardiosiderosis. Risk factors were identified in 73 patients with or without cardiosiderosis. Soluble transferrin receptor-1 levels were significantly lower in patients with cardiosiderosis (odds ratio 21). This risk increased when transfusion-iron loading rates exceeded the erythroid transferrin uptake rate (derived from soluble transferrin receptor-1) by >0.21mg/kg/d (odds ratio 48). Labile plasma iron was >3-fold higher where this uptake rate threshold was exceeded, but non-transferrin-bound iron and transferrin saturation were comparable. Cardiosiderosis risk was also decreased in patients with low liver iron, ferritin and labile plasma iron, or high bilirubin, reticulocyte counts or hepcidin. We hypothesized that high erythroid transferrin uptake rate decreases cardiosiderosis through increased erythroid re-generation of apotransferrin. To test this, iron uptake and intracellular reactive oxygen species were examined in HL-1 cardiomyocytes under conditions modelling transferrin effects on non-transferrin-bound iron speciation with ferric citrate. Intracellular iron and reactive oxygen species increased with ferric citrate concentrations especially where iron-to-citrate ratios exceeded 1:100, i.e. conditions favoring kinetically labile monoferric rather than oligomer species. Excess iron-binding equivalents of apotransferrin inhibited iron uptake, decreased intracellular reactive oxygen species and labile plasma iron, under conditions favoring monoferric species. In conclusion, high transferrin iron utilisation, relative to the transfusion-iron load rate, decreases the cardiosiderotic risk. A putative mechanism is the transient re-generation of apotransferrin by an active erythron, rapidly binding labile plasma iron-detectable ferric monocitrate species

Solid-Phase Synthesis and In-Silico Analysis of Iron-Binding Catecholato Chelators

Siderophores are iron-complexing compounds synthesized by bacteria and fungi. They are low molecular weight compounds (500-1500 Daltons) possessing high affinity for iron(III). Since 1970 a large number of siderophores have been characterized, the majority using hydroxamate or catecholate as functional groups. The biosynthesis of siderophores is typically regulated by the iron levels of the environment where the organism is located. Because of their exclusive affinity and specificity for iron(III), natural siderophores and their synthetic derivatives have been exploited in the treatment of human iron-overload diseases, as both diagnostic and therapeutic agents. Here, solid-phase approach for the preparation of hexadentate, peptide-based tricatecholato containing peptides is described. The versatility of the synthetic method allows for the design of a common scaffolding structure whereby diverse ligands can be conjugated. With so many possibilities, a computational approach has been developed which will facilitate the identification of those peptides which are capable of providing a high affinity iron(III) binding site. This study reports an integrated computational/synthetic approach towards a rational development of peptide-based siderophores

The Staffordshire Arthritis, Musculoskeletal, and Back Assessment (SAMBA) Study: a prospective observational study of patient outcome following referral to a primary-secondary care musculoskeletal interface service

<p>Abstract</p> <p>Background</p> <p>Recent healthcare policy has shifted the management of musculoskeletal conditions in the UK away from secondary care towards Clinical Assessment and Treatment Services at the primary-secondary care interface. However, little is known about the outcome of patients with musculoskeletal conditions referred from primary care to Clinical Assessment and Treatment Services or how best to identify those patients at high risk of poor outcome in this setting. We describe the protocol for a twelve-month prospective observational study which aims to describe the outcome of patients referred to musculoskeletal and back pain services at the primary-secondary care interface and to develop simple prognostic measures to guide clinical prioritisation and triage.</p> <p>Methods/Design</p> <p>All patients referred over a twelve-month period from primary care to musculoskeletal and back pain clinics in the primary-secondary care interface Clinical Assessment and Treatment Service in North Staffordshire will be mailed a postal questionnaire prior to their consultation. This will collect information on quality of life, general health, anxiety and depression, pain, healthcare utilisation including medication use, occupational characteristics, and socio-demographics. At the consultation in the interface clinic, the clinical diagnosis, investigations requested, and clinical interventions will be recorded. Follow-up data for the twelve-month period subsequent to recruitment will be collected via mailed follow-up questionnaires at 6 and 12 months, and review of medical records.</p> <p>Discussion</p> <p>This twelve-month prospective observational study of patients referred to a musculoskeletal Clinical Assessment and Treatment Service will assess the management and outcome of musculoskeletal care at the primary-secondary care interface as proposed in the Musculoskeletal Services Framework.</p

Using salt counterions to modify β2-agonist behaviour in vivo

This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. © 2016 American Chemical Society.There is a paucity of data describing the impact of salt counterions on the biological performance of inhaled medicines in vivo. The aim of this study was to determine if the coadministration of salt counterions influenced the tissue permeability and airway smooth muscle relaxation potential of salbutamol, formoterol, and salmeterol. The results demonstrated that only salbutamol, when formulated with an excess of the 1-hydroxy-2-naphthoate (1H2NA) counterion, exhibited a superior bronchodilator effect (p < 0.05) compared to salbutamol base. The counterions aspartate, maleate, fumarate, and 1H2NA had no effect on the ability of formoterol or salmeterol to reduce airway resistance in vivo. Studies using guinea pig tracheal sections showed that the salbutamol:1H2NA combination resulted in a significantly faster (p < 0.05) rate of tissue transport compared to salbutamol base. Furthermore, when the relaxant activity of salbutamol was assessed in vitro using electrically stimulated, superfused preparations of guinea pig trachea, the inhibition of contraction by salbutamol in the presence of 1H2NA was greater than with salbutamol base (a total inhibition of 94.13%, p < 0.05). The reason for the modification of salbutamol’s behavior upon administration with 1H2NA was assigned to ion-pair formation, which was identified using infrared spectroscopy. Ion-pair formation is known to modify a drug’s physicochemical properties, and the data from this study suggested that the choice of counterion in inhaled pharmaceutical salts should be considered carefully as it has the potential to alter drug action in vivo.Peer reviewe

Biomarkers of oxidant stress, insulin sensitivity and endothelial activation in rheumatoid arthritis: a cross-sectional study of their association with accelerated atherosclerosis

<p>Abstract</p> <p>Background</p> <p>Women with rheumatoid arthritis (RA) have increased morbidity and mortality due to coronary heart disease. Chronic systemic inflammation is known to accelerate atherosclerosis and increase arterial stiffness in patients, but other mechanisms may also be involved. Biomarkers of oxidant stress, inflammation, insulinaemia and endothelial dysfunction were measured in blood and urine from 46 RA patients and 48 age-matched controls. Plaque formation and intima-medial thickness (IMT) were measured using B-mode carotid Doppler scan.</p> <p>Findings</p> <p>The prevalence of plaque was increased (p = 0.042) in RA patients between 50–59 years old compared to the same age group in controls. 8-isoprostane (p = 0.004), C-reactive protein (p < 0.001), interleukin-6 (p < 0.001), insulin (p = 0.035), adiponectin (p = 0.012), vascular cell adhesion molecule (VCAM) (p = 0.029) and E-selectin (p < 0.001) were all increased while selenium (p = 0.003) and LDL-cholesterol (p = 0.025) were both decreased in all RA patients. 8-isoprostane correlated with 10 year cardiac risk (r = 0.55, p < 0.001), VCAM with IMT (r = 0.37, p = 0.012) and E-selectin with rheumatoid factor titre (r = 0.43, p = 0.003) in RA patients. In the control group, age, carotid IMT, VCAM, systolic blood pressure and smoking status were all associated with plaque development whereas in RA patients only age was associated with plaque.</p> <p>Conclusion</p> <p>The burden of atherosclerosis is particularly increased in middle-aged women with RA. Patients with RA have increased levels of oxidant stress, inflammation, insulin and soluble adhesion molecules. As the association between classical risk factors was much weaker in RA patients compared to controls, these additional factors may be more important in the accelerated development of atheroma in RA.</p

Design of Bifunctional Dendritic 5-Aminolevulinic Acid and Hydroxypyridinone Conjugates for Photodynamic Therapy

Iron chelators have recently attracted interest in the field of photodynamic therapy (PDT) owing to their role in enhancement of intracellular protoporphyrin IX (PpIX) generation induced by 5-aminolevulinic acid (ALA) via the biosynthetic heme cycle. Although ALA is widely used in PDT, cellular uptake of ALA is limited by its hydrophilicity. In order to improve ALA delivery and enhance the PpIX production, several dendrimers incorporating both ALA and 3-hydroxy-4-pyridinone (HPO) were synthesized. The ability of the dendrimers to enter cells and be metabolized to the PpIX photosensitizer was studied in several human cancer cell lines. The dendrimers were found to be significantly more efficient than ALA alone in PpIX production. The higher intracellular PpIX levels showed a clear correlation with enhanced cellular phototoxicity following light exposure. Dendritic derivatives are therefore capable of efficiently delivering both ALA and HPO, which act synergistically to amplify in vitro PpIX levels and enhance PDT efficacy

How We Talk about the Movies: A Comparison of Australian, British and American Film Genre Terms

© 2020 Hollie White and Philip Hider. Vocabulary or terminological control has been an issue of critical information practice for Australian information professionals for many years. In the 1970s Australian libraries began to supplement Library of Congress Subject Headings with their own List of Australian Subject Headings, and today there remains the bibliographic need to cover uniquely Australian terms and concepts, including those about Indigenous Australian culture. The library world is not the only domain, however, to have developed vocabularies to describe and make sense of information resources. Comparison of film genre vocabularies is of particular interest because film studies have often assumed a fixed set of categories, regardless of geography, culture or time. Although much of today’s film industry is ‘global’, with a strong Hollywood influence on genre to sell movies, this does not mean that filmmakers, nor film audiences, use a set vocabulary. This paper looks at whether similar geographical biases may be discerned in vocabularies used in the domain of film curation by examining the variation in terminology and the classification of film genres used by film institutes based in Australia, the United Kingdom and the United States

The impact of polymyalgia rheumatica on intimate sexual relationships: findings from the PMR Cohort Study

Objectives To determine the impact of polymyalgia rheumatica (PMR) on intimate and sexual relationships over time. Methods The PMR Cohort study (UKCRN ID16477) is a longitudinal study of patients with incident PMR in English primary care. Participants were sent questions about their PMR symptoms, treatments and overall health, including an item about how their PMR symptoms affected intimate and sexual relationships. The proportion reporting the relevance of intimate and sexual relationships, the effect of PMR on these relationships and the associations with PMR symptoms and general health were explored. Results 652/739 patients (response 90.1%) completed the baseline survey, with 446/576 (78.0%) responding at two years. Mean age of responders was 72.4 years. 62.2% were female. 363/640 (56.7%) participants reported that intimate and sexual relationships were not relevant to them at baseline. 113/277 (40.8%) reported that PMR had a large effect on intimate relationships. This proportion decreased over time in those responding to 12- and 24-month surveys, but continued to be associated with younger age, male gender, worse PMR symptoms, poorer physical function and worse mental health. Conclusion Intimate and sexual relationships are increasingly recognised as important for healthy ageing and health professionals should consider this as part of a holistic approach to the management of PMR. Lay summary What does this mean for patients? Polymyalgia rheumatica (PMR) is a condition that affects older people. It causes pain and stiffness in the hips and shoulders, as well as making people feel very tired. It can stop people from doing routine things that they previously did with no problem (e.g. walking upstairs, getting out of a car). We know very little about how PMR affects people’s personal lives. Therefore, we sent a questionnaire to 652 people in England with newly diagnosed PMR. One question asked people whether their PMR affected their “intimate and sexual relationships”. We asked the same question again 1 and 2 years later. Just over half of people said this wasn’t relevant for them. For people where it mattered to them, 4 in 10 said PMR had a large effect on their relationships. Men, people who were younger, those with worse PMR symptoms and worse mental health were more likely to report a negative effect of PMR on their relationships. The proportion of people reporting a problem reduced over time, as people’s PMR symptoms improved. We suggest that doctors should consider people’s intimate and sexual relationships as part of their care for people with PMR

Fraction size in radiation treatment for breast conservation in early breast cancer

Backgroun

Health-related quality of life in gout in primary care: baseline findings from a cohort study

Objectives: To examine gout-related, comorbid, and sociodemographic characteristics associated with generic and disease-specific health-related quality of life (HRQOL) in gout. Methods: Adults with gout from 20 general practices were mailed a questionnaire containing the Health Assessment Questionnaire-Disability Index (HAQ-DI), Short-Form-36 Physical Function subscale (PF-10), Gout Impact Scale (GIS), and questions about gout-specific, comorbid and sociodemographic characteristics. Variables associated with HRQOL were examined using multivariable linear regression models. Results: A total of 1184 completed questionnaires were received (response 65.9%). Worse generic and gout-specific HRQOL was associated with frequent gout attacks (>= 5 attacks PF-10 beta = -4.90, HAQ-DI beta = 0.14, GIS subscales beta = 8.94, 33.26), current attack (HAQ-DI beta = 0.15, GIS beta = -1.94, 18.89), oligo/polyarticular attacks (HAQ-DI beta = 0.11, GIS beta = 0.78, 7.86), body pain (PF-10 beta = -10.68, HAQ-DI beta = 0.29, GIS beta = 2.61, 11.89), anxiety (PF-10 beta = -1.81, HAQ-DI beta = 0.06, GIS beta = 0.38, 1.70), depression (PF-10 beta = -1.98, HAQ-DI beta = 0.06, GIS 0.42, 1.47) and alcohol non-consumption (PF-10 beta = -16.10, HAQ-DI beta = 0.45). Gout-specific HRQOL was better in Caucasians than non-Caucasians (GIS beta = -13.05, -13.48). Poorer generic HRQOL was associated with diabetes mellitus (PF-10 beta = -4.33, HAQ-DI beta = 0.14), stroke (PF-10 beta = -12.21, HAQ-DI beta = 0.37), renal failure (PF-10 beta = -9.43, HAQ-DI beta = 0.21), myocardial infarction (HAQ-DI beta = 0.17), female gender (PF-10 beta = -17.26, HAQ-DI beta = 0.43), deprivation (PF-10 beta = 7.80, HAQ-DI beta = 0.19), and body mass index >= 35 kg/m(2) (PF-10 beta = -6.10, HAQ-DI beta = 0.21). Conclusions: HRQOL in gout is impaired by gout-specific, comorbid, and sociodemographic characteristics, highlighting the importance of comorbidity screening and early urate-lowering therapy. Both gout specific and generic questionnaires identify the impact of disease-specific features on HRQOL but studies focusing on comorbidity should include generic instruments