Enhanced Glutathione Levels and Oxidoresistance Mediated by Increased Glucose-6-phosphate Dehydrogenase Expression *

Glucose-6-phosphate dehydrogenase (G6PD) is the key enzyme of the pentose phosphate pathway that is responsible for the generation of NADPH, which is required in many detoxifying reactions. We have recently demonstrated that G6PD expression is induced by a variety of chemical agents acting at different steps in the biochemical pathway controlling the intracellular redox status. Although we obtained evidence that the oxidative stress-mediated enhancement of G6PD expression is a general phenomenon, the functional significance of such G6PD induction after oxidant insult is still poorly understood. In this report, we used a GSH-depleting drug that determines a marked decrease in the intracellular pool of reduced glutathione and a gradual but notable increase in G6PD expression. Both effects are seen soon after drug addition. Once G6PD activity has reached the maximum, the GSH pool is restored. We suggest and also provide the first direct evidence that G6PD induction serves to maintain and regenerate the intracellular GSH pool. We used HeLa cell clones stably transfected with the human G6PD gene that display higher G6PD activity than the parent HeLa cells. Although the activities of glutathione peroxidase, glutathione reductase, and catalase were comparable in all strains, the concentrations of GSH were significantly higher in G6PD-overexpressing clones. A direct consequence of GSH increase in these cells is a decreased reactive oxygen species production, which makes these cells less sensitive to the oxidative burst produced by external stimuli. Indeed, all clones that constitutively overexpress G6PD exhibited strong protection against oxidants-mediated cell killing. We also observe that NF-kappa B activation, in response to tumor necrosis factor-alpha treatment, is strongly reduced in human HeLa cells overexpressing G6PD

Lipid profile changes in patients with rheumatic diseases receiving a treatment with TNF-α blockers: a meta-analysis of prospective studies.

Some studies showed an anti-atherogenic effect of TNF-α blockers on lipid profile, but these data have been challenged.To perform a meta-analysis on lipid profile changes induced by TNF-α blocker treatment.Prospective studies on rheumatic patients receiving TNF-α blockers and providing before-and-after treatment values of triglycerides (TGs), total cholesterol (TC), HDL-cholesterol (HDLc), LDL-cholesterol (LDLc), and atherogenic index (AI) were included. Standardized mean differences (SMD) in lipid profile were analyzed at short-term (2-12 weeks), middle-term (13-24 weeks), and long-term (25-52 weeks) assessments.Thirty articles (1707 patients) were included. TNF-α blockers determined an increase in TC at short-term, middle-term, and long-term assessments (SMD: 0.20 mmol/L [95% CI: 0.04, 0.35]; SMD: 0.27 mmol/L [95% CI: 0.08, 0.46]; SMD: 0.22 mmol/L [95% CI: 0.01, 0.43]). HDLc increased only at the short-term assessment (SMD: 0.19 mmol/L [95% CI: 0.10, 0.28]), and TGs achieved a significant increase at the long-term assessment (SMD: 0.19 mmol/L [95% CI: 0.04, 0.34]). LDLc and AI were not affected by TNF-α blocker treatment.Slight but significant increases in TC occurred without any significant change in LDLc and AI. Changes in HDLc and TGs were not consistent among the different time point assessments. These quantitative changes in lipid profile do not seem to be able to explain cardiovascular risk improvement reported in patients receiving TNF-α blockers. Further studies on other mechanisms are needed to address this issue

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

La fatica Reumatoide: nuovi approcci clinici e riabilitativi

La fatica è la sensazione duratura di debolezza, mancanza di energia, stanchezza o spossatezza, riferita dal 40%-80% dei pazienti con artrite reumatoide (AR) come il loro sintomo più invalidante. Sia la riduzione della massa muscolare che l'aumento della massa grassa, fenomeno noto come cachessia, sono evidenti in pazienti con AR. A differenza del dolore e della disabilità, la fatica è raramente affrontata come un obiettivo terapeutico primario. Essa è correlata almeno in parte all'aumento della produzione delle citochine pro-infiammatorie, soprattutto il TNF-α e l'IL-6 ed ai loro effetti metabolici su muscoli e tessuto adiposo. Protocolli specifici per la terapia medica/riabilitativa della fatica, sono attualmente inesistenti. Il progetto di ricerca sviluppato, è stato finalizzato alla valutazione dell'efficacia ed alla messa a punto di progetti riabilitativi intensivi tradizionali e/o mediante nuove tecnologie per la terapia della fatica "reumatoide". Il progetto si è articolato in 2 differenti momenti: 1. Valutare l'efficacia di un progetto riabilitativo tradizionale intensivo personalizzato nel ridurre la fatica di pazienti con AR inveterata, in high disease activity e severa compromissione funzionale 2. Valutare l'efficacia di un progetto riabilitativo estensivo basato su nuove tecnologie disponibili sul mercato, nel ridurre la fatica e migliorare la funzione articolare in giovani pazienti con AR

An Adaptive Approach for Impulsive Formation Maintenance Relevant to Distributed SAR Missions

This paper proposes an approach for impulsive formation maintenance tailored to distributed synthetic aperture radar, i.e., a spaceborne system composed by several antennas working together to provide enhanced remote sensing capabilities. The analyzed configuration is designed to guarantee the presence of a safety tube surrounding each satellite as the dynamics evolve. Formation requirements are related to general constraints on the acceptable along-track and radial/cross-track separations. The paper introduces an adaptive maintenance logic which fulfills these constraints. Specifically, the formation is adaptively redesigned around the chief every time geometry constraints are violated by means of a procedure developed by the authors in previous works and based on relative orbit parameters. Once these parameters are defined, the optimal impulsive burns required for orbit transfer are computed using state-of-the-art approaches. Performance in terms of delta-v and maneuver frequency is analyzed for a two-spacecraft formation exploiting a simulation environment based on MATLAB and GMAT. In ideal conditions, it is shown that maintenance costs are limited, while close proximity requires fine sensitivity on the applied impulses. A first assessment of the impact of relative navigation and maneuvering execution errors indicates that they play an important role in defining the overall control effort

An Adaptive Approach for Impulsive Formation Maintenance Relevant to Distributed SAR Missions

This paper proposes an approach for impulsive formation maintenance tailored to distributed synthetic aperture radar, i.e., a spaceborne system composed by several antennas working together to provide enhanced remote sensing capabilities. The analyzed configuration is designed to guarantee the presence of a safety tube surrounding each satellite as the dynamics evolve. Formation requirements are related to general constraints on the acceptable along-track and radial/cross-track separations. The paper introduces an adaptive maintenance logic which fulfills these constraints. Specifically, the formation is adaptively redesigned around the chief every time geometry constraints are violated by means of a procedure developed by the authors in previous works and based on relative orbit parameters. Once these parameters are defined, the optimal impulsive burns required for orbit transfer are computed using state-of-the-art approaches. Performance in terms of delta-v and maneuver frequency is analyzed for a two-spacecraft formation exploiting a simulation environment based on MATLAB and GMAT. In ideal conditions, it is shown that maintenance costs are limited, while close proximity requires fine sensitivity on the applied impulses. A first assessment of the impact of relative navigation and maneuvering execution errors indicates that they play an important role in defining the overall control effort

Carotid intima-media thickness in psoriatic arthritis: Differences between tumor necrosis factor-α blockers and traditional disease-modifying antirheumatic drugs

Objective-: Subjects with psoriatic arthritis (PsA) have an abnormally high prevalence of vascular risk factors (VRFs) and are predisposed to vascular mortality. Tumor necrosis factor (TNF)-α, a major determinant of inflammation, is involved in atherosclerosis. Ultrasonographic carotid intima-media thickness (C-IMT) evaluation allows for subclinical atherosclerosis detection. Methods and Results-: Two hundred twenty-four PsA patients (120 on TNF-α blockers and 104 on traditional disease-modifying antirheumatic drugs [DMARDs]) underwent a C-IMT ultrasound assessment. As many as 305 matched subjects without any inflammatory/rheumatologic disease served as controls. The C-IMT of PsA subjects without VRFs was higher (P<0.0001) than that of controls, the C-IMT of PsA subjects with ≥1 VRF(s) was lower (P<0.0001) than that of controls, and the C-IMT was lower (P<0.0001) in those on TNF-α blockers than in those on DMARDs. Carotid plaques were detected in 15.8% of those on TNF-α blockers and in 40.4% of those on DMARDs (P<0.0001). Treatment duration inversely (β=-0.317, P<0.0001) predicted C-IMT in PsA subjects on TNF-α blockers but not in those on DMARDs (P=0.313). Conclusion-: Among PsA individuals, the C-IMT is higher in subjects on DMARDs than in those on TNF-α blockers. The reduction of inflammation may hamper the cascade that causes the raised vascular risk in PsA patients