Transient ischaemia leads to tolerance to subsequent protracted ischaemia. This ‘ischaemia pre‐conditioning’ results from the induction of numerous protective genes, involved in cell metabolism, ...proliferation and survival, in antioxidant capacity, angiogenesis, vascular tone and erythropoiesis. Hypoxia‐inducible factors (HIF) play a pivotal role in this transcriptional adaptive response. HIF prolyl hydroxylases (PHDs), serving as oxygen sensors, control HIFα degradation. HIF‐mediated ischaemic pre‐conditioning can be achieved with the administration of PHD inhibitors, with the attenuation of organ injury under various hypoxic and toxic insults. Clinical trials are currently under way, evaluating PHD inhibitors as inducers of erythropoietin. Once their safety is established, their potential use might be further tested in clinical trials in various forms of acute ischaemic and toxic organ damage.
Repeated transient limb ischaemia was also found to attenuate ischaemic injury in remote organs. This ‘remote ischaemic pre‐conditioning’ phenomenon (RIP) has been extensively studied recently in small clinical trials, preceding, or in parallel with an abrupt insult, such as myocardial infarction, cardiac surgery or radiocontrast administration. Initial results are promising, suggesting organ protection. Large‐scale multi‐centre studies are currently under way, evaluating the protective potential of RIP in cardiac surgery, in the management of myocardial infarction and in organ transplantation. The mechanisms of organ protection provided by RIP are poorly understood, but HIF seemingly play a role as well.
Thus, Inhibition of HIF degradation with PHD inhibitors, as well as RIP (in part through HIF), might develop into novel clinical interventions in organ protection in the near future.
Locating moving objects in a video sequence is the first step of many computer vision applications. Among the various motion-detection techniques, background subtraction methods are commonly ...implemented, especially for applications relying on a fixed camera. Since the basic inter-frame difference with global threshold is often a too simplistic method, more elaborate (and often probabilistic) methods have been proposed. These methods often aim at making the detection process more robust to noise, background motion and camera jitter. In this paper, we present commonly-implemented background subtraction algorithms and we evaluate them quantitatively. In order to gauge performances of each method, tests are performed on a wide range of real, synthetic and semi-synthetic video sequences representing different challenges.
Aim
Cyclosporine A (CsA) induces renal vasoconstriction and hypoxia and enhances the expression of endothelin‐1 (ET‐1) pro‐hormone (pre‐pro‐ET‐1), plausibly leading to a feed‐forward loop of renal ...vasoconstriction, hypoxia and enhanced synthesis of the potent vasoconstrictor ET‐1. Endothelin‐converting enzyme (ECE)‐1 cleaves big endothelin to generate endothelin (ET)‐1 and is upregulated by hypoxia via hypoxia‐inducible factor (HIF). We hypothesized that in addition to the direct induction of ET‐1 synthesis, CsA might also intensify renal ECE‐1 expression, thus contributing to enhanced ET‐1 synthesis following CsA.
Methods
CsA was administered to Sprague Dawley rats (120 mg/kg/SC) for 4 days, and renal HIF and ECE‐1 expression were assessed with Western blots and immunostaining. Human umbilical vein endothelial cells (HUVEC) and proximal tubular cell line (HK‐2) were subjected to CsA, and ECE‐1 induction was evaluated using real‐time mRNA PCR and Western blots.
Results
Cyclosporine A intensified renal parenchymal ECE‐1 expression in the rat kidney, particularly in distal nephron segments, along with renal hypoxia (detected by pimonidazole adducts) and HIF expression, in line with our recent observations showing episodic hypoxia in mice subjected to CsA. Furthermore, in cultured normoxic HUVEC and HK‐2 cells, CsA dose‐dependently induced both pre‐pro‐ET‐1 and ECE‐1 mRNA and protein expression, with enhanced ET‐1 generation.
Conclusion
CsA induces ECE‐1 via both hypoxic and non‐hypoxic pathways. ECE‐1 may contribute to increased renal ET‐1 generation following CsA, participating in a feed‐forward loop of renal parenchymal hypoxia and ET synthesis.
Vasoconstriction plays an important role in the development of acute kidney injury in rhabdomyolysis. We hypothesized that myoglobin enhances the angiotensin II (ANG II) response in afferent ...arterioles by increasing superoxide and reducing nitric oxide (NO) bioavailability. Afferent arterioles of C57Bl6 mice were isolated perfused, and vasoreactivity was analyzed using video microscopy. NO bioavailability, superoxide concentration in the vessel wall, and changes in cytosolic calcium were measured using fluorescence techniques. Myoglobin treatment (10
M) did not change the basal arteriolar diameter during a 20-min period compared with control conditions.
-nitro-l-arginine methyl ester (l-NAME, 10
M) and l-NAME + myoglobin reduced diameters to 94.7 and 97.9% of the initial diameter, respectively. Myoglobin or l-NAME enhanced the ANG II-induced constriction of arterioles compared with control (36.6 and 34.2%, respectively, vs. 65.9%). Norepinephrine responses were not influenced by myoglobin. Combined application of myoglobin and l-NAME further facilitated the ANG II response (7.0%). Myoglobin or l-NAME decreased the NO-related fluorescence in arterioles similarly. Myoglobin enhanced the superoxide-related fluorescence, and tempol prevented this enhancement. Tempol also partly prevented the myoglobin effect on the ANG II response. Myoglobin increased the fura 2 fluorescence ratio (cytosolic calcium) during ANG II application (10
to 10
M). The results suggest that the enhanced afferent arteriolar reactivity to ANG II is mainly due to a myoglobin-induced increase in superoxide and associated reduction in the NO bioavailability. Signaling pathways for the augmented ANG II response include enhanced cytosolic calcium transients. In conclusion, myoglobin may contribute to the afferent arteriolar vasoconstriction in this rhabdomyolysis model.
Early kidney development is associated with the coordinated branching of the renal tubular and vascular system and hypoxia has been proposed to be a major regulatory factor in this process. Under low ...oxygen levels, the hypoxia-inducible transcription factor (HIF) regulates the expression of genes involved in angiogenesis, erythropoiesis and glycolysis. To investigate the role of HIF in kidney development, we analyzed the temporal and spatial expression of the oxygen regulated HIF-1α and -2α subunits at different stages of rat and human kidney development. Using double-staining procedures, localization of the HIF target geneproducts vascular endothelial growth factor (VEGF) and endoglin was studied in relation to HIFα. In both species, we found marked nuclear expression of HIF-1α in medullary and cortical collecting ducts and in glomerular cells. In contrast, HIF-2α was expressed in interstitial and peritubular cells podocytes of the more mature glomeruli. After completion of glomerulogenesis and nephrogenesis, HIF-1α and -2α were no longer detectable. The HIF-target gene VEGF colocalized with HIF-1α protein in glomeruli and medullary collecting ducts. HIF-2α colocalized with the endothelium-associated angiogenic factor, endoglin. Both HIFα isoforms are activated in the developing kidney in a cell-specific and temporally controlled manner, indicating a regulatory role of oxygen tension in nephrogenesis. HIF-1α seems to be primarily involved in tubulogenesis and HIF-2α in renal vasculogenesis. Both isoforms are found in glomerulogenesis, potentially having synergistic effects.
Prognostic models for chronic postsurgical pain (CPSP) aim to predict the likelihood for development and severity of CPSP in individual patients undergoing surgical procedures. Such models might ...provide valuable information for healthcare providers, allowing them to identify patients at higher risk and implement targeted interventions to prevent or manage CPSP effectively. This review discusses the latest developments of prognostic models for CPSP, their challenges, limitations, and future directions.
Numerous studies have been conducted aiming to develop prognostic models for CPSP using various perioperative factors. These include patient-related factors like demographic variables, preexisting pain conditions, psychosocial aspects, procedure-specific characteristics, perioperative analgesic strategies, postoperative complications and, as indicated most recently, biomarkers. Model generation, however, varies and performance and accuracy differ between prognostic models for several reasons and validation of models is rather scarce.
Precise methodology of prognostic model development needs advancements in the field of CPSP. Development of more accurate, validated and refined models in large-scale cohorts is needed to improve reliability and applicability in clinical practice and validation studies are necessary to further refine and improve the performance of prognostic models for CPSP.
Antimicrobial peptides have established an important role in the defense against extracellular infections, but the expression of cationic peptides within macrophages as an antibacterial effector ...mechanism against intracellular pathogens has not been demonstrated. Macrophage expression of the murine cathelicidin-related antimicrobial peptide (CRAMP) was increased after infection by the intracellular pathogen Salmonella typhimurium, and this increase required reactive oxygen intermediates. By using CRAMP-deficient mice or synthetic CRAMP peptide, we found that CRAMP impaired Salmonella cell division in vivo and in vitro, resulting in long filamentous bacteria. This impaired bacterial cell division also depended on intracellular elastase-like serine protease activity, which can proteolytically activate cathelicidins. Macrophage serine protease activity induced filamentation and enhanced the activity of CRAMP in vitro. A peptide-sensitive Salmonella mutant showed enhanced survival within macrophages derived from CRAMP-deficient mice, indicating that Salmonella can sense and respond to cationic peptides in the intracellular environment. Although cationic peptides have been hypothesized to have activity against pathogens within macrophages, this work provides experimental evidence that the antimicrobial arsenal of macrophages includes cathelicidins. These results show that intracellular reactive oxygen intermediates and proteases regulate macrophage CRAMP expression and activity to impair the replication of an intracellular bacterial pathogen, and they highlight the cooperativity between macrophage antibacterial effectors.
Background. Preconditional activation of HIF with specific prolyl-hydroxylase inhibitors (PHD-I) attenuates proximal tubular injury, induced by warm ischaemia/ reperfusion (Bernhardt, JASN, 2006). ...Distal tubular damage occurs in humans with acute kidney injury (AKI), in experimental contrast media-induced nephropathy (CIN), as well as in cell-free isolated perfused kidneys (IPKs). Since in the IPK distal tubular damage inversely correlates with HIF activation (Rosenberger, KI, 2005), we explored the potential of PHD-I to improve morpho-functional outcome in this model. Methods. Male SD rats were randomly given the synthetic PHD-inhibitor FG-4497 (FibroGen®, 50 mg/kg IV) or its vehicle (CTR, n = 10 per group). Six hours later, the right kidney was perfused for 90 min with cell-free oxygenated medium and subsequently perfusion-fixed for morphologic assessment. The left kidney was used for HIF immunostaining. Results. As compared with CTR kidneys, at 6 h after FG-4497 HIF-α isoforms were markedly up-regulated in all renal zones: HIF-1α in tubules and in papillary interstitial cells (IC), HIF-2α in IC and vascular endothelial cells. FG-4497 treatment resulted in a higher perfusate flow rate (P < 0.04, ANOVA). Tubular injury to medullary thick ascending limbs (mTALs) was significantly attenuated in the treatment versus control group (38.9 ± 7.4% versus 62.7 ± 4.9% of mTALs in the mid-inner stripe (P < 0.02); 23.8 ± 6.8% versus 45.6 ± 7.4% in the innermost zone of the inner stripe (P < 0.05). Conclusions. These findings illustrate that PHD-I preconditioning attenuates hypoxic distal tubular injury produced in the IPK in the same fashion in which it protects proximal tubules. mTAL conservation may be related to the stabilization of cellular HIF, as well as to preserved endothelial function and microcirculation.
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