Heterogeneous natural history of Addison’s disease: mineralocorticoid deficiency may predominate

Autoimmune Addison’s disease (AAD) is defined as primary adrenal insufficiency due to immune-mediated destruction of the adrenal cortex. This destruction of steroid-producing cells has historically been thought of as an irreversible process, with linear progression from an ACTH-driven compensated phase to overt adrenal insufficie ncy requiring lifelong glucocorticoid replacement. However, a growing body of evidence suggests that this process may be more heterogeneous than previously thought, with potential for complete or partial recovery of glucocorticoid secretion. Although patients with persistent mineralocorticoid deficiency despite preserved or recovered glucocorticoid function are anecdotally mentioned, few well-documented cases have been reported to date. We present three patients in the United Kingdom who further challenge the long-standing hypothesis that AAD is a progressive, irreversible disease process. We describe one patient with a 4-year history of mineralocorticoid-only Addison’s disease, a patient with spontaneous recovery of adrenal function and one patient with clinical features of adrenal insufficiency despite significant residual cortisol function. All three patients show varying degrees of mineralocorticoid deficiency, suggesting that recovery of zona fasciculata function in the adrenal cortex may occur independently to that of the zona glomerulosa. We outline the current evidence for heterogeneity in the natural history of AAD and discuss possible mechanisms for the recovery of adrenal function

H2O2 Enables Convenient Removal of RAFT End-Groups from Block Copolymer Nano-Objects Prepared via Polymerization-Induced Self-Assembly in Water

RAFT-synthesized polymers are typically colored and malodorous due to the presence of the sulfur-based RAFT end-group(s). In principle, RAFT end-groups can be removed by treating molecularly dissolved copolymer chains with excess free radical initiators, amines, or oxidants. Herein we report a convenient method for the removal of RAFT end-groups from aqueous dispersions of diblock copolymer nano-objects using H2O2. This oxidant is relatively cheap, has minimal impact on the copolymer morphology, and produces benign side products that can be readily removed via dialysis. We investigate the efficiency of end-group removal for various diblock copolymer nano-objects prepared with either dithiobenzoate- or trithiocarbonate-based RAFT chain transfer agents. The advantage of using UV GPC rather than UV spectroscopy is demonstrated for assessing both the kinetics and extent of end-group removal

Differential effects of apolipoprotein E isoforms on phosphorylation at specific sites on tau by glycogen synthase kinase-3β identified by nano-electrospray mass spectrometry

AbstractPreviously published data have shown an allele-specific variation in the in vitro binding of apolipoprotein E (apoE) to tau, which prompted the hypothesis that apoE binding may protect tau from phosphorylation, apoE3 being more efficient than apoE4. We have, therefore, investigated the effects of apoE on tau phosphorylation in vitro by the proline-directed kinase, glycogen synthase kinase (GSK)-3β. The phosphopeptide maps of tau alone, of tau with apoE3 and of tau with apoE4 were very similar. When apoE2 was present a further four spots were evident. Additionally, of the 15 peptides phosphorylated in the presence or absence of apoE, subtle differences, some isoform-specific, in the relative amounts of phosphorylation were observed

The tensor structure on the representation category of the Wp\mathcal{W}_p triplet algebra

We study the braided monoidal structure that the fusion product induces on the abelian category $\mathcal{W}_p$-mod, the category of representations of the triplet $W$-algebra $\mathcal{W}_p$. The $\mathcal{W}_p$-algebras are a family of vertex operator algebras that form the simplest known examples of symmetry algebras of logarithmic conformal field theories. We formalise the methods for computing fusion products, developed by Nahm, Gaberdiel and Kausch, that are widely used in the physics literature and illustrate a systematic approach to calculating fusion products in non-semi-simple representation categories. We apply these methods to the braided monoidal structure of $\mathcal{W}_p$-mod, previously constructed by Huang, Lepowsky and Zhang, to prove that this braided monoidal structure is rigid. The rigidity of $\mathcal{W}_p$-mod allows us to prove explicit formulae for the fusion product on the set of all simple and all projective $\mathcal{W}_p$-modules, which were first conjectured by Fuchs, Hwang, Semikhatov and Tipunin; and Gaberdiel and Runkel.Comment: 58 pages; edit: added references and revisions according to referee reports. Version to appear on J. Phys.

A Study of Cosmic Ray Composition in the Knee Region using Multiple Muon Events in the Soudan 2 Detector

Deep underground muon events recorded by the Soudan 2 detector, located at a depth of 2100 meters of water equivalent, have been used to infer the nuclear composition of cosmic rays in the "knee" region of the cosmic ray energy spectrum. The observed muon multiplicity distribution favors a composition model with a substantial proton content in the energy region 800,000 - 13,000,000 GeV/nucleus.Comment: 38 pages including 11 figures, Latex, submitted to Physical Review

Absence of Phase Transition for Antiferromagnetic Potts Models via the Dobrushin Uniqueness Theorem

We prove that the $q$-state Potts antiferromagnet on a lattice of maximum coordination number $r$ exhibits exponential decay of correlations uniformly at all temperatures (including zero temperature) whenever $q > 2r$. We also prove slightly better bounds for several two-dimensional lattices: square lattice (exponential decay for $q \ge 7$), triangular lattice ($q \ge 11$), hexagonal lattice ($q \ge 4$), and Kagom\'e lattice ($q \ge 6$). The proofs are based on the Dobrushin uniqueness theorem.Comment: 32 pages including 3 figures. Self-unpacking file containing the tex file, the needed macros (epsf.sty, indent.sty, subeqnarray.sty, and eqsection.sty) and the 3 ps file

Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement

Persistent symptoms in patients treated for hypothyroidism are common. Despite more than 20 years of debate, the use of liothyronine for this indication remains controversial, as numerous randomised trials have failed to show a benefit of treatment regimens that combine liothyronine (T3) with levothyroxine over levothyroxine monotherapy. This consensus statement attempts to provide practical guidance to clinicians faced with patients who have persistent symptoms during thyroid hormone replacement therapy. It applies to non‐pregnant adults and is focussed on care delivered within the UK National Health Service, although it may be relevant in other healthcare environments. The statement emphasises several key clinical practice points for patients dissatisfied with treatment for hypothyroidism. Firstly, it is important to establish a diagnosis of overt hypothyroidism; patients with persistent symptoms during thyroid hormone replacement but with no clear biochemical evidence of overt hypothyroidism should first have a trial without thyroid hormone replacement. In those with established overt hypothyroidism, levothyroxine doses should be optimised aiming for a TSH in the 0.3–2.0 mU/L range for 3 to 6 months before a therapeutic response can be assessed. In some patients, it may be acceptable to have serum TSH below reference range (e.g. 0.1–0.3 mU/L), but not fully suppressed in the long term. We suggest that for some patients with confirmed overt hypothyroidism and persistent symptoms who have had adequate treatment with levothyroxine and in whom other comorbidities have been excluded, a trial of liothyronine/levothyroxine combined therapy may be warranted. The decision to start treatment with liothyronine should be a shared decision between patient and clinician. However, individual clinicians should not feel obliged to start liothyronine or to continue liothyronine medication provided by other health care practitioners or accessed without medical advice, if they judge this not to be in the patient's best interest

Residual adrenal function in autoimmune addison's disease - effect of dual therapy with rituximab and depot tetracosactide

Context In autoimmune Addison’s disease (AAD), exogenous glucocorticoid (GC) therapy is an imperfect substitute for physiological GC secretion. Patients on long-term steroid replacement have increased morbidity, reduced life expectancy and poorer quality of life. Objective To restore adrenocortical steroidogenic function in recent onset AAD. Design Open-label, multi-centre trial of immunotherapy and trophic stimulation in new-onset AAD. Serial measurement of serum and urine corticosteroids at baseline and throughout 72-week follow-up period. Setting Endocrine Departments and Clinical Research Facilities at 5 UK tertiary centres. Patients Thirteen subjects (9 female, 4 male; aged 19-64 years) with AAD confirmed by high ACTH, low circulating cortisol (basal <100nmol/L or post-tetracosactide <300nmol/L) and positive serum 21-hydroxylase antibodies. Intervention All subjects received dual therapy with B-lymphocyte depleting immunotherapy (rituximab 1g given twice) and repeated depot tetracosactide (1mg alternate days for 12 weeks). Main Outcome Measure Restoration of normal glucocorticoid secretion (stimulated cortisol >550nmol/L) at Week 48. Results Ten of 13 (77%) had detectable stimulated serum cortisol (26-265nmol/L) at trial entry. Following intervention, 7/13 (54%) had an increase in stimulated cortisol measurement, with a peak response of 325nmol/L at Week 18 in one subject. Increased steroid metabolites, assayed by urine GC-MS at Week 12 and Week 48, was detected in 8/13 (62%), reflecting an increase in endogenous steroidogenesis. Four of 13 had Residual Adrenal Function at 72 weeks. Conclusion Combined treatment with rituximab and depot tetracosactide did not restore normal adrenal function. Nevertheless, adrenocortical plasticity is demonstrated in some patients and this has the potential to be exploited to improve adrenal function

Conducting robust ecological analyses with climate data

Although the number of studies discerning the impact of climate change on ecological systems continues to increase, there has been relatively little sharing of the lessons learnt when accumulating this evidence. At a recent workshop entitled ‘Using climate data in ecological research’ held at the UK Met Office, ecologists and climate scientists came together to discuss the robust analysis of climate data in ecology. The discussions identified three common pitfalls encountered by ecologists: 1) selection of inappropriate spatial resolutions for analysis; 2) improper use of publically available data or code; and 3) insufficient representation of the uncertainties behind the adopted approach. Here, we discuss how these pitfalls can be avoided, before suggesting ways that both ecology and climate science can move forward. Our main recommendation is that ecologists and climate scientists collaborate more closely, on grant proposals and scientific publications, and informally through online media and workshops. More sharing of data and code (e.g. via online repositories), lessons and guidance would help to reconcile differing approaches to the robust handling of data. We call on ecologists to think critically about which aspects of the climate are relevant to their study system, and to acknowledge and actively explore uncertainty in all types of climate data. And we call on climate scientists to make simple estimates of uncertainty available to the wider research community. Through steps such as these, we will improve our ability to robustly attribute observed ecological changes to climate or other factors, while providing the sort of influential, comprehensive analyses that efforts to mitigate and adapt to climate change so urgently require