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.

The interest in regulatory B cells (Bregs) began in the 1970s with the evidence that B cells could downregulate the immune system by the production of “inhibitory” antibodies. Subsequently, a series of results from different studies have emphasized that B cells have antibody‐independent immunoregulatory functions. Since then, different subsets of B cells with regulatory functions and their development and mechanisms of action have been identified both in human and in animal models of inflammation, transplantation, and autoimmunity. The present review outlines the suggested pathways by which Bregs develop, describes the different subsets of Bregs with their phenotypes and function as well as their role in transplantation, highlighting the differences between human and animal studies throughout.

Chronic antibody-mediated rejection, a common cause of renal transplant failure, has a variable clinical phenotype. Understanding why some with chronic antibody-mediated rejection progress slowly may help develop more effective therapies. B lymphocytes act as antigen-presenting cells for in vitro indirect antidonor interferon-γ production in chronic antibody-mediated rejection, but many patients retain the ability to regulate these responses. Here we test whether particular patterns of T and B cell antidonor response associate with the variability of graft dysfunction in chronic antibody-mediated rejection. Our results confirm that dynamic changes in indirect antidonor CD4+ T-cell responses correlate with changes in estimated glomerular filtration rates, independent of other factors. Graft dysfunction progressed rapidly in patients who developed unregulated B-cell–driven interferon-γ production. However, conversion to a regulated or nonreactive pattern, which could be achieved by optimization of immunosuppression, associated with stabilization of graft function. Functional regulation by B cells appeared to activate an interleukin-10 autocrine pathway in CD4+ T cells that, in turn, impacted on antigen-specific responses. Thus, our data significantly enhance the understanding of graft dysfunction associated with chronic antibody-mediated rejection and provide the foundation for strategies to prolong renal allograft survival, based on regulation of interferon-γ production.

Dehydrohalogenation of secondary diarylphosphine ruthenium complexes in the presence of benzonitrile yields stable, isolable nitrile adducts of the formula [Ru(η 5indenyl)(PAr 2 )(NCPh)(PPh 3 )], in which the terminal phosphido ligand is pyramidal at P and contains a stereochemically active lone pair. Unlike the analogous carbonyl adducts [Ru(η 5 -indenyl)(PAr 2 )(CO)(PPh 3 )], these benzonitrile complexes behave as masked sources of the highly reactive planar phosphido complexes [Ru(η 5 -indenyl)(PAr 2 )(PPh 3 )], which contain a RuPAr 2 π bond. This is illustrated by the addition (or cycloaddition) reactions of the benzonitrile adducts with dihydrogen, methyl iodide, and 1-hexene, as well as their thermal decomposition via orthometalation of the PPh 3 ligand. Enthalpies of CO vs NCPh dissociation from the [Ru(η 5indenyl)(PR 2 )(PPh 3 )] fragments (R = alkyl, aryl) have been calculated, as has the trajectory of addition of H 2 to the model planar phosphido complex [Ru(η 5 -indenyl)(PMe 2 )(PMe 3 )]. The latter study shows the intermediacy of an η 2 -H 2 adduct, [Ru(η 5 -indenyl)(PAr 2 )(η 2 -H 2 )(PPh 3 )], in the formation of [RuH(η 5 -indenyl)(HPMe 2 )(PMe 3 )], a further indication of the importance of the variable binding modes of the terminal phosphido ligand in this system.

Summary The impact of the duration of delayed graft function (DGF) on graft survival is poorly characterized in controlled donation after circulatory death (DCD) donor kidney transplantation. A retrospective analysis was performed on 225 DCD donor kidney transplants between 2011 and 2016. When patients with primary nonfunction were excluded (n = 9), 141 recipients (65%) had DGF, with median (IQR) duration of dialysis dependency of 6 (2–11.75) days. Longer duration of dialysis dependency was associated with lower estimated glomerular filtration rate at 1 year, and a higher rate of acute rejection. On Kaplan–Meier analysis, the presence of DGF was associated with lower graft survival (log‐rank test P = 0.034), though duration of DGF was not (P = 0.723). However, multivariable Cox regression analysis found that only acute rejection was independently associated with lower graft survival [HR (95% CI) 4.302 (1.617–11.450); P = 0.003], whereas the presence of DGF and DGF duration were not. In controlled DCD kidney transplantation, DGF duration itself may not be independently associated with graft survival; rather, it may be that acute rejection associated with prolonged DGF is the poor prognostic factor.

Pituitary carcinoma occurs in ~0.2% of resected pituitary tumours and carries a poor prognosis (mean survival <4 years), with standard chemotherapy regimens showing limited efficacy. Recent evidence suggests that temozolomide (TMZ), an orally-active alkylating agent used principally in the management of glioblastoma, may also be effective in controlling aggressive/invasive pituitary adenomas/carcinomas. A low level of expression of the DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) predicts TMZ responsiveness in glioblastomas, and a similar correlation has been observed in the majority of aggressive pituitary adenomas/carcinomas reported to date. Here, we report a case of a silent pituitary corticotroph adenoma, which subsequently re-presented with Cushing's syndrome due to functioning hepatic metastases. The tumour exhibited low immunohistochemical MGMT expression in both primary (pituitary) and secondary (hepatic) lesions. Initial TMZ therapy (200 mg/m² for 5 days every 28 days-seven cycles) resulted in marked clinical, biochemical [>50% fall in adrenocorticotrophic hormone (ACTH)] and radiological [partial RECIST (response evaluation criteria in solid tumors) response] improvements. The patient then underwent bilateral adrenalectomy. However, despite reintroduction of TMZ therapy (further eight cycles) ACTH levels plateaued and no further radiological regression was observed. We review the existing literature reporting TMZ efficacy in pituitary corticotroph tumours, and highlight the pointers/lessons for treating aggressive pituitary neoplasia that can be drawn from experience of susceptibility and evolving resistance to TMZ therapy in glioblastoma. Possible strategies for mitigating resistance developing during TMZ treatment of pituitary adenomas/carcinomas are also considered.

Background. Improvement in long-term renal allograft survival is impeded by incomplete or erroneous coding of causes of allograft loss. This study reports 13-year trends in causes of graft failure across the UK. Methods. National Health Service Blood and Transplant (NHSBT) and UK Renal Registry data were linked to describe UK kidney patients transplanted 2000-2013. NHSBT graft failure categories were used, with 'other' recoded when free text was available. Adjusted analyses examined the influence of age, ethnicity and donor type on causes of graft failure. Results. In 22,730 recipients, 5,389 (23.7%) grafts failed within a median follow-up of five years. The two most frequent causes were death with a functioning graft (40.8%) and alloimmune pathology (25.0%). Graft survival was higher in recipients who were younger (mean 47.3 vs. 50.7 years), received a pre-emptive transplant (20.2% vs. 10.4%), spent less time on dialysis (median 1.6 vs. 2.4 years) and received a living donor transplant (36.3% vs. 22.2%), with no differences by sex, ethnicity or human leukocyte antigen mismatch. Allograft failure within two years of transplantation fell from 12.5% (2000-2004) to 9.8% (2009-2013). Surgical and alloimmune related failures decreased over time while death with a functioning graft became more common. Age, ethnicity and donor type were factors in recurrent primary disease and alloimmune pathology. Conclusions. Since 2000 there have been reductions in surgical and alloimmune graft failures in the UK. However, graft failure codes need to be revised if they are to remain useful and effective in epidemiological and quality improvement trials.

RituxiCAN-C4 combined an open-labeled randomized controlled trial (RCT) in 7 UK centers to assess whether rituximab could stabilize kidney function in patients with chronic rejection, with an exploratory analysis of how B cell-depletion influenced T cell anti-donor responses relative to outcome. Between January 2007 and March 2015, 59 recruits were enrolled after screening, 23 of whom consented to the embedded RCT. Recruitment was halted when in a pre-specified per protocol interim analysis, the RCT was discovered to be significantly underpowered. This report therefore focuses on the exploratory analysis, in which we confirmed that when B cells promoted CD4+ anti-donor IFNγ production assessed by ELISPOT, this associated with inferior clinical outcome; these patterns were inhibited by optimized immunosuppression but not rituximab. B cell suppression of IFNγ production, which associated with number of transitional B cells and correlated with slower declines in kidney function was abolished by rituximab, which depleted transitional B cells for prolonged periods. We conclude that in this patient population, optimized immunosuppression but not rituximab promotes anti-donor alloresponses associated with favorable outcomes. Clinical Trial Registration: Registered with EudraCT (2006-002330-38) and www. ClinicalTrials.gov, identifier: NCT00476164.