POEMS neuropathy: optimising diagnosis and management

POEMS syndrome is a rare and disabling autoinflammatory condition characterised by a typical peripheral neuropathy and the presence of a monoclonal plasma cell disorder. The acronym 'POEMS' represents the complex and multisystem features of the disease, including polyneuropathy, organomegaly, endocrinopathy, a monoclonal plasma cell disorder and skin disease. The diagnosis of POEMS is a significant challenge because of the heterogeneity of clinical presentations and variation of POEMS features. Patients are often misdiagnosed with another cause of inflammatory neuropathy and receive one or more ineffective immunomodulatory medications, resulting in delayed diagnosis and further clinical deterioration before a diagnosis is made. University College London Hospitals sees one of the largest reported POEMS cohorts in Europe, and runs a multispecialist clinic to assist with diagnosis, treatment and ongoing support. This review draws upon our experience to present the typical features of POEMS syndrome and highlight diagnostic conundrums commonly experienced, supplemented with clinical cases. We provide an investigative guide for clinicians when considering POEMS as the diagnosis, and propose a treatment algorithm that centres on the site and degree of monoclonal cell proliferation

Mutations in noncoding regions of GJB1 are a major cause of X-linked CMT

OBJECTIVE: To determine the prevalence and clinical and genetic characteristics of patients with X-linked Charcot-Marie-Tooth disease (CMT) due to mutations in noncoding regions of the gap junction β-1 gene (GJB1). METHODS: Mutations were identified by bidirectional Sanger sequence analysis of the 595 bases of the upstream promoter region, and 25 bases of the 3′ untranslated region (UTR) sequence in patients in whom mutations in the coding region had been excluded. Clinical and neurophysiologic data were retrospectively collected. RESULTS: Five mutations were detected in 25 individuals from 10 kindreds representing 11.4% of all cases of CMTX1 diagnosed in our neurogenetics laboratory between 1996 and 2016. Four pathogenic mutations, c.-17G>A, c.-17+1G>T, c.-103C>T, and c.-146-90_146-89insT were detected in the 5′UTR. A novel mutation, c.*15C>T, was detected in the 3′ UTR of GJB1 in 2 unrelated families with CMTX1 and is the first pathogenic mutation in the 3′UTR of any myelin-associated CMT gene. Mutations segregated with the phenotype, were at sites predicted to be pathogenic, and were not present in the normal population. CONCLUSIONS: Mutations in noncoding DNA are a major cause of CMTX1 and highlight the importance of mutations in noncoding DNA in human disease. Next-generation sequencing platforms for use in inherited neuropathy should therefore include coverage of these regions

A diagnostic conundrum

A 26-year-old man was referred with facial weakness, dysarthria, dysphagia, ophthalmoparesis and severely weak and wasted legs. His symptoms had begun when aged 20 with electric shock pains and paraesthesia in both feet progressing over 6 months to the lower calves. He then developed buttock numbness and occasional faecal incontinence. By age 22, he had diffuse lower limb weakness and wasting, with difficulty standing from a seated position and frequent tripping. He became wheelchair-dependent within 3 years

Self-amplified photo-induced gap quenching in a correlated electron material.

Capturing the dynamic electronic band structure of a correlated material presents a powerful capability for uncovering the complex couplings between the electronic and structural degrees of freedom. When combined with ultrafast laser excitation, new phases of matter can result, since far-from-equilibrium excited states are instantaneously populated. Here, we elucidate a general relation between ultrafast non-equilibrium electron dynamics and the size of the characteristic energy gap in a correlated electron material. We show that carrier multiplication via impact ionization can be one of the most important processes in a gapped material, and that the speed of carrier multiplication critically depends on the size of the energy gap. In the case of the charge-density wave material 1T-TiSe2, our data indicate that carrier multiplication and gap dynamics mutually amplify each other, which explains-on a microscopic level-the extremely fast response of this material to ultrafast optical excitation

Beyond “Quasi-Norms”: The Challenges and Potential of Engaging with Norms in Cyberspace

As in any realm of human activity, norms are unavoidable in cyberspace. Yet cyber- space is a singularly complex setting within which to understand and try to shape norms. The problem is not simply the nature of cyberspace, although, as we will address below, acknowledging the unique characteristics of cyberspace is crucial when exploring norms in this realm. Rather, the challenge lies in the often over- looked nature of norms themselves and how their defining features render them especially difficult to decipher – and, by extension, to attempt to design – in the context of cyberspace. Norms are widely-accepted and internalised principles or codes of conduct that indicate what is deemed to be permitted, prohibited, or required of agents within a specific community. The modest aim of our chapter is to explore the challenges and potential of engaging with norms in cyberspace. By ‘engaging with norms in cyberspace’ we mean both understanding existing norms and the more prominent endeavour (prevalent in recent discussions of policies related to both cyber security and Internet governance) of what is variously described as ‘cultivating’, ‘promoting’ or ‘developing’ new norms.2 Our focus throughout most of this chapter will be on the former. Indeed, a central point of the argument that will follow is that one can- not hope to ‘cultivate’ norms in cyberspace without first understanding the existing normative landscape. In order to explore the challenges and potential of engaging with norms in cyberspace, we will take five steps. First, we will elaborate upon the definition of ‘norms’ offered above. In doing this, we will draw on influential work from within the discipline of International Relations (IR), and specifically from the multifaceted approaches labelled ‘normative IR theory’ and ‘constructivism’.3 Second, we will introduce a task that is fundamental to understanding existing norms in any realm, including cyberspace: interpreting the norms themselves. Third, we will highlight the characteristics of cyberspace that render this crucial task particularly difficult; namely, that it is a new and rapidly changing realm in which underlying values are contested and relevant agents are often difficult to identify. Fourth, we will link the difficulties of addressing norms in such a realm with the tendency to invoke what we will call ‘quasi-norms’, or merely purported norms. Fifth and finally, we will turn to the potential to engage with norms in cyberspace, regardless of obstacles, by uncovering what we will call the ‘norm of de-territorialised data’ and, in the process, demonstrating how evidence for its status as such can be uncovered in the justifications and judgements that agents in international politics offer when it is violated. Our hope is that these preliminary steps will take us some distance towards establishing a conceptual framework for speaking more coherently about norms in cyberspace

A False Start in the Race Against Doping in Sport: Concerns With Cycling’s Biological Passport

Professional cycling has suffered from a number of doping scandals. The sport’s governing bodies have responded by implementing an aggressive new antidoping program known as the biological passport. Cycling’s biological passport marks a departure from traditional antidoping efforts, which have focused on directly detecting prohibited substances in a cyclist’s system. Instead, the biological passport tracks biological variables in a cyclist’s blood and urine over time, monitoring for fluctuations that are thought to indirectly reveal the effects of doping. Although this method of indirect detection is promising, it also raises serious legal and scientific concerns. Since its introduction, the cycling community has debated the reliability of indirect biological-passport evidence and the clarity, consistency, and transparency of its use in proving doping violations. Such uncertainty undermines the legitimacy of finding cyclists guilty of doping based on this indirect evidence alone. Antidoping authorities should address these important concerns before continuing to pursue doping sanctions against cyclists solely on the basis of their biological passports

The Energy Landscape, Folding Pathways and the Kinetics of a Knotted Protein

The folding pathway and rate coefficients of the folding of a knotted protein are calculated for a potential energy function with minimal energetic frustration. A kinetic transition network is constructed using the discrete path sampling approach, and the resulting potential energy surface is visualized by constructing disconnectivity graphs. Owing to topological constraints, the low-lying portion of the landscape consists of three distinct regions, corresponding to the native knotted state and to configurations where either the N- or C-terminus is not yet folded into the knot. The fastest folding pathways from denatured states exhibit early formation of the N-terminus portion of the knot and a rate-determining step where the C-terminus is incorporated. The low-lying minima with the N-terminus knotted and the C-terminus free therefore constitute an off-pathway intermediate for this model. The insertion of both the N- and C-termini into the knot occur late in the folding process, creating large energy barriers that are the rate limiting steps in the folding process. When compared to other protein folding proteins of a similar length, this system folds over six orders of magnitude more slowly.Comment: 19 page