Selenium, a trace element that is fundamental to human health, is incorporated into some proteins as selenocysteine (Sec), generating a family of selenoproteins. Sec incorporation is mediated by a multiprotein complex that includes Sec insertion sequence-binding protein 2 (SECISBP2; also known as SBP2). Here, we describe subjects with compound heterozygous defects in the SECISBP2 gene. These individuals have reduced synthesis of most of the 25 known human selenoproteins, resulting in a complex phenotype. Azoospermia, with failure of the latter stages of spermatogenesis, was associated with a lack of testis-enriched selenoproteins. An axial muscular dystrophy was also present, with features similar to myopathies caused by mutations in selenoprotein N (SEPN1). Cutaneous deficiencies of antioxidant selenoenzymes, increased cellular ROS, and susceptibility to ultraviolet radiation-induced oxidative damage may mediate the observed photosensitivity. Reduced levels of selenoproteins in peripheral blood cells were associated with impaired T lymphocyte proliferation, abnormal mononuclear cell cytokine secretion, and telomere shortening. Paradoxically, raised ROS in affected subjects was associated with enhanced systemic and cellular insulin sensitivity, similar to findings in mice lacking the antioxidant selenoenzyme glutathione peroxidase 1 (GPx1). Thus, mutation of SECISBP2 is associated with a multisystem disorder with defective biosynthesis of many selenoproteins, highlighting their role in diverse biological processes.

Key Points• Type I IFN therapies can cause a dose-dependent TMA.• Recombinant type I IFN therapies should be stopped at the earliest opportunity in patients who develop TMA.Many drugs have been reported to cause thrombotic microangiopathy (TMA), yet evidence supporting a direct association is often weak. In particular, TMA has been reported in association with recombinant type I interferon (IFN) therapies, with recent concern regarding the use of IFN in multiple sclerosis patients. However, a causal association has yet to be demonstrated. Here, we adopt a combined clinical and experimental approach to provide evidence of such an association between type I IFN and TMA. We show that the clinical phenotype of cases referred to a national center is uniformly consistent with a direct dose-dependent drug-induced TMA. We then show that dosedependent microvascular disease is seen in a transgenic mouse model of IFN toxicity. This includes specific microvascular pathological changes seen in patient biopsies and is dependent on transcriptional activation of the IFN response through the type I interferon a/b receptor (IFNAR). Together our clinical and experimental findings provide evidence of a causal link between type I IFN and TMA. As such, recombinant type I IFN therapies should be stopped at the earliest stage in patients who develop this complication, with implications for risk mitigation. (Blood. 2016;128(24):2824-2833

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Staff doses arising from the use of X-rays are principally due to scattered radiation. This is related to the dose received by the patient expressed as the dose-area product (DAP). Doses to patients in interventional radiology are generally higher than for other fluoroscopically guided procedures. Doses to interventional radiologists are, therefore, amongst the highest associated with the use of diagnostic X-rays. The results of staff dose monitoring normalized to DAP should provide an indicator of those procedures which are associated with particularly high radiation exposures to staff, and should help to identify those radiologists whose practice may result in unnecessarily high doses to themselves. A study has been made of patient doses in two X-ray rooms used for interventional procedures associated with vascular and liver diseases. Doses to radiologists in these rooms were normalized to DAP. It was found that the average doses to the body, neck and hands were 0.05, 0.89 and 2.45 microSv/(Gy cm2), respectively for those radiologists with no significant involvement in hepatobiliary procedures. Higher doses were found for one radiologist whose workload included biliary drainage. The whole body dose was 0.17 microSv/(Gy cm2) or 5.8 mSv per year. It was shown that the doses to the neck and hands for the biliary drainage work was 6.59 and 29.0 microSv/(Gy cm2), respectively. This study has demonstrated the value of DAP as a measure of radiologist workload in respect of its significance in terms of staff dose.

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