Genetic evaluation of paediatric nephrocalcinosis: phenotype-driven genetic panels reveal a rare diagnosis

Monogenic causes of paediatric nephrocalcinosis are associated with extensive phenotypic variability. We report a 14-year-old male who presented at eight years of age with incidentally identified nephrocalcinosis alongside growth impairment and dental anomalies. Extensive genetic investigation confirmed a molecular diagnosis of Bartter syndrome type II (BSII). This is exceptional in both late presentation and the presence of amelogenesis imperfecta, a very rare association of inherited tubulopathies. Details of the nephrocalcinosis gene panel analysed and associated phenotypes are presented to highlight the utility of a phenotype-driven genetic panel in resolving an atypical presentation of nephrocalcinosis, allowing precise diagnosis, tailored therapy and prognostication

Low dose rituximab is no less effective for nephrotic syndrome measured by 12-month outcome

Objective: Rituximab is an effective treatment for children with steroid dependent or frequently relapsing nephrotic syndrome. The optimum dosing schedule for rituximab has not been established. We hypothesized that a single low dose of 375 mg/m2 would have comparable outcomes to higher doses in reducing the frequency of relapse and time to B cell reconstitution. Methods: We conducted a multicenter retrospective observational cohort study of children with steroid-sensitive frequently relapsing nephrotic syndrome. Data were extracted from clinical records including the dates of diagnosis, treatment, relapses, the use of concomitant immunosuppression, and lymphocyte subset profiling. Patients treated earlier received variable doses of rituximab, although typically two doses of 750 mg/m2. Later, patients received the current regimen of a single dose of 375 mg/m2. The primary outcome was an absence of clinically confirmed relapse 12 months following rituximab administration. Secondary outcomes were median time to relapse, probability of being relapse-free at 6 and 24 months and time to reconstitution of CD19+ B cells. Results: Sixty patients received 143 courses of rituximab. Seven different dosing regimen strategies were used, ranging between 375 and 750 mg/m2 per dose, with administration of 1–4 doses. There was no significant difference in event-free survival at 12 months between dosing strategies. The median time to reconstitution of B cells was not significantly different between groups. Conclusions: Use of a single low-dose regimen of rituximab in the management of frequently relapsing nephrotic syndrome does not affect the probability of relapse at 12 months or time to B cell reconstitution compared to a conventional higher dose

Southern Ocean control of silicon stable isotope distribution in the deep Atlantic Ocean

Author Posting. © American Geophysical Union, 2012. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Global Geochemical Cycles 26 (2012): GB2035, doi:10.1029/2011GB004141.The fractionation of silicon (Si) stable isotopes by biological activity in the surface ocean makes the stable isotope composition of silicon (δ30Si) dissolved in seawater a sensitive tracer of the oceanic biogeochemical Si cycle. We present a high-precision dataset that characterizes the δ30Si distribution in the deep Atlantic Ocean from Denmark Strait to Drake Passage, documenting strong meridional and smaller, but resolvable, vertical δ30Si gradients. We show that these gradients are related to the two sources of deep and bottom waters in the Atlantic Ocean: waters of North Atlantic and Nordic origin carry a high δ30Si signature of ≥+1.7‰ into the deep Atlantic, while Antarctic Bottom Water transports Si with a low δ30Si value of around +1.2‰. The deep Atlantic δ30Si distribution is thus governed by the quasi-conservative mixing of Si from these two isotopically distinct sources. This disparity in Si isotope composition between the North Atlantic and Southern Ocean is in marked contrast to the homogeneity of the stable nitrogen isotope composition of deep ocean nitrate (δ15N-NO3). We infer that the meridional δ30Si gradient derives from the transport of the high δ30Si signature of Southern Ocean intermediate/mode waters into the North Atlantic by the upper return path of the meridional overturning circulation (MOC). The basin-scale deep Atlantic δ30Si gradient thus owes its existence to the interaction of the physical circulation with biological nutrient uptake at high southern latitudes, which fractionates Si isotopes between the abyssal and intermediate/mode waters formed in the Southern Ocean.This work was supported by Swiss National Science Foundation grants 200021-116473 and 200020-130361.2012-12-1

Thromboprophylaxis in congenital nephrotic syndrome: 15 year experience from a national cohort

Introduction: Congenital nephrotic syndrome (CNS) is an ultra-rare disease associated with a pro-thrombotic state and venous thromboembolisms (VTE). There is very limited evidence evaluating thromboprophylaxis in patients with CNS. This study aimed to determine the doses and duration of treatment required to achieve adequate thromboprophylaxis in patients with CNS. Methods: From 2005 to 2018 children in Scotland with a confirmed genetic or histological diagnosis of CNS were included if commenced on thromboprophylaxis. The primary study endpoint was stable drug monitoring. Secondary outcomes included VTE or significant haemorrhage. Results: Eight patients were included; all initially were commenced on low-molecular weight heparin (enoxaparin). Four patients maintained therapeutic anti-Factor Xa levels (time 3–26 weeks, dose 3.2–5.07 mg/kg/day), and one patient developed a thrombosis (Anti-Factor Xa: 0.27 IU/ml). Four patients were subsequently treated with warfarin. Two patients maintained therapeutic INRs (time 6–11 weeks, dose 0.22–0.25 mg/kg/day), and one patient had two bleeding events (Bleed 1: INR 6, Bleed 2: INR 5.5). Conclusions: Achieving thromboprophylaxis in CNS is challenging. Similar numbers of patients achieved stable anticoagulation on warfarin and enoxaparin. Enoxaparin dosing was nearly double the recommended starting doses for secondary thromboprophylaxis. Bleeding events were all associated with supra-therapeutic anticoagulation

UK experience of ofatumumab in recurrence of focal segmental glomerulosclerosis post-kidney transplant

Background: Steroid-resistant nephrotic syndrome (SRNS), commonly caused by focal segmental glomerulosclerosis (FSGS), is associated with progression to stage 5 chronic kidney disease, requirement for kidney replacement therapy and a risk of disease recurrence post-kidney transplantation. Ofatumumab (OFA) is a fully humanised monoclonal antibody to CD20, with similar mechanisms of action to rituximab (RTX). Methods: We report a case series of seven UK patients (five paediatric, two adult), all of whom developed FSGS recurrence after kidney transplantation and received OFA as part of their therapeutic intervention. All also received concomitant plasmapheresis. The 2-year outcome of these seven patients is reported, describing clinical course, kidney function and proteinuria. Results: Four patients (all paediatric) achieved complete urinary remission with minimal proteinuria 12 months post-treatment. Three of those four also had normal graft function. Two patients showed partial remission—brief improvement to non-nephrotic proteinuria (197 mg/mmol) in one patient, maintained improvement in kidney function (estimated glomerular filtration rate 76 ml/min/1.73 m2) in the other. One patient did not demonstrate any response. Conclusions: OFA may represent a useful addition to therapeutic options in the management of FSGS recurrence post-transplantation, including where RTX has shown no benefit. Concomitant plasmapheresis in all patients prevents any definitive conclusion that OFA was the beneficial intervention

How does flow in a pipe become turbulent?

The transition to turbulence in pipe flow does not follow the scenario familiar from Rayleigh-Benard or Taylor-Couette flow since the laminar profile is stable against infinitesimal perturbations for all Reynolds numbers. Moreover, even when the flow speed is high enough and the perturbation sufficiently strong such that turbulent flow is established, it can return to the laminar state without any indication of the imminent decay. In this parameter range, the lifetimes of perturbations show a sensitive dependence on initial conditions and an exponential distribution. The turbulence seems to be supported by three-dimensional travelling waves which appear transiently in the flow field. The boundary between laminar and turbulent dynamics is formed by the stable manifold of an invariant chaotic state. We will also discuss the relation between observations in short, periodically continued domains, and the dynamics in fully extended puffs.Comment: for the proceedings of statphys 2

To what extent is behaviour a problem in English schools?:Exploring the scale and prevalence of deficits in classroom climate

The working atmosphere in the classroom is an important variable in the process of education in schools, with several studies suggesting that classroom climate is an important influence on pupil attainment. There are wide differences in the extent to which classroom climate is considered to be a problem in English schools. Some ‘official’ reports suggest that behaviour in schools is ‘satisfactory or better’ in the vast majority of schools; other sources have pointed to behaviour being a serious and widespread problem. The paper details four studies conducted over the past decade which aimed to explore these disparities. The aim of the research was to gain a more accurate insight into the extent to which deficits in classroom climate limit educational attainment and equality of educational opportunity in English schools. The findings question the suggestion that behaviour is satisfactory or better in 99.7% of English schools and the concluding section suggests ways in which deficits in classroom climate might be addressed. Although the study is limited to classrooms in England, OECD studies suggest that deficits in the working atmosphere in classrooms occur in many countries. The study therefore has potential relevance for education systems in other countries

Complexity, Development, and Evolution in Morphogenetic Collective Systems

Many living and non-living complex systems can be modeled and understood as collective systems made of heterogeneous components that self-organize and generate nontrivial morphological structures and behaviors. This chapter presents a brief overview of our recent effort that investigated various aspects of such morphogenetic collective systems. We first propose a theoretical classification scheme that distinguishes four complexity levels of morphogenetic collective systems based on the nature of their components and interactions. We conducted a series of computational experiments using a self-propelled particle swarm model to investigate the effects of (1) heterogeneity of components, (2) differentiation/re-differentiation of components, and (3) local information sharing among components, on the self-organization of a collective system. Results showed that (a) heterogeneity of components had a strong impact on the system's structure and behavior, (b) dynamic differentiation/re-differentiation of components and local information sharing helped the system maintain spatially adjacent, coherent organization, (c) dynamic differentiation/re-differentiation contributed to the development of more diverse structures and behaviors, and (d) stochastic re-differentiation of components naturally realized a self-repair capability of self-organizing morphologies. We also explored evolutionary methods to design novel self-organizing patterns, using interactive evolutionary computation and spontaneous evolution within an artificial ecosystem. These self-organizing patterns were found to be remarkably robust against dimensional changes from 2D to 3D, although evolution worked efficiently only in 2D settings.Comment: 13 pages, 8 figures, 1 table; submitted to "Evolution, Development, and Complexity: Multiscale Models in Complex Adaptive Systems" (Springer Proceedings in Complexity Series

Multifocal multi-organ ischaemia and infarction in a preterm baby due to maternal intravenous cocaine use: a case report

<p>Abstract</p> <p>Introduction</p> <p>Although the adverse effects of cocaine use in pregnancy are well recognised, we believe this case highlights the importance of considering the route of administration, and suggests the possibility of multifocal damage relating to intravenous use.</p> <p>Case presentation</p> <p>A Caucasian female baby of 29-weeks' gestation was spontaneously delivered and subsequently developed multi-organ failure considered unrelated to simple prematurity. Intensive care was re-orientated following the development of massive intraventricular haemorrhage.</p> <p>Conclusion</p> <p>This case illustrates the need for regular cranial ultrasound in babies of pregnancies at risk due to intravenous cocaine use and also the necessity of counselling women who misuse cocaine in the antenatal period. As such, this article will be of most interest to paediatric and obstetric staff.</p