Evaluation of "appropriate use criteria" for surgical decision-making in lumbar degenerative spondylolisthesis. A controlled, multicentre, prospective observational study.

INTRODUCTION: Selecting patients with lumbar degenerative spondylolisthesis (LDS) for surgery is difficult. Appropriate use criteria (AUC) have been developed to clarify the indications for LDS surgery but have not been evaluated in controlled studies. METHODS: This prospective, controlled, multicentre study involved 908 patients (561 surgical and 347 non-surgical controls; 69.5 ± 9.7y; 69% female), treated as per normal clinical practice. Their appropriateness for surgery was afterwards determined using the AUC. They completed the Core Outcome Measures Index (COMI) at baseline and 12 months' follow-up. Multiple regression adjusting for confounders evaluated the influence of appropriateness designation and treatment received on the 12-month COMI and achievement of MCIC (≥ 2.2-point-reduction). RESULTS: As per convention, appropriate (A) and uncertain (U) groups were combined for comparison with the inappropriate (I) group. For the adjusted 12-month COMI, the benefit of surgery relative to non-surgical care was not significantly greater for the A/U than the I group (p = 0.189). There was, however, a greater treatment effect of surgery for those with higher baseline COMI (p = 0.035). The groups' adjusted probabilities of achieving MCIC were: 83% (A/U, receiving surgery), 71% (I, receiving surgery), 50% (A/U, receiving non-surgical care), and 32% (I, receiving non-surgical care). CONCLUSIONS: A/U patients receiving surgery had the highest chances of achieving MCIC, but the AUC were not able to identify which patients had a greater treatment effect of surgery relative to non-surgical care. The identification of other characteristics that predict a greater treatment effect of surgery, in addition to baseline COMI, is required to improve decision-making.

Limited Utility of Self-made Oxygen Generators Assembled From Everyday Commodities During the COVID-19 Pandemic.

The current COVID-19 pandemic has aggravated pre-existing oxygen supply gaps all over the world. In fact, oxygen shortages occurred in affluent areas with highly developed healthcare systems. The state-of-affairs created much suffering and resulted in potentially preventable deaths. Meanwhile, several international activities have been initiated to improve oxygen availability in the long-term by creating new networks of oxygen plants and supply channels. However, disasters such as the current pandemic may require rapid, autarkic oxygen production. Therefore, we determined whether oxygen resilience could conceivably be improved through self-made oxygen generators using material that is easily available even in remote areas. The team comprised engineers and physicians with hands-on experience in low- and middle-income countries. We constructed and tested self-made setups for water hydrolysis and membrane-based oxygen purification. We must conclude, however, that the massive amounts of oxygen patients with COVID-19 require cannot be reasonably met with such simple measures, which would require high efforts and hold potential risks.

Accelerometry-based physical activity, disability and quality of life before and after lumbar decompression surgery from a physiotherapeutic perspective: An observational cohort study.

BACKGROUND: The effect of lumbar decompression on physical activity (PA) measures (measured as number of steps/day and as moderate to vigorous PA (MVPA)) is poorly understood. The aim of the current study was to compare PA in patients before and after lumbar decompression and to determine the association between change in steps/day and MVPA with change in disability, health-related quality of life (HRQOL) and pain. METHODS: Patients undergoing lumbar decompression surgery were recruited. Steps/day and MVPA MVPA were recorded with an accelerometer. Oswestry Disability Index (ODI), HRQOL (Short Form 36 questionnaire (SF-36)) and pain levels (visual analogue scale (VAS)) were collected prior to surgery and six and twelve weeks postoperatively. Steps/day were compared to the lower bound of steps/day in healthy persons (7,000 steps per day), and the relationship between changes in steps/day, MVPA, ODI, SF-36, and VAS were calculated. RESULTS: Twenty-six patients aged 37 to 75 years met inclusion criteria and were included in the study. Lumbar decompressions were performed for stenosis and/or disc herniation. Preoperatively, patients took an average 5,073±2,621 (mean±standard deviation) steps/day. At 6 weeks postoperatively, patients took 6,131±2,343 steps/day. At 12 weeks postoperatively, patients took 5,683±2,128 steps/day. Postoperative MVPA minutes per week increased compared to preoperative MVPA (preoperative: 94.6±122.9; 6 weeks: 173.9±181.9; 12 weeks: 145.7±132.8). From preoperative to 12 weeks postoperative, change in steps correlated with MVPA (R=0.775; P<0.001), but not with ODI (R=0.069; P=0.739), SF-36 (R=0.138; P=0.371), VAS in the back (R=0.230; P=0.259) or VAS in the leg (R=-0.123; P=0.550). CONCLUSIONS: During the first 12 postoperative weeks, daily steps did not reach the lower bound of normal step activity of 7,000 steps/day, however postoperative steps/day were higher than before surgery. Steps/day and MVPA appear to be independent of ODI and SF-36 and represent additional outcome parameters in patients undergoing lumbar decompression surgery and should be considered e.g., by physiotherapists especially from 6 to 12 weeks postoperatively. LEVEL OF EVIDENCE: 2, prospective cohort study.

Immunoglobulin expression in the endoplasmic reticulum shapes the metabolic fitness of B lymphocytes.

The major function of B lymphocytes is to sense antigens and to produce protective antibodies after activation. This function requires the expression of a B-cell antigen receptor (BCR), and evolutionary conserved mechanisms seem to exist that ensure that B cells without a BCR do not develop nor survive in the periphery. Here, we show that the loss of BCR expression on Burkitt lymphoma cells leads to decreased mitochondrial function and impaired metabolic flexibility. Strikingly, this phenotype does not result from the absence of a classical Syk-dependent BCR signal but rather from compromised ER expansion. We show that the reexpression of immunoglobulins (Ig) in the absence of the BCR signaling subunits Igα and Igß rescues the observed metabolic defects. We demonstrate that immunoglobulin expression is needed to maintain ER homeostasis not only in lymphoma cells but also in resting B cells. Our study provides evidence that the expression of BCR components, which is sensed in the ER and shapes mitochondrial function, represents a novel mechanism of metabolic control in B cells.

Limbostomy: Longitudinal Intravital Microendoscopy in Murine Osteotomies.

Bone healing involves the interplay of immune cells, mesenchymal cells, and vasculature over the time course of regeneration. Approaches to quantify the spatiotemporal aspects of bone healing at cellular resolution during long bone healing do not yet exist. Here, a novel technique termed Limbostomy is presented, which combines intravital microendoscopy with an osteotomy. This design allows a modular combination of an internal fixator plate with a gradient refractive index (GRIN) lens at various depths in the bone marrow and can be combined with a surgical osteotomy procedure. The field of view (FOV) covers a significant area of the fracture gap and allows monitoring cellular processes in vivo. The GRIN lens causes intrinsic optical aberrations which have to be corrected. The optical system was characterized and a postprocessing algorithm was developed. It corrects for wave front aberration-induced image plane deformation and for background and noise signals, enabling us to observe subcellular processes. Exemplarily, we quantitatively and qualitatively analyze angiogenesis in bone regeneration. We make use of a transgenic reporter mouse strain with nucleargreen fluorescent protein and membrane-bound tdTomato under the Cadherin-5 promoter. We observe two phases of vascularization. First, rapid vessel sprouting pervades the FOV within 3-4 days after osteotomy. Second, the vessel network continues to be dynamically remodeled until the end of our observation time, 14 days after surgery. Limbostomy opens a unique set of opportunities and allows further insight on spatiotemporal aspects of bone marrow biology, for example, hematopoiesis, analysis of cellular niches, immunological memory, and vascularization in the bone marrow during health and disease. © 2020 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.

Systematic Enzyme Mapping of Cellular Metabolism by Phasor-Analyzed Label-Free NAD(P)H Fluorescence Lifetime Imaging.

In the past years, cellular metabolism of the immune system experienced a revival, as it has become clear that it is not merely responsible for the cellular energy supply, but also impacts on many signaling pathways and, thus, on diverse cellular functions. Label-free fluorescence lifetime imaging of the ubiquitous coenzymes NADH and NADPH (NAD(P)H-FLIM) makes it possible to monitor cellular metabolism in living cells and tissues and has already been applied to study metabolic changes both under physiologic and pathologic conditions. However, due to the complex distribution of NAD(P)H-dependent enzymes in cells, whose distribution continuously changes over time, a thorough interpretation of NAD(P)H-FLIM results, in particular, resolving the contribution of various enzymes to the overall metabolic activity, remains challenging. We developed a systematic framework based on angle similarities of the phase vectors and their length to analyze NAD(P)H-FLIM data of cells and tissues based on a generally valid reference system of highly abundant NAD(P)H-dependent enzymes in cells. By using our analysis framework, we retrieve information not only about the overall metabolic activity, i.e., the fraction of free to enzyme-bound NAD(P)H, but also identified the enzymes predominantly active within the sample at a certain time point with subcellular resolution. We verified the performance of the approach by applying NAD(P)H-FLIM on a stromal-like cell line and identified a different group of enzymes that were active in the cell nuclei as compared to the cytoplasm. As the systematic phasor-based analysis framework of label-free NAD(P)H-FLIM can be applied both in vitro and in vivo, it retains the unique power to enable dynamic enzyme-based metabolic investigations, at subcellular resolution, in genuine environments.

Spatial Distribution of Macrophages During Callus Formation and Maturation Reveals Close Crosstalk Between Macrophages and Newly Forming Vessels.

Macrophages are essential players in the process of fracture healing, acting by remodeling of the extracellular matrix and enabling vascularization. Whilst activated macrophages of M1-like phenotype are present in the initial pro-inflammatory phase of hours to days of fracture healing, an anti-inflammatory M2-like macrophage phenotype is supposed to be crucial for the induction of downstream cascades of healing, especially the initiation of vascularization. In a mouse-osteotomy model, we provide a comprehensive characterization of vessel (CD31+, Emcn+) and macrophage phenotypes (F4/80, CD206, CD80, Mac-2) during the process of fracture healing. To this end, we phenotype the phases of vascular regeneration-the expansion phase (d1-d7 after injury) and the remodeling phase of the endothelial network, until tissue integrity is restored (d14-d21 after injury). Vessels which appear during the bone formation process resemble type H endothelium (CD31hiEmcnhi), and are closely connected to osteoprogenitors (Runx2+, Osx+) and F4/80+ macrophages. M1-like macrophages are present in the initial phase of vascularization until day 3 post osteotomy, but they are rare during later regeneration phases. M2-like macrophages localize mainly extramedullary, and CD206+ macrophages are found to express Mac-2+ during the expansion phase. VEGFA expression is initiated by CD80+ cells, including F4/80+ macrophages, until day 3, while subsequently osteoblasts and chondrocytes are main contributors to VEGFA production at the fracture site. Using Longitudinal Intravital Microendoscopy of the Bone (LIMB) we observe changes in the motility and organization of CX3CR1+ cells, which infiltrate the injury site after an osteotomy. A transient accumulation, resulting in spatial polarization of both, endothelial cells and macrophages, in regions distal to the fracture site, is evident. Immunofluorescence histology followed by histocytometric analysis reveals that F4/80+CX3CR1+ myeloid cells precede vascularization.

Combustion Chemistry of Fuels: Quantitative Speciation Data Obtained from an Atmospheric High-temperature Flow Reactor with Coupled Molecular-beam Mass Spectrometer.

This manuscript describes a high-temperature flow reactor experiment coupled to the powerful molecular beam mass spectrometry (MBMS) technique. This flexible tool offers a detailed observation of chemical gas-phase kinetics in reacting flows under well-controlled conditions. The vast range of operating conditions available in a laminar flow reactor enables access to extraordinary combustion applications that are typically not achievable by flame experiments. These include rich conditions at high temperatures relevant for gasification processes, the peroxy chemistry governing the low temperature oxidation regime or investigations of complex technical fuels. The presented setup allows measurements of quantitative speciation data for reaction model validation of combustion, gasification and pyrolysis processes, while enabling a systematic general understanding of the reaction chemistry. Validation of kinetic reaction models is generally performed by investigating combustion processes of pure compounds. The flow reactor has been enhanced to be suitable for technical fuels (e.g. multi-component mixtures like Jet A-1) to allow for phenomenological analysis of occurring combustion intermediates like soot precursors or pollutants. The controlled and comparable boundary conditions provided by the experimental design allow for predictions of pollutant formation tendencies. Cold reactants are fed premixed into the reactor that are highly diluted (in around 99 vol% in Ar) in order to suppress self-sustaining combustion reactions. The laminar flowing reactant mixture passes through a known temperature field, while the gas composition is determined at the reactors exhaust as a function of the oven temperature. The flow reactor is operated at atmospheric pressures with temperatures up to 1,800 K. The measurements themselves are performed by decreasing the temperature monotonically at a rate of -200 K/h. With the sensitive MBMS technique, detailed speciation data is acquired and quantified for almost all chemical species in the reactive process, including radical species.

Early cysteine-dependent inactivation of 26S proteasomes does not involve particle disassembly.

Under oxidative stress 26S proteasomes suffer reversible disassembly into its 20S and 19S subunits, a process mediated by HSP70. This inhibits the degradation of polyubiquitinated proteins by the 26S proteasome and allows the degradation of oxidized proteins by a free 20S proteasome. Low fluxes of antimycin A-stimulated ROS production caused dimerization of mitochondrial peroxiredoxin 3 and cytosolic peroxiredoxin 2, but not peroxiredoxin overoxidation and overall oxidation of cellular protein thiols. This moderate redox imbalance was sufficient to inhibit the ATP stimulation of 26S proteasome activity. This process was dependent on reversible cysteine oxidation. Moreover, our results show that this early inhibition of ATP stimulation occurs previous to particle disassembly, indicating an intermediate step during the redox regulation of the 26S proteasome with special relevance under redox signaling rather than oxidative stress conditions.

Impact of Alternative Jet Fuels on Engine Exhaust Composition During the 2015 ECLIF Ground-Based Measurements Campaign.

The application of fuels from renewable sources ("alternative fuels") in aviation is important for the reduction of anthropogenic carbon dioxide emissions, but may also attribute to reduced release of particles from jet engines. The present experiment describes ground-based measurements in the framework of the ECLIF (Emission and Climate Impact of Alternative Fuels) campaign using an Airbus A320 (V2527-A5 engines) burning six fuels of chemically different composition. Two reference Jet A-1 with slightly different chemical parameters were applied and further used in combination with a Fischer-Tropsch synthetic paraffinic kerosene (FT-SPK) to prepare three semi synthetic jet fuels (SSJF) of different aromatic content. In addition, one commercially available fully synthetic jet fuel (FSJF) featured the lowest aromatic content of the fuel selection. Neither the release of nitrogen oxide or carbon monoxide was significantly affected by the different fuel composition. The measured particle emission indices showed a reduction up to 50% (number) and 70% (mass) for two alternative jet fuels (FSJF, SSJF2) at low power settings in comparison to the reference fuels. The reduction is less pronounced at higher operating conditions but the release of particle number and particle mass is still significantly lower for the alternative fuels than for both reference fuels. The observed correlation between emitted particle mass and fuel aromatics is not strict. Here, the H/C ratio is a better indicator for soot emission.

Pharmacological and Genetic Manipulation of p53 in Brown Fat at Adult But Not Embryonic Stages Regulates Thermogenesis and Body Weight in Male Mice.

p53 is a well-known tumor suppressor that plays multiple biological roles, including the capacity to modulate metabolism at different levels. However, its metabolic role in brown adipose tissue (BAT) remains largely unknown. Herein we sought to investigate the physiological role of endogenous p53 in BAT and its implication on BAT thermogenic activity and energy balance. To this end, we generated and characterized global p53-null mice and mice lacking p53 specifically in BAT. Additionally we performed gain-and-loss-of-function experiments in the BAT of adult mice using virogenetic and pharmacological approaches. BAT was collected and analyzed by immunohistochemistry, thermography, real-time PCR, and Western blot. p53-deficient mice were resistant to diet-induced obesity due to increased energy expenditure and BAT activity. However, the deletion of p53 in BAT using a Myf5-Cre driven p53 knockout did not show any changes in body weight or the expression of thermogenic markers. The acute inhibition of p53 in the BAT of adult mice slightly increased body weight and inhibited BAT thermogenesis, whereas its overexpression in the BAT of diet-induced obese mice reduced body weight and increased thermogenesis. On the other hand, pharmacological activation of p53 improves body weight gain due to increased BAT thermogenesis by sympathetic nervous system in obese adult wild-type mice but not in p53(-/-) animals. These results reveal that p53 regulates BAT metabolism by coordinating body weight and thermogenesis, but these metabolic actions are tissue specific and also dependent on the developmental stage.

An atmospheric pressure high-temperature laminar flow reactor for investigation of combustion and related gas phase reaction systems.

A new high-temperature flow reactor experiment utilizing the powerful molecular beam mass spectrometry (MBMS) technique for detailed observation of gas phase kinetics in reacting flows is presented. The reactor design provides a consequent extension of the experimental portfolio of validation experiments for combustion reaction kinetics. Temperatures up to 1800 K are applicable by three individually controlled temperature zones with this atmospheric pressure flow reactor. Detailed speciation data are obtained using the sensitive MBMS technique, providing in situ access to almost all chemical species involved in the combustion process, including highly reactive species such as radicals. Strategies for quantifying the experimental data are presented alongside a careful analysis of the characterization of the experimental boundary conditions to enable precise numeric reproduction of the experimental results. The general capabilities of this new analytical tool for the investigation of reacting flows are demonstrated for a selected range of conditions, fuels, and applications. A detailed dataset for the well-known gaseous fuels, methane and ethylene, is provided and used to verify the experimental approach. Furthermore, application for liquid fuels and fuel components important for technical combustors like gas turbines and engines is demonstrated. Besides the detailed investigation of novel fuels and fuel components, the wide range of operation conditions gives access to extended combustion topics, such as super rich conditions at high temperature important for gasification processes, or the peroxy chemistry governing the low temperature oxidation regime. These demonstrations are accompanied by a first kinetic modeling approach, examining the opportunities for model validation purposes.

[Addiction in psychiatric ambulatory service]. / Der Suchtpatient in der psychiatrischen Ambulanz.

Addictive disorders are of high prevalence and often associated with other psychiatric and somatic diseases. Diagnostic procedures must be targeted to this topic and should also cover the exclusion of comorbidities, such as OCD, psychotic, mood disorders and ADHD. Severe cases, often complicated by multiple dependencies of substances and advanced stages of the disease can require the involvement of a variety of caregivers, who are requested to sufficiently cooperate and interact to guarantee an optimal outcome of treatment. The caregivers can be additionally confronted with problems such as intoxications, psychosocial and somatic complications, which can demand legal protective measures. The responsible caregivers should highly regard the task of distinguishing between therapeutic and official magisterial assignments, including compulsory treatment. In geriatric patients addictive disorders become even more frequent. Diagnostically often overlooked and trivialized they are of major interest, as these problems can lead to complications including falls with injuries, namely seen in patients with low dose dependency of sedatives. Therefore the prescription of these drugs should be very carefully evaluated.

High-order harmonic generation enhanced by XUV light.

The combination of high-order harmonic generation (HHG) with resonant XUV excitation of a core electron into the transient valence vacancy that is created in the course of the HHG process is investigated theoretically. In this setup, the first electron performs a HHG three-step process, whereas the second electron Rabi flops between the core and the valence vacancy. The modified HHG spectrum due to recombination with the valence and the core is determined and analyzed for krypton on the 3d→4p resonance in the ion. We assume an 800 nm laser with an intensity of about 10(14) W/cm2 and XUV radiation from the Free Electron Laser in Hamburg (FLASH) with an intensity in the range 10(13)-10(16)W cm2. Our prediction opens perspectives for nonlinear XUV physics, attosecond x rays, and HHG-based spectroscopy involving core orbitals.

A novel vacuum ultra violet lamp for metastable rare gas experiments.

We report on a new design of a vacuum ultra violet (VUV) lamp for direct optical excitation of high laying atomic states, e.g., for excitation of metastable rare gas atoms. The lamp can be directly mounted to ultra-high vacuum vessels (p ≤ 10(-10)mbar). It is driven by a 2.45 GHz microwave source. For optimum operation, it requires powers of ~20 W. The VUV light is transmitted through a magnesium fluoride window, which is known to have a decreasing transmittance for VUV photons with time. In our special setup, after a run-time of the VUV lamp of 550 h the detected signal continuously decreased to 25% of its initial value. This corresponds to a lifetime increase of two orders of magnitude compared to previous setups or commercial lamps.

Attochirp-free high-order harmonic generation.

A method is proposed for arbitrarily engineering the high-order harmonic generation phase achieved by shaping a laser pulse and employing xuv light or x rays for ionization. This renders the production of bandwidth-limited attosecond pulses possible while avoiding the use of filters for chirp compensation. By adding the first 8 Fourier components to a sinusoidal field of 1016 W/cm2, the bandwidth-limited emission of 8 as is shown to be possible from a Li2+ gas. The scheme is extendable to the zs-scale.

Quantitative laser diagnostic and modeling study of C2 and CH chemistry in combustion.

Quantitative concentration measurements of CH and C(2) have been performed in laminar, premixed, flat flames of propene and cyclopentene with varying stoichiometry. A combination of cavity ring-down (CRD) spectroscopy and laser-induced fluorescence (LIF) was used to enable sensitive detection of these species with high spatial resolution. Previously, CH and C(2) chemistry had been studied, predominantly in methane flames, to understand potential correlations of their formation and consumption. For flames of larger hydrocarbon fuels, however, quantitative information on these small intermediates is scarce, especially under fuel-rich conditions. Also, the combustion chemistry of C(2) in particular has not been studied in detail, and although it has often been observed, its role in potential build-up reactions of higher hydrocarbon species is not well understood. The quantitative measurements performed here are the first to detect both species with good spatial resolution and high sensitivity in the same experiment in flames of C(3) and C(5) fuels. The experimental profiles were compared with results of combustion modeling to reveal details of the formation and consumption of these important combustion molecules, and the investigation was devoted to assist the further understanding of the role of C(2) and of its potential chemical interdependences with CH and other small radicals.

High harmonic generation via continuum wave-packet interference.

High-order harmonic generation (HHG) is investigated theoretically in the over-the-barrier ionization regime revealing the strong signature of interference between two separately ionized and separately propagating free wave packets of a single electron. The interference leads to the emission of coherent light at a photon energy corresponding to the kinetic-energy difference of the two recolliding electron quantum paths, thus complementary to the well-known classical three-step picture of HHG. As will be shown by time-frequency analysis of the emitted radiation, the process entirely dominates the coherent HHG emission after the atomic ground state has been depleted by a strong field. Moreover, it can be isolated from the continuum-bound harmonics via phase matching.

Designer femtosecond pulse shaping using grating-engineered quasi-phase-matching in lithium niobate.

The generation of tailored femtosecond pulses with fully engineered intensity and phase profiles is demonstrated using second-harmonic generation of an Er:fiber laser in an aperiodically poled lithium niobate crystal in the undepleted pump regime. Second-harmonic pulse shapes, including Gaussian, stepped, square, and multiple pulses have been characterized using cross-correlation frequency-resolved optical gating and have been shown to agree well with theory.

The advanced glycation end product pentosidine correlates to IL-6 and other relevant inflammatory markers in rheumatoid arthritis.

OBJECTIVE: Oxidative stress and inflammatory processes accelerate the formation of advanced glycation end products (AGE), e.g. of pentosidine. The aim of this study was to investigate the relationships between levels of pentosidine in serum and synovial fluid, proinflammatory cytokines, other markers of inflammatory activity, and the state of radiologically visible bone destruction in patients with rheumatoid arthritis (RA). OBJECTIVES: One hundred thirty-three nondiabetic RA patients and 56 age-matched, healthy subjects were included. Serum and synovial fluid pentosidine, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and rheumatoid factor levels were determined. In 30 patients, the proinflammatory cytokines interleukin (IL)-1beta, IL-6, and TNF-alpha and the soluble receptors sIL-2R, sIL-6R, sTNF-alpha, and RI/RII were also measured. RESULTS: Serum levels of pentosidine were on average significantly higher in RA patients than in healthy subjects and correlated significantly to ESR, CRP, and serum levels of IL-6. Serum and synovial fluid pentosidine did not show any differences. Rheumatoid factor-positive RA patients had higher pentosidine levels in the synovial fluid than rheumatoid factor-negative patients. Correlations could not be found between pentosidine and the other cytokines or cytokine receptors measured. CONCLUSION: The binding of AGE on cell receptors induces activation of nuclear factor kappa B, resulting in enhanced synthesis of proinflammatory cytokines. Moreover, AGE generation may also lead to the formation of new, immunologically relevant epitopes at synovial proteins. Both mechanisms could contribute to initiation and perpetuation of the inflammatory and destructive processes in RA.