Protection against Radiotherapy-Induced Toxicity

Radiation therapy is a highly utilized therapy in the treatment of malignancies with up to 60% of cancer patients receiving radiation therapy as a part of their treatment regimen. Radiation therapy does, however, cause a wide range of adverse effects that can be severe and cause permanent damage to the patient. In an attempt to minimize these effects, a small number of compounds have been identified and are in use clinically for the prevention and treatment of radiation associated toxicities. Furthermore, there are a number of emerging therapies being developed for use as agents that protect against radiation-induced toxicities. The aim of this review was to evaluate and summarise the evidence that exists for both the known radioprotectant agents and the agents that show promise as future radioprotectant agents

Molecular mechanisms underlying the effects of statins in the central nervous system

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, commonly referred to as statins, are widely used in the treatment of dyslipidaemia, in addition to providing primary and secondary prevention against cardiovascular disease and stroke. Statins’ effects on the central nervous system (CNS), particularly on cognition and neurological disorders such as stroke and multiple sclerosis, have received increasing attention in recent years, both within the scientific community and in the media. Current understanding of statins’ effects is limited by a lack of mechanism-based studies, as well as the assumption that all statins have the same pharmacological effect in the central nervous system. This review aims to provide an updated discussion on the molecular mechanisms contributing to statins’ possible effects on cognitive function, neurodegenerative disease, and various neurological disorders such as stroke, epilepsy, depression and CNS cancers. Additionally, the pharmacokinetic differences between statins and how these may result in statin-specific neurological effects are also discussed

Recognizing thyrotoxicosis in a patient with bipolar mania: a case report

<p>Abstract</p> <p>Background</p> <p>A thyroid stimulating hormone level is commonly measured in patients presenting with symptoms of mania in order to rule out an underlying general medical condition such as hyperthyroidism or thyrotoxicosis. Indeed, many cases have been reported in which a patient is initially treated for bipolar mania, but is later found to have a thyroid condition. Several case reports have noted the development of a thyroid condition in bipolar patients either on lithium maintenance treatment or recently on lithium treatment.</p> <p>Case presentation</p> <p>We review a case in which a patient with a long history of bipolar disorder presents with comorbid hyperthyroidism and bipolar mania after recent discontinuation of lithium treatment.</p> <p>Conclusion</p> <p>Physicians should consider a comorbid hyperthyroidism in bipolar manic patients only partially responsive to standard care treatment with a mood stabilizer and antipsychotic.</p

Reconstituted B cell receptor signaling reveals carbohydrate-dependent mode of activation

Activation of immune cells (but not B cells) with lectins is widely known. We used the structurally defined interaction between influenza hemagglutinin (HA) and its cell surface receptor sialic acid (SA) to identify a B cell receptor (BCR) activation modality that proceeded through non-cognate interactions with antigen. Using a new approach to reconstitute antigen-receptor interactions in a human reporter B cell line, we found that sequence-defined BCRs from the human germline repertoire could be triggered by both complementarity to influenza HA and a separate mode of signaling that relied on multivalent ligation of BCR sialyl-oligosaccharide. The latter suggested a new mechanism for priming naïve B cell responses and manifested as the induction of SA-dependent pan-activation by peripheral blood B cells. BCR crosslinking in the absence of complementarity is a superantigen effect induced by some microbial products to subvert production of antigen-specific immune responses. B cell superantigen activity through affinity for BCR carbohydrate is discussed

<i>RPA3-UMAD1</i> rs12702634 and rheumatoid arthritis-associated interstitial lung disease in European ancestry

Objective Recently, a genome-wide association study identified an association between RA-associated interstitial lung disease (ILD) and RPA3-UMAD1 rs12702634 in the Japanese population, especially for patients with a usual interstitial pneumonia (UIP) pattern. We aimed to replicate this association in a European population and test for interaction with MUC5B rs35705950.Methods In this genetic case-control association study, patients with RA and ILD and controls with RA and no ILD were included from France, the USA and the Netherlands. Only cases and controls from European genetic ancestries determined by principal components analysis were included in the analyses. RA was defined by the 1987 ACR or 2010 ACR/EULAR criteria and ILD by chest high-resolution CT scan, except in the control dataset from the Netherlands, where the absence of ILD was determined by chart review. Patients were genotyped for RPA3-UMAD1 rs12702634 and MUC5B rs35705950. Associations were tested using logistic regression adjusted for sex, age at RA onset, age at ILD onset or at certified absence of ILD, tobacco smoking status and country of origin.Results Among the 883 patients included, 322 were RA-ILD cases (36.5%). MUC5B rs35705950 was strongly associated with RA-ILD in all datasets {combined adjusted odds ratio [OR] 2.9 [95% CI 2.1, 3.9], P = 1.1 x 10-11. No association between RPA3-UMAD1 rs12702634 and RA-ILD was observed [combined OR 1.2 (95% CI 0.8, 1.6), P = 0.31. No interaction was found between RPA3-UMAD1 rs12702634 and MUC5B rs35705950 (P = 0.70).Conclusion Our findings did not support a contribution of RPA3-UMAD1 rs12702634 to the overall RA-ILD susceptibility in the European population.What does this mean for patients?Interstitial lung disease (ILD) can develop in 10-60% of patients with rheumatoid arthritis (RA) and is associated with an increased risk of death. We do not yet fully understand why RA-ILD occurs, but risk factors include genetics and environmental factors such as tobacco smoking. Identifying new genetic risk factors for RA-ILD may improve our understanding of how this disease occurs, help us categorize patients in terms of their risk level and help us to potentially identify new drug targets. A previous Japanese genetic study identified the RPA3-UMAD1 rs12702634 common genetic variant as a risk factor for RA-ILD. However, a second Japanese study failed to replicate these findings. In this international study including patients with European ancestry, we did not find that RPA3-UMAD1 rs12702634 contributed to the overall risk of RA-ILD. Our findings highlight the importance of conducting analyses that try to replicate the results of a study. We also emphasize that genetic associations-even those already reported-require rigorous testing in different groups of people before we can conclude that they contribute to disease risk. Ongoing collaboration and multi-ancestry genetic studies are essential in order to advance our understanding of the complex genetics underlying RA-ILD

Effect of Propranolol on Functional Connectivity in Autism Spectrum Disorder—A Pilot Study

A decrease in interaction between brain regions is observed in individuals with autism spectrum disorder (ASD), which is believed to be related to restricted neural network access in ASD. Propranolol, a beta-adrenergic antagonist, has revealed benefit during performance of tasks involving flexibility of access to networks, a benefit also seen in ASD. Our goal was to determine the effect of propranolol on functional connectivity in ASD during a verbal decision making task as compared to nadolol, thereby accounting for the potential spurious fMRI effects due to peripheral hemodynamic effects of propranolol. Ten ASD subjects underwent fMRI scans after administration of placebo, propranolol or nadolol, while performing a phonological decision making task. Comparison of functional connectivity between pre-defined ROI-pairs revealed a significant increase with propranolol compared to nadolol, suggesting a potential imaging marker for the cognitive effects of propranolol in ASD

A National Survey of Hereditary Angioedema and Acquired C1 Inhibitor Deficiency in the United Kingdom

Background: Detailed demographic data on people with hereditary angioedema (HAE) and acquired C1 inhibitor deficiency in the United Kingdom are relatively limited. Better demographic data would be beneficial in planning service provision, identifying areas of improvement, and improving care./ Objective: To obtain more accurate data on the demographics of HAE and acquired C1 inhibitor deficiency in the United Kingdom, including treatment modalities and services available to patients./ Methods: A survey was distributed to all centers in the United Kingdom that look after patients with HAE and acquired C1 inhibitor deficiency to collect these data./ Results: The survey identified 1152 patients with HAE-1/2 (58% female and 92% type 1), 22 patients with HAE with normal C1 inhibitor, and 91 patients with acquired C1 inhibitor deficiency. Data were provided by 37 centers across the United Kingdom. This gives a minimum prevalence of 1:59,000 for HAE-1/2 and 1:734,000 for acquired C1 inhibitor deficiency in the United Kingdom. A total of 45% of patients with HAE were on long-term prophylaxis (LTP) with the most used medication being danazol (55% of all patients on LTP). Eighty-two percent of patients with HAE had a home supply of acute treatment with C1 inhibitor or icatibant. A total of 45% of patients had a supply of icatibant and 56% had a supply of C1 inhibitor at home./ Conclusions: Data obtained from the survey provide useful information about the demographics and treatment modalities used in HAE and acquired C1 inhibitor deficiency in the United Kingdom. These data are useful for planning service provision and improving services for these patients

Three low-mass companions around aged stars discovered by TESS

We report the discovery of three transiting low-mass companions to aged stars: a brown dwarf (TOI-2336b) and two objects near the hydrogen burning mass limit (TOI-1608b and TOI-2521b). These three systems were first identified using data from the Transiting Exoplanet Survey Satellite (TESS). TOI-2336b has a radius of $1.05\pm 0.04\ R_J$, a mass of $69.9\pm 2.3\ M_J$ and an orbital period of 7.71 days. TOI-1608b has a radius of $1.21\pm 0.06\ R_J$, a mass of $90.7\pm 3.7\ M_J$ and an orbital period of 2.47 days. TOI-2521b has a radius of $1.01\pm 0.04\ R_J$, a mass of $77.5\pm 3.3\ M_J$ and an orbital period of 5.56 days. We found all these low-mass companions are inflated. We fitted a relation between radius, mass and incident flux using the sample of known transiting brown dwarfs and low-mass M dwarfs. We found a positive correlation between the flux and the radius for brown dwarfs and for low-mass stars that is weaker than the correlation observed for giant planets.Comment: 20 pages, 13 figures; submitted to MNRA