Can we withdraw immunosuppressants in patients with lupus nephritis in remission? An expert debate.

Lupus nephritis (LN) treatment requires an initial intensive period of therapy followed by a long-term maintenance treatment in order to stabilize disease control and eventually reach renal remission. In this section, Authors discuss the feasibility of safely lowering and even suspending maintenance therapy in LN patients having entered remission, highlighting hurdles in predicting the depth and durability of disease quiescence together with the need for minimizing potentially toxic therapies. Even though no firm conclusions can still be drawn, the treating physician has to find the wise balance between disease control and treatment-related drawbacks by following patients closely and recognizing as early as possible the ones who are likely to reach a deep and durable renal remission; there is consensus that is these are the only patients in whom a potential safe complete withdrawal can be foreseen so far

Environmental effects on the structure of metal ion-DOTA complexes: An ab initio study of radiopharmaceutical metals.

Quantum mechanical calculations were performed to study the differences between the important radiopharmaceutical metals yttrium (Y) and indium (In) bound by DOTA and modified DOTA molecules. Energies were calculated at the MP2/6-31+G(d)//HF/6-31G(d) levels, using effective core potentials on the Y and In ions. Although the minimum energy structures obtained are similar for both metal ion-DOTA complexes, changes in coordination and local environment significantly affect the geometries and energies of these complexes. Coordination by a single water molecule causes a change in the coordination number and a change in the position of the metal ion in In-DOTA; but, Y-DOTA is hardly affected by water coordination. When one of the DOTA carboxylates is replaced by an amide, the coordination energy for the amide arm shows a large variation between the Y and In ions. Optimizations including water and guandinium moieties to approximate the effects of antibody binding indicate a large energy cost for the DOTA-chelated In to adopt the ideal conformation for antibody binding

Insights into the O-Acetylation Reaction of Hydroxylated Heterocyclic Amines by Human Arylamine N-Acetyltransferases: A Computational Study

A computational study was performed to better understand the differences between human arylamine N-acetyltransferase (NAT) 1 and 2. Homology models were constructed from available crystal structures and comparisons of the active site residues 125, 127, and 129 for these two enzymes provide insight into observed substrate differences. The NAT2 model provided a basis for understanding how some of the common mutations may affect the structure of the protein. Molecular dynamics simulations of the human NAT models and the template structure (NAT from Mycobacterium smegmatis) were performed and showed the models to be stable and reasonable. Docking studies of hydroxylated heterocyclic amines in the models of NAT1 and NAT2 probed the differences exhibited by these two proteins with mutagenic agents. The hydroxylated heterocyclic amines were only able to fit into the NAT2 active site, and an alternative binding site by the P-loop was found using our models and will be discussed. Additionally, quantum mechanical calculations were performed to study the O-acetylation reaction of the hydroxylated heterocyclic amines N-OH MeIQx and N-OH PhIP. This study has given us insight into why there are substrate differences among isoenzymes and explains some of the polymorphic activity differences

Understanding the Mechanism of Human P450 CYP1A2 Using Coupled Quantum-Classical Simulations in a Dynamical Environment

The reaction mechanism of the human P450 CYP1A2 enzyme plays a fundamental role in understanding the effects of environmental carcinogens and mutagens on humans. Despite extensive experimental research on this enzyme system, key questions regarding its catalytic cycle and oxygen activation mechanism remain unanswered. In order to elucidate the reaction mechanism in human P450, new computational methods are needed to accurately represent this system. To enable us to perform computational simulations of unprecedented accuracy on these systems, we developed a dynamic quantum-classical (QM/MM) hybrid method, in which ab initio molecular dynamics are coupled with classical molecular mechanics. This will provide the accuracy needed to address such a complex, large biological system in a fully dynamic environment. We also present detailed calculations of the P450 active site, including the relative charge transfer between iron porphine and tetraphenyl porphyrin

A Cauchy-Dirac delta function

The Dirac delta function has solid roots in 19th century work in Fourier analysis and singular integrals by Cauchy and others, anticipating Dirac's discovery by over a century, and illuminating the nature of Cauchy's infinitesimals and his infinitesimal definition of delta.Comment: 24 pages, 2 figures; Foundations of Science, 201

The effects of resistant starch and whole grains on appetite, food intake and metabolic response.

With the rise in obesity, there has been an increased interest in foods which may beneficially affect appetite. Resistant starch (RS) and whole grains (of which RS is a main dietary fibre component) have been proposed to affect satiety and therefore may be beneficial in weight management. There is little direct evidence confirming this in humans. Whilst animal data suggest a positive effect of RS on appetite, the few existing human intervention studies provide inconsistent findings. For whole grains the majority of evidence is from epidemiological work as opposed to intervention studies. Therefore a series of studies was conducted to investigate effects of RS and whole grains on appetite and food intake. Two studies were conducted using RS. The first investigated the acute (24 hours) effects of 48 g RS in healthy adult males compared with an energy and available carbohydrate matched placebo. Following RS there was a significantly lower energy intake compared with placebo. There was also a significantly lower postprandial insulin response with RS, possibly explained by increased hepatic insulin clearance determined by a higher C-peptide to insulin ratio. In the second study 40 g RS consumed daily for 4 weeks was compared with the placebo, in overweight and obese participants. Effects on food intake were assessed and a frequently sampled intravenous glucose tolerance test (FSIVGTT) was conducted. This study found no effect on either appetite or energy intake, but did find significantly higher glucose, insulin and C-peptide concentrations, measured during the FSIVGTT, with the RS compared with the placebo, possibly explained by an improved first-phase insulin response. This finding did not translate into differences in parameters obtained from modelling the FSIVGTT data, but this and the lack of appetite and food intake differences could be explained by the small participant numbers. Two intervention studies were conducted with whole grains incorporated into bread rolls. The first, a crossover study, involved 3 weeks' daily consumption of 48 g milled whole grain or control, in young healthy adults. Whilst no significant difference was found between interventions in energy intake or subjective appetite ratings, a significantly lower systolic blood pressure was observed with the milled whole grains. The second was an 8 week parallel study (48 g intact or 48 g milled whole grains or control) in overweight and obese adults. No significant difference was found between groups on energy intake, subjective appetite ratings, cholesterol or postprandial metabolite concentrations. RS appears to be a possible satiating ingredient when consumed acutely and, whilst this was not confirmed in our chronic study, effects may have been masked by small participant numbers. A novel finding from our RS studies was an effect on the insulin response. These studies suggest that RS could have a beneficial role in weight management and favourable metabolic effects. Our whole grain interventions appear not to agree with epidemiological work that suggests a beneficial role on appetite, but there maybe effects on blood pressure regulation. In all instances further investigations are required in other population groups, with more participants and for longer time periods

A multi-centre qualitative study exploring the experiences of UK South Asian and White Diabetic Patients referred for renal care

Background An exploration of renal complications of diabetes from the patient perspective is important for developing quality care through the diabetic renal disease care pathway. Methods Newly referred South Asian and White diabetic renal patients over 16 years were recruited from nephrology outpatient clinics in three UK centres - Luton, West London and Leicester – and their experiences of the diabetes and renal care recorded. A semi-structured qualitative interview was conducted with 48 patients. Interview transcripts were analysed thematically and comparisons made between the White and South Asian groups. Results 23 South Asian patients and 25 White patients were interviewed. Patient experience of diabetes ranged from a few months to 35 years with a mean time since diagnosis of 12.1 years and 17.1 years for the South Asian and White patients respectively. Confusion emerged as a response to referral shared by both groups. This sense of confusion was associated with reported lack of information at the time of referral, but also before referral. Language barriers exacerbated confusion for South Asian patients. Conclusions The diabetic renal patients who have been referred for specialist renal care and found the referral process confusing have poor of awareness of kidney complications of diabetes. Healthcare providers should be more aware of the ongoing information needs of long term diabetics as well as the context of any information exchange including language barriers

Leibniz's Infinitesimals: Their Fictionality, Their Modern Implementations, And Their Foes From Berkeley To Russell And Beyond

Many historians of the calculus deny significant continuity between infinitesimal calculus of the 17th century and 20th century developments such as Robinson's theory. Robinson's hyperreals, while providing a consistent theory of infinitesimals, require the resources of modern logic; thus many commentators are comfortable denying a historical continuity. A notable exception is Robinson himself, whose identification with the Leibnizian tradition inspired Lakatos, Laugwitz, and others to consider the history of the infinitesimal in a more favorable light. Inspite of his Leibnizian sympathies, Robinson regards Berkeley's criticisms of the infinitesimal calculus as aptly demonstrating the inconsistency of reasoning with historical infinitesimal magnitudes. We argue that Robinson, among others, overestimates the force of Berkeley's criticisms, by underestimating the mathematical and philosophical resources available to Leibniz. Leibniz's infinitesimals are fictions, not logical fictions, as Ishiguro proposed, but rather pure fictions, like imaginaries, which are not eliminable by some syncategorematic paraphrase. We argue that Leibniz's defense of infinitesimals is more firmly grounded than Berkeley's criticism thereof. We show, moreover, that Leibniz's system for differential calculus was free of logical fallacies. Our argument strengthens the conception of modern infinitesimals as a development of Leibniz's strategy of relating inassignable to assignable quantities by means of his transcendental law of homogeneity.Comment: 69 pages, 3 figure

Stevin numbers and reality

We explore the potential of Simon Stevin's numbers, obscured by shifting foundational biases and by 19th century developments in the arithmetisation of analysis.Comment: 22 pages, 4 figures. arXiv admin note: text overlap with arXiv:1104.0375, arXiv:1108.2885, arXiv:1108.420