Macrophage activation syndrome triggered by active systemic lupus erythematosus : Successful treatment by interleukin-1 inhibition (anakinra).

This article presents a case of fulminant macrophage activation syndrome (MAS) as a rare complication of active systemic lupus erythematosus in a 33-year-old female patient. Initial presentation showed severe lupus disease exacerbation with renal involvement, hemolytic anemia, and neuropsychiatric changes. Early therapy focused on broad immunosuppression (high-dose corticosteroids and cyclophosphamide); however, disease remission could not be achieved. After an additional inflammatory focus and underlying malignancy were excluded, the triplet of pancytopenia, fever, and high ferritin levels indicated MAS, a bone marrow biopsy confirmed secondary hemophagocytic histiocytosis. Treatment with an interleukin­1 antagonist (anakinra) induced a fast, effective therapeutic success.

Links between psychotic and neurotic symptoms in the general population: an analysis of longitudinal British National Survey data using Directed Acyclic Graphs.

BACKGROUND: Non-psychotic affective symptoms are important components of psychotic syndromes. They are frequent and are now thought to influence the emergence of paranoia and hallucinations. Evidence supporting this model of psychosis comes from recent cross-fertilising epidemiological and intervention studies. Epidemiological studies identify plausible targets for intervention but must be interpreted cautiously. Nevertheless, causal inference can be strengthened substantially using modern statistical methods. METHODS: Directed Acyclic Graphs were used in a dynamic Bayesian network approach to learn the overall dependence structure of chosen variables. DAG-based inference identifies the most likely directional links between multiple variables, thereby locating them in a putative causal cascade. We used initial and 18-month follow-up data from the 2000 British National Psychiatric Morbidity survey (N = 8580 and N = 2406). RESULTS: We analysed persecutory ideation, hallucinations, a range of affective symptoms and the effects of cannabis and problematic alcohol use. Worry was central to the links between symptoms, with plausible direct effects on insomnia, depressed mood and generalised anxiety, and recent cannabis use. Worry linked the other affective phenomena with paranoia. Hallucinations were connected only to worry and persecutory ideation. General anxiety, worry, sleep problems, and persecutory ideation were strongly self-predicting. Worry and persecutory ideation were connected over the 18-month interval in an apparent feedback loop. CONCLUSIONS: These results have implications for understanding dynamic processes in psychosis and for targeting psychological interventions. The reciprocal influence of worry and paranoia implies that treating either symptom is likely to ameliorate the other.

Effect of microchannel structure and fluid properties on non-inertial particle migration.

In this work, we investigate the influence of channel structure and fluid rheology on non-inertial migration of non-Brownian polystyrene beads. Particle migration in this regime can be found in biomedical, chemical, environmental and geological applications. However, the effect of fluid rheology on particle migration in porous media remains to be clearly understood. Here, we isolate the effects of elasticity and shear thinning by comparing a Newtonian fluid, a purely elastic (Boger) fluid, and a shear-thinning elastic fluid. To mimic the complexity of geometries in real-world application, a random porous structure is created through a disordered arrangement of cylindrical pillars in the microchannel. Experiments are repeated in an empty channel and in channels with an ordered arrangement of pillars, and the similarities and differences in the observed particle focusing are analyzed. It is found that elasticity drives the particles away from the channel walls in an empty microchannel. Notably, particle focusing is unaffected by curved streamlines in an ordered porous microchannel and particles stay away from pillars in elastic fluids. Shear-thinning is found to reduce the effect of focusing and a broader region of particle concentration is observed. It is also noteworthy that the rheological characteristics of the fluid are not important for the particle distribution in a randomly arranged pillared microchannel and particles have a uniform distribution for all suspending fluids. Moreover, discussion on the current discrepancy in the literature about the equilibrium positions of the particles in a channel is extended by analyzing the results obtained in the current experiments.

Adherence and health literacy as related to outcome of patients treated for rheumatoid arthritis : Analyses of a large-scale observational study.

BACKGROUND: Disabilities in daily living and quality of life are key endpoints for evaluating the treatment outcome for rheumatoid arthritis (RA). Factors possibly contributing to good outcome are adherence and health literacy. METHODS: The survey included a representative nationwide sample of German rheumatologists and their patients with RA. The physician questionnaire included the disease activity score (DAS28) and medical prescriptions. The patient questionnaire included fatigue (EORTC QLQ-FA13), health assessment questionnaire (HAQ), quality of life (SF-12), health literacy (HELP), and patients' listings of their medications. Adherence was operationalized as follows: patient-reported (CQR5), behavioral (concordance between physicians' and patients' listings of medications), physician-assessed, and a combined measure of physician rating (1 = very adherent, 0 = less adherent) and the match between physicians' prescriptions and patients' accounts of their medications (1 = perfect match, 0 = no perfect match) that yielded three categories of adherence: high, medium, and low. Simple and multiple linear regressions (controlling for age, sex, smoking, drinking alcohol, and sport) were calculated using adherence and health literacy as predictor variables, and disease activity and patient-reported outcomes as dependent variables. RESULTS: 708 pairs of patient and physician questionnaires were analyzed. The mean patient age (73% women) was 60 years (SD = 12). Multiple regression analyses showed that high adherence was significantly associated with 5/7 outcome variables and health literacy with 7/7 outcome variables. CONCLUSION: Adherence and health literacy had weak but consistent effects on most outcomes. Thus, enhancing adherence and understanding of medical information could improve outcome, which should be investigated in future interventional studies.

[S2e guideline: treatment of rheumatoid arthritis with disease-modifying drugs]. / S2e-Leitlinie: Therapie der rheumatoiden Arthritis mit krankheitsmodifizierenden Medikamenten.

BACKGROUND: Medication-based strategies to treat rheumatoid arthritis are crucial in terms of outcome. They aim at preventing joint destruction, loss of function and disability by early and consistent inhibition of inflammatory processes. OBJECTIVE: Achieving consensus about evidence-based recommendations for the treatment of rheumatoid arthritis with disease-modifying anti-rheumatic drugs in Germany. METHODS: Following a systematic literature research, a structured process among expert rheumatologists was used to reach consensus. RESULTS: The results of the consensus process can be summed up in 6 overarching principles and 10 recommendations. There are several new issues compared to the version of 2012, such as differentiated adjustments to the therapeutic regime according to time point and extent of treatment response, the therapeutic goal of achieving remission as assessed by means of the simplified disease activity index (SDAI) as well as the potential use of targeted synthetic DMARDs (JAK inhibitors) and suggestions for a deescalating in case of achieving a sustained remission. Methotrexate still plays the central role at the beginning of the treatment and as a combination partner in the further treatment course. When treatment response to methotrexate is inadequate, either switching to or combining with another conventional synthetic DMARD is an option in the absence of unfavourable prognostic factors. Otherwise biologic or targeted synthetic DMARDs are recommended according to the algorithm. Rules for deescalating treatment with glucocorticoids and-where applicable-DMARDs give support for the management of patients who have reached a sustained remission. DISCUSSION: The new guidelines set up recommendations for RA treatment in accordance with the treat-to-target principle. Modern disease-modifying drugs, now including also JAK inhibitors, are available in an algorithm.

Viscoelastic flow past mono- and bidisperse random arrays of cylinders: flow resistance, topology and normal stress distribution.

We investigate creeping viscoelastic fluid flow through two-dimensional porous media consisting of random arrangements of monodisperse and bidisperse cylinders, using our finite volume-immersed boundary method introduced in S. De, et al., J. Non-Newtonian Fluid Mech., 2016, 232, 67-76. The viscoelastic fluid is modeled with a FENE-P model. The simulations show an increased flow resistance with increase in flow rate, even though the bulk response of the fluid to shear flow is shear thinning. We show that if the square root of the permeability is chosen as the characteristic length scale in the determination of the dimensionless Deborah number (De), then all flow resistance curves collapse to a single master curve, irrespective of the pore geometry. Our study reveals how viscoelastic stresses and flow topologies (rotation, shear and extension) are distributed through the porous media, and how they evolve with increasing De. We correlate the local viscoelastic first normal stress differences with the local flow topology and show that the largest normal stress differences are located in shear flow dominated regions and not in extensional flow dominated regions at higher viscoelasticity. The study shows that normal stress differences in shear flow regions may play a crucial role in the increase of flow resistance for viscoelastic flow through such porous media.

[Therapy of ANCA-associated vasculitis with severe renal manifestation under routine conditions]. / Therapie der ANCA-assoziierten Vaskulitis mit schwerer renaler Beteiligung unter Routinebedingungen.

INTRODUCTION: In the MEPEX trial the poor prognosis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis with severe renal manifestation (AAVr) could be significantly improved in the first year by plasmapheresis. How and to what extent is this knowledge of AAVr therapy implemented into routine practice and what effectiveness and adverse events resulted? METHODS: This was a retrospective cohort study in which all patients who received remission induction therapy for AAVr under routine clinical conditions (RCC) in this hospital from 2009 to 2014 after publication of the MEPEX trial (n = 22) were compared with those in the plasmapheresis arm of the MEPEX trial (n = 70). Endpoints were dialysis-dependent chronic kidney disease and mortality after 3 and 12 months and severe life-threatening adverse events during the first 12 months. RESULTS: All patients with AAVr were treated by plasmapheresis under RCC. The two groups showed no differences with respect to the rate of dialysis dependency (after 3 months RCC 14 % versus MEPEX 16 %, P = 1.00 and after 12 months RCC 23 % versus MEPEX 14 %, P = 0.55) or mortality (after 3 months RCC 18 % versus MEPEX 16 %, P = 0.75 and after 12 months RCC 18 % versus MEPEX 27 %, P = 0.57). The rate of severe life-threatening adverse events was similar under RCC and under controlled study conditions (64 % versus 69 %, P = 0.87). CONCLUSION: Under RCC there is a high quality of medical treatment for AAVr. All patients received plasmapheresis for remission induction with comparable effectiveness and safety compared to controlled study conditions.

Use of clinical scores to guide therapeutic decisions in patients with rheumatoid arthritis in daily care.

OBJECTIVES: This study focuses on the application and impact of different clinical scores for treatment changes in daily practice in patients with rheumatoid arthritis (RA), as achieving remission is a feasible aim due to considerable improvements in therapeutic options. METHODS: In this prospective study, 1467 RA patients aged 15 to 88 years (72.5% female, 27.5% male) who had undergone treatment change or were treated with a disease-modifying antirheumatic drug (DMARD) for the first time were analysed. At three consecutive visits (T-1, T0, T1), scores were used to assess disease activity, loss of function, quality of life and imaging. In addition, the impact of the scores on treatment change was addressed (numerical rating scale, 1-10). RESULTS: The most commonly used scores were the DAS28 (65% of all visits), the Hanover functional ability questionnaire (FFbH, 36%) and the HAQ (11%). Other scores for evaluating RA are of little relevance in daily practice. No scores were calculated in only 10% of visits. Among the commonly used scores, the DAS28 had the highest influence on therapy decisions, followed by HAQ and FFbH (mean weight 6.62, 4.99 and 4.41, respectively). CONCLUSIONS: In daily practice, rheumatologists very often take scores for disease activity (especially DAS28) and loss of physical function into consideration when deciding on treatment for patients with RA. However, scores for measuring structural changes or quality of life, are not yet very well established with German rheumatologists.

Optimized testing for C. trachomatis DNA in synovial fluid samples in clinical practice.

AIM: No standardized polymerase chain reaction (PCR) assay is available for detection of Chlamydia trachomatis (C. tr.) in synovial fluid (SF) for diagnostic use in clinical practice. This study tested the performance of two optimized molecular biology methods, to determine which is best suited for detecting C. tr. in SF clinical samples from patients with various rheumatologic diseases. METHODS: Two DNA extraction methods, i.e., (1) alkaline lysis and (2) QIAEX II Gel Extraction Kit® + cetyltrimethylammonium bromide (CTAB; Qiagen, Hilden, Germany), and C. tr.-omp1-152 bp PCR were tested in SF samples from a total of 329 patients with the following diagnoses: reactive arthritis (ReA; n = 10, 4 patients had posturethritic ReA), undifferentiated arthritis (UA; n = 66), rheumatoid arthritis (RA; n = 169), psoriatic arthritis (PSA; n = 12), and osteoarthritis (OA) n = 72. RESULTS: In SF samples, C. tr.-omp1-152 bp PCR in combination with alkaline lysis DNA extraction allowed detection of more C. tr.-positive samples: 3/10 (30%) ReA patients (all with posturethritic ReA) and 20/66 (38%) UA patients were positive, compared to the 0/10 (0%) patients with ReA and 1/66 (2%) with UA detected using the QIAEX II Gel Extraction Kit® + CTAB. Moreover, 2/12 (17%) SF samples from PSA patients tested positive with alkaline lysis. All samples from patients with OA and RA tested negative. CONCLUSION: Alkaline lysis in combination with C. tr.-omp1-152 bp PCR emerged as the most sensitive method for identification of C. tr. in clinical SF samples.

[Evidence-based recommendations for the management of undifferentiated peripheral inflammatory arthritis (UPIA). The German perspective on the international 3e initiative]. / Evidenzbasierte Empfehlungen zum Management einer undifferenzierten peripheren entzündlichen Arthritis (UPIA). Die deutsche Perspektive zur internationalen 3e-Initiative.

INTRODUCTION: Peripheral arthritis is the most common presenting complaint in clinical rheumatology. Unequivocal identification of the underlying entity can be difficult, particularly at an early stage. Such cases are commonly referred to as undifferentiated peripheral inflammatory arthritis (UPIA). Since evidence-based recommendations for the clinical management of UPIA are lacking, this international 3e initiative convened 697 rheumatologists from 17 countries to develop appropriate recommendations. METHODS: Based on a systematic literature research in Medline, EMBASE, Cochrane Library, and the ACR/EULAR abstracts of 2007/2008, 10 multinational recommendations were developed by 3 rounds of a Delphi process. In Germany, a national group of experts worked on 3 additional recommendations using the same method. The recommendations were discussed among the members of the 3e initiative and the degree of consensus was analyzed as well as the potential impact of the recommendations on clinical practice. RESULTS: A total of 39,756 references were identified, of which 250 were systematically reviewed for the development of 10 multinational recommendations concerning differential diagnosis, diagnostic and prognostic value of clinical assessments, laboratory tests and imaging techniques, and monitoring of UPIA. In addition, 3 national recommendations on the diagnostic and prognostic value of a response to anti-inflammatory therapy on the analysis of synovial fluid and on enthesitis were developed by the German experts based on 35 out of 5542 references. CONCLUSIONS: The article translates the 2011 published original paper of the international 3e initiative (Machado et al., Ann Rheum Dis 70:15-24, 2011) and reports the methods and results of the national vote and the additional 3 national recommendations.

CFD-DEM Fluidized Bed Drying Study Using a Coarse-Graining Technique.

Fluidized beds are commonly applied to industrial drying applications. Modeling using the computational fluid dynamics-discrete element method (CFD-DEM) can be employed to increase the fundamental understanding of solids drying. A large drawback of CFD-DEM is the computational requirements, leading to a limitation regarding the system size. Coarse-grained CFD-DEM is an approach to reduce computational costs, allowing one to simulate larger fluidized beds. In this article, coarse-graining CFD-DEM scaling laws are used for fluidized bed solids drying. Three superficial gas velocities are investigated. The particle temperature and density are accurately described. Besides, the Sherwood number is well captured by the coarse-graining simulations.

[German 2012 guidelines for the sequential medical treatment of rheumatoid arthritis. Adapted EULAR recommendations and updated treatment algorithm]. / S1-Leitlinie der DGRh zur sequenziellen medikamentösen Therapie der rheumatoiden Arthritis 2012. Adaptierte EULAR-Empfehlungen und aktualisierter Therapiealgorithmus.

Following the EULAR recommendations published in 2010 German guidelines for the medical treatment of rheumatoid arthritis were developed based on an update of the systematic literature search and expert consensus. Methotrexate is the standard treatment option at the time of diagnosis, preferably in combination with low dose glucocorticoids. Combined disease-modifying antirheumatic drugs (DMARD) therapy should be considered in patients not responding within 12 weeks. Treatment with biologicals should be initiated in patients with persistent high activity no later than 6 months after conventional treatment and in exceptional situations (e.g. early destruction or unfavorable prognosis) even earlier. If treatment with biologicals remains ineffective, changing to another biological is recommended after 3-6 months. In cases of long-standing remission a controlled reduction of medical treatment can be considered.

Mutations in the APC tumour suppressor gene cause chromosomal instability.

Two forms of genetic instability have been described in colorectal cancer: microsatellite instability and chromosomal instability. Microsatellite instability results from mutations in mismatch repair genes; chromosomal instability is the hallmark of many colorectal cancers, although it is not completely understood at the molecular level. As truncations of the Adenomatous Polyposis Coli (APC) gene are found in most colorectal tumours, we thought that mutations in APC might be responsible for chromosomal instability. To test this hypothesis, we examined mouse embryonic stem (ES) cells homozygous for Min (multiple intestinal neoplasia) or Apc1638T alleles. Here we show that Apc mutant ES cells display extensive chromosome and spindle aberrations, providing genetic evidence for a role of APC in chromosome segregation. Consistent with this, APC accumulates at the kinetochore during mitosis. Apc mutant cells form mitotic spindles with an abundance of microtubules that inefficiently connect with kinetochores. This phenotype is recapitulated by the induced expression of a 253-amino-acid carboxy-terminal fragment of APC in microsatellite unstable colorectal cancer cells. We conclude that loss of APC sequences that lie C-terminal to the beta-catenin regulatory domain contributes to chromosomal instability in colorectal cancer.

[Reactive arthritis: from pathogenesis to novel strategies]. / Reaktive Arthritis: Von der Pathogenese zu neuen Therapiekonzepten.

Reactive arthritis (ReA) was first described 100 years ago. It is defined as a sterile joint inflammation following a primary, extra-articular infection often in the form of urethritis or enteritis and less frequently respiratory infection and is characterized by the presence of bacterial antigens or non-culturable bacteria in the joint,. The prevalence is estimated to be 40/100,000 adults, while the incidence is 4-5/100,000. The classic HLA-B27-associated form with asymmetric involvement of the lower extremities and/or the spine is part of the spondyloarthritis concept. The phenomenon of persistence, which will be discussed in detail herein, plays an important role in the pathogenesis of ReA. Up to 30% of patients develop chronic symptoms posing a therapeutic challenge. Combination antibiotic treatment showing a response in up to 63% of patients has recently been proposed. Biologics could represent an alternative therapeutic option for patients showing a severe and highly active disease course.

Non-Markovian dynamics of clusters during nucleation.

Most theories of homogeneous nucleation are based on a Fokker-Planck-like description of the behavior of the mass of clusters. Here we will show that these approaches are incomplete for a large class of nucleating systems, as they assume the effective dynamics of the clusters to be Markovian, i.e., memoryless. We characterize these non-Markovian dynamics and show how this influences the dynamics of clusters during nucleation. Our results are validated by simulations of a three-dimensional Ising model with locally conserved magnetization.

Simulation of density segregation in vibrated beds.

We have investigated by numerical simulation the density segregation of fine equal-sized bronze and glass particles subject to vertical vibrations. The model was found to be capable of predicting the two main segregation forms ("bronze on top" and "sandwich") in roughly the same regions of the phase diagram as was found experimentally by Burtally We investigated the effects of pressure air forcing, friction and restitution of kinetic energy in collisions, and box size on the segregation behavior. We find that next to the interstitial air friction also has a large influence on the formation of the sandwich structure.

Nonspherical particles in a pseudo-2D fluidized bed: Experimental study.

Fluidization is widely used in industries and has been extensively studied, both experimentally and theoretically, in the past. However, most of these studies focus on spherical particles while in practice granules are rarely spherical. Particle shape can have a significant effect on fluidization characteristics. It is therefore important to study the effect of particle shape on fluidization behavior in detail. In this study, experiments in pseudo-2D fluidized beds are used to characterize the fluidization of spherocylindrical (rod-like) Geldart D particles of aspect ratio 4. Pressure drop and optical measurement methods (Digital Image Analysis, Particle Image Velocimetry, Particle Tracking Velocimetry) are employed to measure bed height, particle orientation, particle circulation, stacking, and coordination number. The commonly used correlations to determine the pressure drop across a bed of nonspherical particles are compared to experiments. Experimental observations and measurements have shown that rod-like particles are prone to interlocking and channeling behavior. Well above the minimum fluidization velocity, vigorous bubbling fluidization is observed, with groups of interlocked particles moving upwards, breaking up, being thrown high in the freeboard region and slowly raining down as dispersed phase. At high flowrates, a circulation pattern develops with particles moving up through the center and down at the walls. Particles tend to orient themselves along the flow direction.

Viscoelastic effects on residual oil distribution in flows through pillared microchannels.

HYPOTHESIS: Multiphase flow through porous media is important in a number of industrial, natural and biological processes. One application is enhanced oil recovery (EOR), where a resident oil phase is displaced by a Newtonian or polymeric fluid. In EOR, the two-phase immiscible displacement through heterogonous porous media is usually governed by competing viscous and capillary forces, expressed through a Capillary number Ca, and viscosity ratio of the displacing and displaced fluid. However, when viscoelastic displacement fluids are used, elastic forces in the displacement fluid also become significant. It is hypothesized that elastic instabilities are responsible for enhanced oil recovery through an elastic microsweep mechanism. EXPERIMENTS: In this work, we use a simplified geometry in the form of a pillared microchannel. We analyze the trapped residual oil size distribution after displacement by a Newtonian fluid, a nearly inelastic shear thinning fluid, and viscoelastic polymers and surfactant solutions. FINDINGS: We find that viscoelastic polymers and surfactant solutions can displace more oil compared to Newtonian fluids and nearly inelastic shear thinning polymers at similar Ca numbers. Beyond a critical Ca number, the size of residual oil blobs decreases significantly for viscoelastic fluids. This critical Ca number directly corresponds to flow rates where elastic instabilities occur in single phase flow, suggesting a close link between enhancement of oil recovery and appearance of elastic instabilities.

Identification of APC2, a homologue of the adenomatous polyposis coli tumour suppressor.

The adenomatous polyposis coli (APC) tumour-suppressor protein controls the Wnt signalling pathway by forming a complex with glycogen synthase kinase 3beta (GSK-3beta), axin/conductin and betacatenin. Complex formation induces the rapid degradation of betacatenin. In colon carcinoma cells, loss of APC leads to the accumulation of betacatenin in the nucleus, where it binds to and activates the Tcf-4 transcription factor (reviewed in [1] [2]). Here, we report the identification and genomic structure of APC homologues. Mammalian APC2, which closely resembles APC in overall domain structure, was functionally analyzed and shown to contain two SAMP domains, both of which are required for binding to conductin. Like APC, APC2 regulates the formation of active betacatenin-Tcf complexes, as demonstrated using transient transcriptional activation assays in APC -/- colon carcinoma cells. Human APC2 maps to chromosome 19p13.3. APC and APC2 may therefore have comparable functions in development and cancer.