A closer look at chaotic advection in the stratosphere: part II: statistical diagnostics

Statistical diagnostics of mixing and transport are computed for a numerical model of forced shallow-water flow on the sphere and a middle-atmosphere general circulation model. In particular, particle dispersion statistics, transport fluxes, Liapunov exponents (probability density functions and ensemble averages), and tracer concentration statistics are considered. It is shown that the behavior of the diagnostics is in accord with that of kinematic chaotic advection models so long as stochasticity is sufficiently weak. Comparisons with random-strain theory are made

On the bistable zone of milling processes

A modal-based model of milling machine tools subjected to time-periodic nonlinear cutting forces is introduced. The model describes the phenomenon of bistability for certain cutting parameters. In engineering, these parameter domains are referred to as unsafe zones, where steady-state milling may switch to chatter for certain perturbations. In mathematical terms, these are the parameter domains where the periodic solution of the corresponding nonlinear, time-periodic delay differential equation is linearly stable, but its domain of attraction is limited due to the existence of an unstable quasi-periodic solution emerging from a secondary Hopf bifurcation. A semi-numerical method is presented to identify the borders of these bistable zones by tracking the motion of the milling tool edges as they might leave the surface of the workpiece during the cutting operation. This requires the tracking of unstable quasi-periodic solutions and the checking of their grazing to a time-periodic switching surface in the infinite-dimensional phase space. As the parameters of the linear structural behaviour of the tool/machine tool system can be obtained by means of standard modal testing, the developed numerical algorithm provides efficient support for the design of milling processes with quick estimates of those parameter domains where chatter can still appear in spite of setting the parameters into linearly stable domains

Structure of a potential therapeutic antibody bound to Interleukin-16 (IL-16): mechanistic insights and new therapeutic opportunities

Interleukin-16 (IL-16) is reported to be a chemoattractant cytokine and modulator of T-cell activation, and has been proposed as a ligand for the co-receptor CD4. The secreted active form of IL-16 has been detected at sites of TH1-mediated inflammation, such as those seen in autoimmune diseases, ischemic reperfusion injury (IRI), and tissue transplant rejection. Neutralization of IL-16 recruitment to its receptor, using an anti-IL16 antibody, has been shown to significantly attenuate inflammation and disease pathology in IRI, as well as in some autoimmune diseases. The 14.1 antibody is a monoclonal anti-IL-16 antibody, which when incubated with CD4+ cells is reported to cause a reduction in the TH1-type inflammatory response. Secreted IL-16 contains a characteristic PDZ domain. PDZ domains are typically characterized by a defined globular structure, along with a peptide-binding site located in a groove between the αB and βB structural elements and a highly conserved carboxylate-binding loop. In contrast to other reported PDZ domains, the solution structure previously reported for IL-16 reveals a tryptophan residue obscuring the recognition groove. We have solved the structure of the 14.1Fab fragment in complex with IL-16, revealing that binding of the antibody requires a conformational change in the IL-16 PDZ domain. This involves the rotation of the αB-helix, accompanied movement of the peptide groove obscuring tryptophan residue, and consequent opening up of the binding site for interaction. Our study reveals a surprising mechanism of action for the antibody and identifies new opportunities for the development of IL-16-targeted therapeutics, including small molecules that mimic the interaction of the antibody

Anticoagulant treatment in primary health care in Sweden – prevalence, incidence and treatment diagnosis: a retrospective study on electronic patient records in a registered population

BACKGROUND: The indications for warfarin treatment in primary health care are increasing. An undertreatment with warfarin is reported in the prevention of embolic stroke in patients with chronic atrial fibrillation, and can be suspected for other indications. Information on the prevalence and incidence of diseases treated with warfarin would reveal useful data for audits concerning management of anticoagulant treatment. We aimed to assess warfarin treatment in primary health care with regard to prevalence, incidence, treatment diagnosis and patient characteristics. METHODS: A one-year retrospective study of electronic patient records up to May 2000 in primary health care in Stockholm, Sweden. Five primary health care centres with a registered population of 75 146. Main outcome measures were prevalence, incidence and treatment diagnosis. RESULTS: Five hundred and seven patients, mean age 71.9 years, were on warfarin treatment. The prevalence was 0.67% (age-adjusted 0.75%), and it was significantly higher for men (0.78%) than for women (0.58%) (p = 0.01). In the age group 75–84 years the prevalence was 4.54%. The most prevalent treatment diagnosis was chronic atrial fibrillation (0.28%), which was more predominant for males (p = 0.02), followed by cerebrovascular disease (0.13%) and deep venous thrombosis (0.13%). The yearly incidence of warfarin treatment was 0.17%, with chronic atrial fibrillation as the predominant treatment diagnosis. CONCLUSION: Warfarin treatment in primary health care is prevalent among the elderly. Chronic atrial fibrillation is the main treatment diagnosis. There is a gender difference favouring men in general and chronic atrial fibrillation as the treatment diagnosis

Modelling human performance within manufacturing systems design:from a theoretical towards a practical framework

Computer-based simulation is frequently used to evaluate the capabilities of proposed manufacturing system designs. Unfortunately, the real systems are often found to perform quite differently from simulation predictions and one possible reason for this is an over-simplistic representation of workers' behaviour within current simulation techniques. The accuracy of design predictions could be improved through a modelling tool that integrates with computer-based simulation and incorporates the factors and relationships that determine workers' performance. This paper explores the viability of developing a similar tool based on our previously published theoretical modelling framework. It focuses on evolving this purely theoretical framework towards a practical modelling tool that can actually be used to expand the capabilities of current simulation techniques. Based on an industrial study, the paper investigates how the theoretical framework works in practice, analyses strengths and weaknesses in its formulation, and proposes developments that can contribute towards enabling human performance modelling in a practical way

Population pharmacokinetics of artesunate and amodiaquine in African children

<p>Abstract</p> <p>Background</p> <p>Pharmacokinetic (PK) data on amodiaquine (AQ) and artesunate (AS) are limited in children, an important risk group for malaria. The aim of this study was to evaluate the PK properties of a newly developed and registered fixed dose combination (FDC) of artesunate and amodiaquine.</p> <p>Methods</p> <p>A prospective population pharmacokinetic study of AS and AQ was conducted in children aged six months to five years. Participants were randomized to receive the new artesunate and amodiaquine FDC or the same drugs given in separate tablets. Children were divided into two groups of 70 (35 in each treatment arm) to evaluate the pharmacokinetic properties of AS and AQ, respectively. Population pharmacokinetic models for dihydroartemisinin (DHA) and desethylamodiaquine (DeAq), the principal pharmacologically active metabolites of AS and AQ, respectively, and total artemisinin anti-malarial activity, defined as the sum of the molar equivalent plasma concentrations of DHA and artesunate, were constructed using the non-linear mixed effects approach. Relative bioavailability between products was compared by estimating the ratios (and 95% CI) between the areas under the plasma concentration-time curves (AUC).</p> <p>Results</p> <p>The two regimens had similar PK properties in young children with acute malaria. The ratio of loose formulation to fixed co-formulation AUCs, was estimated as 1.043 (95% CI: 0.956 to 1.138) for DeAq. For DHA and total anti-malarial activity AUCs were estimated to be the same. Artesunate was rapidly absorbed, hydrolysed to DHA, and eliminated. Plasma concentrations were significantly higher following the first dose, when patients were acutely ill, than after subsequent doses when patients were usually afebrile and clinically improved. Amodiaquine was converted rapidly to DeAq, which was then eliminated with an estimated median (range) elimination half-life of 9 (7 to 12) days. Efficacy was similar in the two treatments groups, with cure rates of 0.946 (95% CI: 0.840–0.982) in the AS+AQ group and 0.892 (95% CI: 0.787 – 0.947) in the AS/AQ group. Four out of five patients with PCR confirmed recrudescences received AQ doses < 10 mg/kg. Both regimens were well tolerated. No child developed severe, post treatment neutropaenia (<1,000/μL). There was no evidence of AQ dose related hepatotoxicity, but one patient developed an asymptomatic rise in liver enzymes that was resolving by Day-28.</p> <p>Conclusion</p> <p>The bioavailability of the co-formulated AS-AQ FDC was similar to that of the separate tablets for desethylamodiaquine, DHA and the total anti-malarial activity. These data support the use this new AS-AQ FDC in children with acute uncomplicated falciparum malaria.</p

Alexithymia, emotion processing and social anxiety in adults with ADHD

<p>Abstract</p> <p>Objective</p> <p>Given sparse research on the issue, this study sought to shed light upon the interactions of alexithymia, emotion processing, and social anxiety in adults with attention-deficit hyperactivity disorder (ADHD).</p> <p>Subjects and methods</p> <p>73 German adults with ADHD according to DSM-IV diagnostic criteria participated. We used the Toronto Alexithymia Scale (TAS-20) to assess alexithymia, the Social Phobia Scale (SPS) and the Social Interaction Anxiety Scale (SIAS) to assess different features of social anxiety, and we applied the German 'Experience of Emotions Scale' (SEE) to measure emotion processing.</p> <p>Results</p> <p>40% of the sample were found to meet the DSM-IV criteria of social anxiety disorder, and about 22% were highly alexithymic according to a TAS-20 total score ≥ 61; however, the mean TAS-20 total score of 50.94 ± 9.3 was not much higher than in community samples. Alexithymic traits emerged to be closely linked to emotion processing problems, particularly 'difficulty accepting own emotions', and to social anxiety features.</p> <p>Discussion/conclusion</p> <p>Our findings suggest interactions of alexithymia, emotion processing dysfunction, and social anxiety in adults with ADHD, which may entail the therapeutic implication to thoroughly instruct these patients to identify, accept, communicate, and regulate their emotions to aid reducing interaction anxiety.</p