text:
Anesthetics attenuate ischemia–reperfusion induced renal injury: Effects and mechanisms
Volume 52, Issue 4, Pages 176-184
AnkurKhajuria 1 , CharisonTay 1 , JiaqiShi 1 , HailinZhao 1 , DaqingMa 1
1 Anaesthetics, Pain Medicine, and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Campus, 369 Fulham Road, London SW10 9NH, UK
.2. Epidemiology of AKI
.3. Causes of AKI and risk factors
.4. Mechanisms of IRI-induced AKI
.5. The renoprotective effects of anesthetics
.5.1. Sedative dexmedetomidine
.5.2. Volatile anesthetics
.5.3. Intravenous anesthetics
.5.4. Anesthetic gas xenon
.6. Clinical applications
An analysis of surgical outcomes in patients aged 80 years and older
Cesarean under general or epidural anesthesia: Does it differ in terms of regional cerebral oxygenation?
Attenuation of morphine-induced dependence and tolerance by ceftriaxone and amitriptyline in mice
Acute kidney injury (AKI) secondary to ischemia–reperfusion injury (IRI) is a major cause of patient morbidity and mortality in the perioperative period. It can lead to new onset of chronic kidney disease and accelerate its progression. Patients with risk factors undergoing cardiac, vascular, and liver transplantation surgeries, which may inevitably involve IRI, are more susceptible to AKI. Anesthetic agents have been postulated to possess renoprotective properties. Thus, exploring the utilization of selective perioperative anesthetic agents with renoprotective properties may be a promising avenue to reduce the risk of AKI. This review discusses the effects and mechanisms of dexmedetomidine, inhalational and intravenous anesthetics, and xenon-mediated renoprotection. Although the renoprotective effects of these agents obtained in the laboratory are promising, much work especially via clinical trials is required to determine the translational value from the bench to the bedside.
anesthetics; ischemia–reperfusion injury; mechanism; renal injury;
Acute kidney injury (AKI) secondary to ischemia–reperfusion injury (IRI) is a key contributor to morbidity and mortality in the perioperative period, presenting a major health care and economic burden.1, 2, 3, 4 It also leads to new onset of chronic kidney disease (CKD) while concomitantly expediting its progression. The term AKI that is used throughout this review has gained recognition to replace the previously used term, acute renal failure (ARF), in order to achieve two main objectives: first, to establish a conventional terminology that enables comparison of data more efficiently; and second, to illustrate the wide range of disease states the term incorporates.5, 6 Delayed graft function, which can be defined as a patient needing dialysis within 7 days of renal transplantation,7 is an unfortunate extension of AKI in the transplant process that is associated with a higher incidence of acute rejection and poorer long-term graft survival.8 In this review, we discuss the epidemiology, cause, and mechanisms of AKI together with dexmedetomidine, inhalational and intravenous anesthetics, and xenon gas-mediated renoprotection and their potential clinical applications.
The Risk, Injury, Failure, Loss, and End-stage renal disease classification (RIFLE) is now used as a valuable criteria for diagnosis and monitoring prognosis of AKI (Table 1).6 A meta-analysis identified that the overall mortality rate from AKI remained unchanged at 50% for the past 5 decades.9Approximately 1% of surgical patients develop AKI, however, perioperative AKI mortality can be as high as 83% in cardiac surgery.10 In a large retrospective study of 2672 patients undergoing coronary artery bypass grafting (CABG), perioperative AKI was found to be associated with a 14-fold increase in mortality.11 It is also linked to vascular intervention12 and surgery,13 as well as urology, kidney, and liver transplantation.14 A prospective multicenter cohort study of 29,269 intensive care unit (ICU) patients demonstrated an incidence of 5.7% and mortality of 60.3%.15 Its high incidence is comparable with acute lung injury and severe sepsis.16 In addition, AKI significantly prolonged the length of hospitalization by up to 50%.17 As a consequence of advancing techniques, the surgical population is steadily ageing with increasing comorbidities, causing AKI to become a worsening problem, which continues to be a substantial burden on the health care system.18 Moreover, there is evidence to suggest that AKI can not only predispose but compound the effects of an existing diagnosis of CKD to increase the risk of end-stage renal disease amongst the elderly.19
Table 1. The Risk, Injury, Failure, Loss, and End-stage renal disease (RIFLE) classification for acute renal injury—a hierarchical classification to categorize the risk, diagnosis of ARF, and ESKD.
Causes of AKI have traditionally been classified as prerenal (occurring in 30–60% of cases), intrinsic renal (20–40%), or postrenal (10%).5 Prerenal causes are associated with hypoperfusion and acute tubular necrosis (ATN), which is linked to trauma, hemorrhage, cardiogenic shock, sepsis, systemic inflammatory response syndrome (SIRS), and IRI in surgical patients. IRI is a major cause of perioperative AKI, involving the inevitable temporary cessation and restoration of blood supply during surgeries such as cardiopulmonary bypass, renal artery angioplasty, and liver and kidney transplantation.5 The short-term hypoxia is detrimental to the kidneys. Up to 50% of donor kidneys are involved in short-term hypoxia in renal transplantation, further diminishing the donor rate and leading to a 10% failure rate of primary grafts in those transplanted. The resurgence of blood flow may commence the recovery of the injured tissues from the ischemic phase yet also paradoxically induce further damage. Patients with high risk factors, such as advanced age, hypertension, diabetes, decreased cardiac function, and pre-existing renal disease20 undergoing cardiac,21 vascular, and liver transplantation surgeries, which inevitably involve IRI, are more susceptible to AKI and higher mortality.22
IRI is defined as "the cellular damage after reperfusion of previously viable ischemic tissues".23 Its pathogenesis is a multifactorial interplay between biochemical, cellular, vascular endothelial, and tissue-specific factors, with inflammation being a common feature.24 Renal hypoperfusion triggers vasoconstriction, alteration of the ultrafiltration coefficient, tubular obstruction, and vascular congestion.25 However, recent experimental work has challenged this established "decreased perfusion paradigm". It has been postulated that intrarenal circulation changes such as modification in efferent arteriolar function and intrarenal shunting may be more likely drivers of AKI than changes in global blood flow.26
Hypoxia as a result of ischemia and subsequent reperfusion is associated with increased reactive oxygen species (ROS) production and dysfunction of the antioxidant system, resulting in tubular cell injury and death.27 Inflammatory cytokines and chemokines are secreted, initiating the innate immune response. There is induction of toll-like receptors, activation of polymorphonuclear cells, with neutrophil infiltration following expression of adhesion molecules27 causing microvascular plugging and promoting local tissue destruction. Complement activation via the alternative pathway is also involved.28 Local inflammation causes ATN, which accounts for 75% of AKI. The necrotic debris acts as a danger signal and stimulates further inflammatory response in a vicious cycle. The molecular mechanisms of AKI are summarized in Fig. 1.
Fig. 1. Putative molecular mechanisms of ischemia–reperfusion injury (IRI). DAMP = damage-associated molecular pattern; IL-1β = interleukin-1β; NF-κB = nuclear factor-κB; ROS = reactive oxygen species; TNF-α = tumor necrosis factor-α.
There is a distinct lack of effective strategies to obviate the number of surgical cases of patients developing AKI. Therefore, formulating effective strategies to prevent and treat AKI, which especially occur during the perioperative period, are urgently needed. Utilization of selective perioperative anesthetic agents with renoprotective properties may be a promising avenue. The most recent publications in this regard are shown in Table 2 and the details of these publications are discussed below.
Table 2. Anesthetics offer renal protection under various experimental settings.
Gamma-aminobutyric acid (GABA)-based medication such as benzodiazepines (usually midazolam) and propofol are commonly used sedative agents in the ICU but have potentially fatal adverse effects including respiratory depression and other acute brain dysfunction disorders.29 As a result, other classes of drugs are often trialed as alternatives or adjuncts to the traditional GABA-based agents, one of which are the α2-adrenoceptor agonists. α2-Adrenoceptor agonists act on the locus coeruleus and spinal cord to exert sedative, analgesic, and anxiolytic effects,30 and one example of such an agent is dexmedetomidine. In addition to its indicated use in the ICU, dexmedetomidine has also been investigated for its potential renoprotective effects in the surgical setting.
AKI can occur peri- or postoperatively following hemodynamic changes leading to renal vasoconstriction, hypoperfusion,31 and reduced urine output. α2-Adrenoceptors are known to be present in the human kidney32 and animal models have shown that these adrenoceptors are important in mediating several renal functions including reducing renin release32 and increasing water and sodium excretion.33 During surgery, dexmedetomidine has been shown to decrease catecholamine plasma levels,33, 34 maintain hemodynamic stability,35, 36 and also increase urinary output in both humans37 and animals.38, 39 Canine models have shown that this increase in urinary output may be a result of aqueous diuresis secondary to central inhibition of vasopressin secretion.38 Dexmedetomidine may also have a role in tubular regeneration as one study found that dexmedetomidine stimulated the α2B-adrenoceptors in the proximal tubule cells of rats, which activated the extracellular signal-regulated kinase (ERK) pathway leading to enhanced mitogen-activated protein kinase (MAPK) activity, translocation of ERK2 to the nucleus, and increased proliferation of epithelial cells in the proximal tubules.40 Therefore, several studies have looked at whether dexmedetomidine may have a renoprotective effect in certain settings; the two most commonly used settings are IRI and cardiothoracic surgery.
IRI is injury to tissue due to its reperfusion after being ischemic for a period of time as the return of blood to the ischemic tissue carries with it immune cells that release inflammatory mediators in response to the tissue damage caused by the ischemia and production of oxygen free radicals. IRI is a common cause of perioperative AKI25 because transient deprivation of blood flow to the kidneys results in severe, continuous damage to the renal parenchyma when blood flow is restored. Dexmedetomidine has been shown to attenuate renal injury in murine models of IRI41, 42, 43 with normal glomeruli found in mice treated with dexmedetomidine whereas the untreated mice had tubular cell swelling, medullary congestion, and renal cell necrosis on histology.43 The mechanism by which dexmedetomidine exerts its renoprotective effects is unclear, but it is thought to activate the cell survival signal phosphoinositide-3-kinase (PI3)–AKT, which upregulates anti-apoptotic proteins such as Bcl-2 and Bcl-xl and inhibits the inflammatory-associated high-mobility group protein B1 (HMGB-1)/Toll-like receptor 4 (TLR-4)41 and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways44 via its actions on the α2-adrenoceptors, thus reducing renal cell death and preserving tubular structure. Si et al44 explored the link between dexmedetomidine and the JAK/STAT pathway. Evidence has shown that the control group exhibited significant increase in expression of phosphorylated JAK2 (p-JAK2) protein in comparison to the sham-operated group of Wistar rats, whereas the dexmedetomidine-treated group and a second group treated with AG490 (JAK2 inhibitor tyrphostin) both showed a comparatively significant reduced level of p-JAK2 and its downstream effectors p-STAT1 and STAT3. This suggested a similarity in their mechanisms and further establishes a relationship between dexmedetomidine and its inhibition on the JAK/STAT signaling pathway. Evidence from Yang et al45 further demonstrated that preconditioning with AG490 in rats resulted in a better histological profile with a lower tubular necrosis score and reduced cell apoptosis in epithelial cells compared with the vehicle-alone control group. Dexmedetomidine has also been shown to have a protective effect over lung injuries induced by renal IRI through both α2-adrenoceptor-dependent and -independent mechanisms.41
The renoprotective effects of dexmedetomidine have also been investigated in CABG because it may attenuate renal function by stimulating the sympathetic nervous system and influencing the body's hemodynamics and renal blood flow.46 The first human study in this area was a double-blinded, placebo-controlled randomized controlled trial (RCT) of 80 patients undergoing CABG who were given either a saline placebo or dexmedetomidine before induction of anesthesia and then perioperatively until the end of the operation.37 The authors found that dexmedetomidine reduced intraoperative sympathetic tone and attenuated hemodynamic instability with reduced incidence of tachycardia and decreased variation of systolic arterial pressure.37 Renal function, however, was not analyzed. Subsequent RCTs46, 47, 48 have shown no significant improvement or worsening renal function using creatinine clearance or serum creatinine (SCr) as a measure of outcome. However, these contrasting results were due to using lower than normal dosages,47 and either recruiting patients who had normal renal function and SCr and hence were at relatively lower risk of AKI,46 or recruiting patients with a greater incidence of preoperative renal failure into the dexmedetomidine group.49 Additionally, one of the RCTs did notice a mean 74% increase in urinary output in patients given dexmedetomidine.46 A third RCT50 investigating dexmedetomidine effects on perioperative renal function during a thoracotomy did find improved renal function in terms of creatinine clearance and SCr. However, the study was performed on a small cohort of patients. Hence further trials are warranted to clarify if dexmedetomidine improves renal function in patients undergoing cardiac surgery. Currently, one study in Korea is recruiting patients undergoing valvular heart surgery to investigate the incidence of AKI postoperatively after receiving perioperative dexmedetomidine or placebo (http://clinicaltrials.gov/ct2/show/NCT01886079).
Isoflurane is a volatile anesthetic commonly used in general anesthesia to maintain loss of consciousness, analgesia, and muscle relaxation. Its mechanism of action as an anesthetic agent is still incompletely understood but it is thought to bind to the GABA,51 glutamate,52 and glycine53 receptors among many others to exert its anesthetic effects.
Volatile anesthetics have also been known to confer some protection against cardiac IRI and this is demonstrated for some volatile anesthetics in renal IRI such as isoflurane.54 Renal IRI mice anesthetized with isoflurane have significantly lower plasma creatinine,55 reduced migration of neutrophils and macrophages into the kidneys,56 reduced expression of adhesion and proinflammatory molecules,56 and attenuated necrotic and apoptotic injury57as compared to renal IRI mice anesthetized with pentobarbital.
Isoflurane may exert its renoprotective effects by inducing, via preconditioning, an acute56, 58 and delayed59 protective effect 24–72 hours later, known as delayed protection. This protective effect includes attenuating the renal tubular apoptotic and renal dysfunction response to IRI, and is mediated by cellular signals, for example, by hypoxia-inducible factor-1α (HIF-1α). HIF-1α is a transcription factor that is expressed and activated in response to low oxygen concentrations to protect against oxygen deprivation and has been shown to confer a renoprotective effect against IRI.60 Other studies have also shown that isoflurane may protect against renal IRI via other pathways that include the release of transforming growth factor-β1 (TGF-β1), which generates adenosine, a potent cytoprotective molecule, via ecto-5′-nucleotidase (CD73),57 and sphingosine-1-phosphate (S1P) via sphingosine kinase (SK).55, 61 It is therefore likely that the renoprotective effects of isoflurane stem from some, if not all, of its downstream effectors.
It has been shown that sevoflurane may also orchestrate anti-inflammatory and anti-apoptotic effects via activation of ERK and AKT as well as a host of heat shock proteins in the HSP family.62 There is further evidence that the signaling pathway is initiated by the externalization of phosphatidylserine on the plasma membrane and the subsequent induction and release of TGF-β1.63In addition, isoflurane has been shown to be linked to the activation of the lysophospholipid S1P signaling pathway, catalyzed by the activation of the SK enzyme; S1P receptor antagonist and SK enzyme inhibitors reversed the effects of renoprotection mediated by isoflurane.55 Song et al64 found that isoflurane causes an increase in caveolae formation on the plasma membrane that contains a number of key components that include ERK and SK1, which is important in the S1P pathway, and receptors for TGF-β1 in human kidney proximal tubule (HK-2) cells.
Desflurane confers the same level of renoprotection in living kidney transplantation recipients as isoflurane and sevoflurane in a retrospective study looking at serum markers of worsening renal function; this analysis included SCr levels and estimated glomerular filtration rate (eGFR).65 The eGFR values taken in patients treated with desflurane were consistently better compared to the isoflurane or the sevoflurane group until 7 days postsurgery.54 However, in a murine model study with induced renal ischemia followed by 3-hour reperfusion with continuous inhalational anesthetic of choice—volatile (desflurane, halothane, isoflurane, or sevoflurane) versus intravenous (pentobarbital or ketamine)—the desflurane-treated group had lower plasma creatinine compared to the intravenous group, but was significantly higher compared to the other volatiles species. This finding is consistent with the histological features observed in the desflurane-treated group, where its renoprotective effects were less compared to the other volatile groups in terms of glomerular tubular swelling, dilatation, and necrosis. Overall, the data achieved from laboratory studies as mentioned are promising but clinical trials are required to elucidate if these findings can be translated to the bedside.
Propofol is the most widely used intravenous anesthetic agent for induction and maintenance of general anesthesia. It is thought to principally target the GABAA receptor to potentiate its inhibitory activity66, 67, 68, 69, 70 and only recently a plausible binding site has been suggested for its action on the receptor71 to induce and maintain anesthesia.
Propofol has also been investigated for its renoprotective effects in IRI-induced AKI after several studies showed propofol can ameliorate IRI in other organs including the brain,72, 73 heart,74, 75 lungs,76 lower limbs,48 and testicles.77 Wang et al78 found that giving propofol 30 minutes before induction of renal ischemia until 30 minutes after reperfusion reduced the increase in blood urea nitrogen and SCr levels in the IRI rats. There was also histological improvement in the cortical tubules of the treated group compared to the untreated group.
The exact molecular mechanism behind the protective effect of propofol towards renal IRI is unclear, but it is thought to involve the upregulation of heme oxygenase-1 (HO-1) expression.78, 79 HO is an enzyme that catalyzes the conversion of heme to biliverdin, carbon monoxide (CO), and free ferrous iron, which may have anti-inflammatory and antioxidant effects. Biliverdin and bilirubin, from the former's conversion by biliverdin reductase, have antioxidant activity and could attenuate the oxidative stress damage induced by IRI.80 CO is often used as a signaling molecule in the body and has been shown to have anti-inflammatory and antioxidant effects too. Its anti-inflammatory effects involve the downregulation of proinflammatory cytokines production such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and upregulation of anti-inflammatory cytokines via the mitogen-activated protein kinase kinase-3 (MAPKK-3)/p38 MAPK pathway.81, 82 Its antioxidant effects, by contrast, are via a pathway that involves ERK1/2, p38 MAPK, and AKT to remove free radicals.83 HO-1 is an inducible isoform of HO, and is strongly induced by various stimuli such as hypoxia, oxidative stress, heavy metals, cytokines, hormones, endotoxins, heat shock, and IRI.78 Hence, propofol may attenuate IRI by increasing the expression of HO-1 in response to the injurious stimuli.
Adenosine triphosphate-sensitive potassium (KATP) channels may also have a part in mediating the protective effect of propofol in renal IRI. Pretreatment with propofol significantly attenuates IRI-induced apoptosis of renal cells84and this has been observed in myocardial and endothelial cells also.85, 86However, the mechanism by which KATP channels contribute to this effect is still incompletely understood and warrants follow-up study. Propofol also contains a phenol hydroxyl group that has an intrinsic antioxidant effect,87either by reacting with lipid peroxyl radicals to form the stable propofol phenoxyl radical88 and/or by scavenging peroxynitrite, a highly reactive oxidant.89 Hence propofol could have a direct protective effect against oxidative stress-induced damage of renal tissue in IRI.
Propofol has also been investigated for its renoprotective effects in sepsis-mediated kidney injury. Sepsis is a systemic inflammatory response in the presence of an infection that leads to cytokine release, neutrophil recruitment, and free radical generation contributing to AKI. Lipopolysaccharide (LPS) is a common endotoxin found in Gram-negative bacteria that stimulates an inflammatory response in the kidney via the nuclear factor-κB (NF-κB) pathway and TNF-α release, an important mediator of inflammation.90 Hsing et al87 found that the inflammatory response in LPS-induced kidney injury is characterized by increased expression of proinflammatory mediators, adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), and pro-apoptotic molecules such as caspase-3 and Bcl-2-associated X protein (Bax). Hence inhibiting NF-κB activation and TNF-α release could have a protective effect in sepsis-mediated AKI.
In murine models of sepsis, preconditioning with propofol has been shown to reduce TNF-α and ICAM-1 expression, neutrophil infiltration of the renal cortex, and necrotic and apoptotic renal cell death with significantly reduced levels of caspase-3 and Bax but increased expression of Bcl-2, an anti-apoptotic protein.87, 91 Propofol also decreased free radical production in a dose-dependent manner and conferred a protective effect against oxidative stress-induced kidney injury due to its antioxidant effects.87, 89, 92 These effects of propofol are thought to be mediated in part by inhibiting the NF-κB pathway87, 93 and by increasing bone morphogenetic protein-7 (BMP-7) expression levels in the kidneys.87 BMP-7 is important for nephrogenesis during development and also helps maintain renal architecture and function.87 In immunoglobulin A (IgA)-induced nephropathy, BMP-7 has been shown to repress TNF-α-mediated inflammation and protect the kidney from injury by inhibiting NF-κB activity and translocation into the nucleus to prevent transcription of proinflammatory genes.94 Hence, propofol may increase BMP-7 levels to inhibit the NF-κB pathway repressing TNF-α-mediated inflammation.
Thiopental was used often for the induction of anesthesia. It is a barbiturate and hence binds to GABAA receptors to prolong its postsynaptic inhibitory effect in the central nervous system. Thiopental is another intravenous anesthetic whose potential renoprotective effects have been investigated albeit less extensively in renal IRI models. Wistar rats given thiopental at subanesthetic doses 15 minutes before the reperfusion phase had less renal damage compared to the control group in terms of significantly reduced levels of malondialdehyde (MDA), a marker of oxidative stress, and less severe histopathological damage.95 Additionally, this effect appeared to be enhanced when thiopental was given at clinically high doses.96 Thiopental has antioxidant and cytoprotective properties demonstrated by its ability to inhibit lipid peroxidation, and hypoxic-induced and glucose-deprivation cell death.97 Thiopental has also been shown to significantly suppress neutrophil functions such as chemotaxis, phagocytosis, and free radical production at clinically relevant concentrations.98 Hence thiopental may exert its renoprotective effects, at least in part, by reducing the free radical-induced damage of the kidney during IRI.
Xenon is a noble gas that has an inert chemical and toxicological profile. Studies have demonstrated that xenon provides organoprotective properties in acute injuries of the brain, heart, and kidneys.99, 100 Rats that were treated with gentamicin with 70% xenon administration showed better renal function with protected SCr and blood urea nitrogen in comparison to the gentamicin-only treatment group after days of intermittent administration. Morphologically, Jia et al101 demonstrated that less structural damage and signs of apoptosis were seen in the xenon-treated group against gentamicin-induced nephrotoxicity in male Wistar rats. The attenuation of gentamicin-induced nephrotoxicity by xenon has been suggested to be related to its antioxidative effects, because MDA was significantly lower in the xenon-treated mice compared with control.101 However, the lack of difference in the TNF-α concentration in the serum between the experimental groups suggests that xenon may not have a role to play in the reduction of gentamicin-induced inflammation. Measurements of HIF-2α and vascular endothelial growth factor (VEGF) showed significant increases 4 days post-last administration of gentamicin in the xenon-treated group compared to the controls, but this difference was not detected prior to this period. Although this study did not report any changes in HIF-1α expression, Ma et al102 demonstrated that 70% xenon preconditioning of adult rat kidney for 2 hours induced upregulation of HIF-1α at 2–24 hours postexposure, which caused a substantial increase in erythropoietin (EPO) and VEGF. This was demonstrated in HK-2 cells with similar results.
Xenon might also have a role in transplantation in ameliorating the results of kidney injury from warm and cold ischemia–reperfusion,101, 103 principally by improving tubular cell proliferation and dampening inflammatory-associated cell apoptosis.104 Bcl-2 is able to enhance the survival of HK-2 cells,103, 105 and thus limit the oxidative damage in mitochondria and the nuclei. Zhao et al103 showed that xenon can attenuate the effects of renal ischemia in renal grafts ex vivo by concomitant enhancement of Bcl-2 and HSP-70 in western blot analysis, and reduction in cytochrome c and apoptosis-inducing factor (AIF) by mitochondrial sequestration, therefore limiting the potential for damage in the tubular model. Zhao and colleagues103 also showed in a separate paper that 70% xenon dampens the immune response in HK-2 cells by inhibiting the translocation process of HMGB-1 by nuclei sequestration. This was further evidenced in the study of tubular renal cells in a Lewis model, where reduced translocation of HMGB-1 into the cytosol resulted in reduced downstream effectors of TLR-4 and NF-κB expressions in vivo.103 Additionally, xenon has a role in attenuating the effects of hypothermic storage conditions, which can induce IRIs in renal grafts.106 Overall, these changes confer renoprotective properties by reducing proinflammatory mediators and suggest that xenon could be useful in transplant settings for improved clinical outcome.
Broadly speaking, most studies investigating the role of anesthetic agents in renoprotection have been in vitro and in vivo studies (Table 2). However, human studies have been performed investigating the role of dexmedetomidine. Leino et al46 conducted a double-blind RCT involving 87 patients with normal renal function scheduled for CABG, randomized to either placebo or a dexmedetomidine infusion. The trial found that intravenous dexmedetomidine did not influence renal function but increased urinary output by 74%. Ji et al49 performed a retrospective analysis of cardiac surgery patients, some of whom (n = 568) had received dexmedetomidine postoperatively in the ICU. There was a greater incidence of postoperative renal failure in patients who received dexmedetomidine, however this was attributed to a greater incidence of pre-existing, preoperative renal failure in the dexmedetomidine group. Thus clinical results are equivocal and further clinical trials are required to elucidate the clinical implications of the use of such anesthetic agents in renoprotection.
Currently, AKI is associated with high mortality during the perioperative period. Selective use of certain anesthetics may confer significant benefit to patients, including better postischemic renal function following surgical procedures in which renal ischemia can be inevitable. However, our understanding of the role of anesthetics in renoprotection is still in its infancy and much work, especially within clinical trials, is required to elucidate the translational value from the bench to the bedside.
This work was supported by grants from the Medical Research Council, London, UK and the European Society of Anesthesiology, Brussels, Belgium.
E.A. Hoste, J.A. Kellum
Acute kidney injury: epidemiology and diagnostic criteria
Curr Opin Crit Care, 12 (2006), pp. 531-537
P.E. Stevens, N.A. Tamimi, M.K. Al-Hasani, A.I. Mikhail, E. Kearney, R. Lapworth, et al.
Non-specialist management of acute renal failure
QJM, 94 (2001), pp. 533-540
M. Thomas, A. Sitch, G. Dowswell
The initial development and assessment of an automatic alert warning of acute kidney injury
Nephrol Dial Transplant, 26 (2011), pp. 2161-2168
Acute kidney injury: prevention, detection and management of acute kidney injury up to the point of renal replacement therapy
NICE Guidelines (2013) CG169
Z. Ricci, C. Ronco
New insights in acute kidney failure in the critically ill
Swiss Med Wkly, 142 (2012), p. w13662
R. Bellomo, C. Ronco, J.A. Kellum, R.L. Mehta, P. Palevsky
Acute Dialysis Quality Initiative workgroup. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group
Crit Care, 8 (2004), pp. R204-R212
S.G. Yarlagadda, S.G. Coca, A.X. Garg, M. Doshi, E. Poggio, R.J. Marcus, et al.
Marked variation in the definition and diagnosis of delayed graft function: a systematic review
S.G. Yarlagadda, S.G. Coca, R.N. Formica Jr., E.D. Poggio, C.R. Parikh
Association between delayed graft function and allograft and patient survival: a systematic review and meta-analysis
Y.P. Ympa, Y. Sakr, K. Reinhart, J.L. Vincent
Has mortality from acute renal failure decreased? A systematic review of the literature
Am J Med, 118 (2005), pp. 827-832
B.G. Loef, A.H. Epema, T.D. Smilde, R.H. Henning, T. Ebels, G. Navis, et al.
Immediate postoperative renal function deterioration in cardiac surgical patients predicts in-hospital mortality and long-term survival
J Am Soc Nephrol, 16 (2005), pp. 195-200
P.J. Conlon, M. Stafford-Smith, W.D. White, M.F. Newman, S. King, M.P. Winn, et al.
Acute renal failure following cardiac surgery
G. Marenzi, A.L. Bartorelli, G. Lauri, E. Assanelli, M. Grazi, J. Campodonico, et al.
Continuous veno-venous hemofiltration for the treatment of contrast-induced acute renal failure after percutaneous coronary interventions
Catheter Cardiovasc Interv, 58 (2003), pp. 59-64
F. Ryckwaert, P. Alric, M.C. Picot, K. Djoufelkit, P. Colson
Incidence and circumstances of serum creatinine increase after abdominal aortic surgery
N. Perico, D. Cattaneo, M.H. Sayegh, G. Remuzzi
Delayed graft function in kidney transplantation
Lancet, 364 (2004), pp. 1814-1827
S. Uchino, J.A. Kellum, R. Bellomo, G.S. Doig, H. Morimatsu, S. Morgera, et al.
Acute renal failure in critically ill patients: a multinational, multicenter study
JAMA, 294 (2005), pp. 813-818
E.A. Hoste, M. Schurgers
Epidemiology of acute kidney injury: how big is the problem?
Crit Care Med, 36 (2008), pp. S146-S151
J. Golledge, P. Goldstraw
Renal impairment after thoracotomy: incidence, risk factors, and significance
Article CrossRef View Record in Scopus
D.M. Vandijck, S. Oeyen, J.M. Decruyenaere, L. Annemans, E.A. Hoste
Acute kidney injury, length of stay, and costs in patients hospitalized in the intensive care unit
Acta Clin Belg Suppl, 2 (2007), pp. 341-345
A. Ishani, J.L. Xue, J. Himmelfarb, P.W. Eggers, P.L. Kimmel, B.A. Molitoris, et al.
Acute kidney injury increases risk of ESRD among elderly
B.K. Novis, M.F. Roizen, S. Aronson, R.A. Thisted
Association of preoperative risk factors with postoperative acute renal failure
Anesth Analg, 78 (1994), pp. 143-149
S. Aronson, R. Blumenthal
Perioperative renal dysfunction and cardiovascular anesthesia: concerns and controversies
J Cardiothorac Vasc Anesth, 12 (1998), pp. 567-586
E. Borthwick, A. Ferguson
Perioperative acute kidney injury: risk factors, recognition, management, and outcomes
BMJ, 341 (2010) c3365
D.L. Carden, D.N. Granger
Pathophysiology of ischaemia-reperfusion injury
J Pathol, 190 (2000), pp. 255-266
Y. Huang, H. Rabb, K.L. Womer
Ischemia-reperfusion and immediate T cell responses
Cell Immunol, 248 (2007), pp. 4-11
R.W. Schrier, W. Wang, B. Poole, A. Mitra
Acute renal failure: definitions, diagnosis, pathogenesis, and therapy
J Clin Invest, 114 (2004), pp. 5-14
J.V. Bonventre, L. Yang
Cellular pathophysiology of ischemic acute kidney injury
J Clin Invest, 121 (2011), pp. 4210-4221
W. Jassem, N.D. Heaton
The role of mitochondria in ischemia/reperfusion injury in organ transplantation
Kidney Int, 66 (2004), pp. 514-517
J.M. Thurman
Triggers of inflammation after renal ischemia/reperfusion
Clin Immunol, 123 (2007), pp. 7-13
Article View Record in Scopus
S. Devabhakthuni, M. Pajoumand, C. Williams, J.A. Kufera, K. Watson, D.M. Stein
Evaluation of dexmedetomidine: safety and clinical outcomes in critically ill trauma patients
J Trauma, 71 (2011), pp. 1164-1171
R. Adams, G.T. Brown, M. Davidson, E. Fisher, J. Mathisen, G. Thomson, et al.
Efficacy of dexmedetomidine compared with midazolam for sedation in adult intensive care patients: a systematic review
Br J Anaesth, 111 (2013), pp. 703-710
M.A. Marangoni, A. Hausch, P.T. Vianna, J.R. Braz, R.M. Viero, Y.M. Castiglia
Renal function and histology after acute hemorrhage in rats under dexmedetomidine action
Acta Cir Bras, 22 (2007), pp. 291-298
M.C. Michel, L.C. Rump
alpha-Adrenergic regulation of human renal function
Fundam Clin Pharmacol, 10 (1996), pp. 493-503
M. Scheinin, A. Kallio, M. Koulu, J. Viikari, H. Scheinin
Sedative and cardiovascular effects of medetomidine, a novel selective alpha 2-adrenoceptor agonist, in healthy volunteers
Br J Clin Pharmacol, 24 (1987), pp. 443-451
A. Kallio, M. Scheinin, M. Koulu, R. Ponkilainen, H. Ruskoaho, O. Viinamaki, et al.
Effects of dexmedetomidine, a selective alpha 2-adrenoceptor agonist, on hemodynamic control mechanisms
Clin Pharmacol Ther, 46 (1989), pp. 33-42
M. Aho, M. Scheinin, A.M. Lehtinen, O. Erkola, J. Vuorinen, K. Korttila
Intramuscularly administered dexmedetomidine attenuates hemodynamic and stress hormone responses to gynecologic laparoscopy
P. Talke, R. Chen, B. Thomas, A. Aggarwall, A. Gottlieb, P. Thorborg, et al.
The hemodynamic and adrenergic effects of perioperative dexmedetomidine infusion after vascular surgery
J. Jalonen, M. Hynynen, A. Kuitunen, H. Heikkila, J. Perttila, M. Salmenpera, et al.
Dexmedetomidine as an anesthetic adjunct in coronary artery bypass grafting
N.R. Villela, P. do Nascimento Junior, L.R. de Carvalho, A. Teixeira
Effects of dexmedetomidine on renal system and on vasopressin plasma levels. Experimental study in dogs
Rev Bras Anestesiol, 55 (2005), pp. 429-440
T. Harada, T. Kigure, K. Yoshida, O. Nishizawa, H. Noto, S. Tsuchida, et al.
The effect of alpha-2 agonists and antagonists on the upper urinary tract of the rat
J Smooth Muscle Res, 28 (1992), pp. 139-151
D. Cussac, S. Schaak, C. Gales, C. Flordellis, C. Denis, H. Paris
alpha(2B)-Adrenergic receptors activate MAPK and modulate proliferation of primary cultured proximal tubule cells
Am J Physiol Renal Physiol, 282 (2002), pp. F943-F952
J. Gu, J. Chen, P. Xia, G. Tao, H. Zhao, D. Ma
Dexmedetomidine attenuates remote lung injury induced by renal ischemia-reperfusion in mice
Acta Anaesthesiol Scand, 55 (2011), pp. 1272-1278
S. Sugita, T. Okabe, A. Sakamoto
Continuous infusion of dexmedetomidine improves renal ischemia-reperfusion injury in rat kidney
J Nippon Med Sch, 80 (2013), pp. 131-139
H. Kocoglu, H. Ozturk, H. Ozturk, F. Yilmaz, N. Gulcu
Effect of dexmedetomidine on ischemia-reperfusion injury in rat kidney: a histopathologic study
Ren Fail, 31 (2009), pp. 70-74
Y. Si, H. Bao, L. Han, H. Shi, Y. Zhang, L. Xu, et al.
Dexmedetomidine protects against renal ischemia and reperfusion injury by inhibiting the JAK/STAT signaling activation
J Transl Med, 11 (2013), p. 141
N. Yang, M. Luo, R. Li, Y. Huang, R. Zhang, Q. Wu, et al.
Blockage of JAK/STAT signalling attenuates renal ischaemia-reperfusion injury in rat
Nephrol Dial Transplant, 23 (2008), pp. 91-100
K. Leino, M. Hynynen, J. Jalonen, M. Salmenpera, H. Scheinin, R. Aantaa, et al.
Renal effects of dexmedetomidine during coronary artery bypass surgery: a randomized placebo-controlled study
BMC Anesthesiol, 11 (2011), 10.1186/1471-2253-11-9
D. Göksedef, O.O. Balkanay, S.N. Ömeroğlu, Z. Talas, B. Arapi, Y. Junusbekov, et al.
The effects of dexmedetomidine infusion on renal functions after coronary artery bypass graft surgery-a randomized, double-blind, placebo-controlled study
Türk Göğüs Kalp Damar Cerrahisi Dergisi, 21 (2013), pp. 594-602
O. Aldemir, H. Celebi, C. Cevik, E. Duzgun
The effects of propofol or halothane on free radical production after tourniquet induced ischaemia-reperfusion injury during knee arthroplasty
F. Ji, Z. Li, H. Nguyen, N. Young, P. Shi, N. Fleming, et al.
Perioperative dexmedetomidine improves outcomes of cardiac surgery
Circulation, 127 (2013), pp. 1576-1584
R.J. Frumento, H.G. Logginidou, S. Wahlander, G. Wagener, H.R. Playford, R.N. Sladen
Dexmedetomidine infusion is associated with enhanced renal function after thoracic surgery
J Clin Anesth, 18 (2006), pp. 422-426
K. Seo, H. Seino, H. Yoshikawa, A.B. Petrenko, H. Baba, N. Fujiwara, et al.
Genetic reduction of GABA(A) receptor gamma2 subunit expression potentiates the immobilizing action of isoflurane
Neurosci Lett, 472 (2010), pp. 1-4
L. Guo, Y. Wang
Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2
Neuroscience, 145 (2007), pp. 100-109
C. Grasshoff, B. Drexler, U. Rudolph, B. Antkowiak
Anaesthetic drugs: linking molecular actions to clinical effects
Curr Pharm Des, 12 (2006), pp. 3665-3679
H.T. Lee, A. Ota-Setlik, Y. Fu, S.H. Nasr, C.W. Emala
Differential protective effects of volatile anesthetics against renal ischemia-reperfusion injury in vivo
Anesthesiology, 101 (2004), pp. 1313-1324
M. Kim, M. Kim, N. Kim, V.D. D'Agati, C.W.S. Emala, H.T. Lee
Isoflurane mediates protection from renal ischemia-reperfusion injury via sphingosine kinase and sphingosine-1-phosphate-dependent pathways
Am J Physiol Renal Physiol, 293 (2007), pp. F1827-F1835
H.T. Lee, M. Kim, M. Kim, N. Kim, I.V.F.T. Billings, V.D. D'Agati, et al.
Isoflurane protects against renal ischemia and reperfusion injury and modulates leukocyte infiltration in mice
M. Kim, J.E. Brady, G. Li
Anesthetic technique and acute kidney injury in endovascular abdominal aortic aneurysm repair
H. Hashiguchi, H. Morooka, H. Miyoshi, M. Matsumoto, T. Koji, K. Sumikawa
Isoflurane protects renal function against ischemia and reperfusion through inhibition of protein kinases, JNK and ERK
Anesth Analg, 101 (2005), pp. 1584-1589
L. Zhang, H. Huang, J. Cheng, J. Liu, H. Zhao, M.P. Vizcaychipi, et al.
Pre-treatment with isoflurane ameliorates renal ischemic-reperfusion injury in mice
Life Sci, 88 (2011), pp. 1102-1107
W.M. Bernhardt, V. Campean, S. Kany, J.S. Jurgensen, A. Weidemann, C. Warnecke, et al.
Preconditional activation of hypoxia-inducible factors ameliorates ischemic acute renal failure
J Am Soc Nephrol, 17 (2006), pp. 1970-1978
M. Kim, M. Kim, S.W. Park, S.M. Pitson, H.T. Lee
Isoflurane protects human kidney proximal tubule cells against necrosis via sphingosine kinase and sphingosine-1-phosphate generation
Am J Nephrol, 31 (2010), pp. 353-362
H.T. Lee, M. Kim, M. Jan, C.W. Emala
Anti-inflammatory and antinecrotic effects of the volatile anesthetic sevoflurane in kidney proximal tubule cells
Am J Physiol Renal Physiol, 291 (2006), pp. F67-78
H.T. Lee, M. Kim, J.H. Song, S.W. Chen, G. Gubitosa, C.W. Emala
Sevoflurane-mediated TGF-beta1 signaling in renal proximal tubule cells
J.H. Song, M. Kim, S.W. Park, S.W. Chen, S.M. Pitson, H.T. Lee
Isoflurane via TGF-beta1 release increases caveolae formation and organizes sphingosine kinase signaling in renal proximal tubules
J.H. Lee, D.J. Joo, J.M. Kim, J.H. Park, Y.S. Kim, B.N. Koo
Preconditioning effects of the anesthetic administered to the donor on grafted kidney function in living donor kidney transplantation recipients
Minerva Anestesiol, 79 (2013), pp. 504-514
T.G. Hales, J.J. Lambert
The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones
Br J Pharmacol, 104 (1991), pp. 619-628
R. Jurd, M. Arras, S. Lambert, B. Drexler, R. Siegwart, F. Crestani, et al.
General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit
FASEB J, 17 (2003), pp. 250-252
G. Trapani, A. Latrofa, M. Franco, C. Altomare, E. Sanna, M. Usala, et al.
Propofol analogues. Synthesis, relationships between structure and affinity at GABAA receptor in rat brain, and differential electrophysiological profile at recombinant human GABAA receptors
J Med Chem, 41 (1998), pp. 1846-1854
M.D. Krasowski, X. Hong, A.J. Hopfinger, N.L. Harrison
4D-QSAR analysis of a set of propofol analogues: mapping binding sites for an anesthetic phenol on the GABA(A) receptor
M.D. Krasowski, A. Jenkins, P. Flood, A.Y. Kung, A.J. Hopfinger, N.L. Harrison
General anesthetic potencies of a series of propofol analogs correlate with potency for potentiation of gamma-aminobutyric acid (GABA) current at the GABA(A) receptor but not with lipid solubility
J Pharmacol Exp Ther, 297 (2001), pp. 338-351
G.M.S. Yip, Z.W. Chen, C.J. Edge, E.H. Smith, R. Dickinson, E. Hohenester, et al.
A propofol binding site on mammalian GABAA receptors identified by photolabeling
Nat Chem Biol, 9 (2013), pp. 715-720
J.P. De La Cruz, M.A. Villalobos, G. Sedeno, F. Sanchez De La Cuesta
Effect of propofol on oxidative stress in an in vitro model of anoxia-reoxygenation in the rat brain
Brain Res, 800 (1998), pp. 136-144
R. Ergun, G. Akdemir, S. Sen, A. Tasci, F. Ergungor
Neuroprotective effects of propofol following global cerebral ischemia in rats
Neurosurg Rev, 25 (2002), pp. 95-98
N. Kokita, A. Hara, Y. Abiko, J. Arakawa, H. Hashizume, A. Namiki
Propofol improves functional and metabolic recovery in ischemic reperfused isolated rat hearts
K.H. Lim, A.P. Halestrap, G.D. Angelini, M.S. Suleiman
Propofol is cardioprotective in a clinically relevant model of normothermic blood cardioplegic arrest and cardiopulmonary bypass
Exp Biol Med, 230 (2005), pp. 413-420
I.V. Balyasnikova, D.J. Visintine, H.B. Gunnerson, C. Paisansathan, V.L. Baughman, R.D. Minshall, et al.
Propofol attenuates lung endothelial injury induced by ischemia-reperfusion and oxidative stress
Anesth Analg, 100 (2005), pp. 929-936
A. Unsal, E. Devrim, C. Guven, M. Eroglu, I. Durak, A. Bozoklu, et al.
Propofol attenuates reperfusion injury after testicular torsion and detorsion
World J Urol, 22 (2004), pp. 461-465
H.H. Wang, H.Y. Zhou, C.C. Chen, X.L. Zhang, G. Cheng
Propofol attenuation of renal ischemia/reperfusion injury involves heme oxygenase-1
Acta Pharmacol Sin, 28 (2007), pp. 1175-1180
S.G. Tullius, M. Nieminen-Kelha, R. Buelow, A. Reutzel-Selke, P.N. Martins, J. Pratschke, et al.
Inhibition of ischemia/reperfusion injury and chronic graft deterioration by a single-donor treatment with cobalt-protoporphyrin for the induction of heme oxygenase-1
Transplantation, 74 (2002), pp. 591-598
R. Stocker, Y. Yamamoto, A.F. McDonagh, A.N. Glazer, B.N. Ames
Bilirubin is an antioxidant of possible physiological importance
Science, 235 (1987), pp. 1043-1046
L.E. Otterbein, F.H. Bach, J. Alam, M. Soares, H. Tao Lu, M. Wysk, et al.
Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway
Nat Med, 6 (2000), pp. 422-428
N.G. Klimova, N. Hanna, M.R. Peltier
Does carbon monoxide inhibit proinflammatory cytokine production by fetal membranes?
J Perinat Med, 41 (2013), pp. 683-690
S. Basuroy, D. Tcheranova, S. Bhattacharya, C.W. Leffler, H. Parfenova
Nox4 NADPH oxidase-derived reactive oxygen species, via endogenous carbon monoxide, promote survival of brain endothelial cells during TNF-alpha-induced apoptosis
Am J Physiol Cell Physiol, 300 (2011), pp. C256-C265
A.R. Assad, J.M. Delou, L.M. Fonseca, N.R. Villela, J.H. Nascimento, N. Vercosa, et al
The role of KATP channels on propofol preconditioning in a cellular model of renal ischemia-reperfusion
M.W. Broadhead, R.K. Kharbanda, M.J. Peters, R.J. MacAllister
KATP channel activation induces ischemic preconditioning of the endothelium in humans in vivo
L. Testai, S. Rapposelli, V. Calderone
Cardiac ATP-sensitive potassium channels: a potential target for an anti-ischaemic pharmacological strategy
Cardiovasc Hematol Agents Med Chem, 5 (2007), pp. 79-90
C.H. Hsing, W. Chou, J.J. Wang, H.W. Chen, C.H. Yeh
Propofol increases bone morphogenetic protein-7 and decreases oxidative stress in sepsis-induced acute kidney injury
P.G. Murphy, J.R. Bennett, D.S. Myers, M.J. Davies, J.G. Jones
The effect of propofol anaesthesia on free radical-induced lipid peroxidation in rat liver microsomes
Eur J Anaesthesiol, 10 (1993), pp. 261-266
M. Mathy-Hartert, A. Mouithys-Mickalad, S. Kohnen, G. Deby-Dupont, M. Lamy, P. Hans
Effects of propofol on endothelial cells subjected to a peroxynitrite donor (SIN-1)
Anaesthesia, 55 (2000), pp. 1066-1071
E. Andreakos, S.M. Sacre, C. Smith, A. Lundberg, S. Kiriakidis, T. Stonehouse, et al.
Distinct pathways of LPS-induced NF-kappa B activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of MyD88 and Mal/TIRAP
Blood, 103 (2004), pp. 2229-2237
W.Y. Cui, A.Y. Tian, T. Bai
Protective effects of propofol on endotoxemia-induced acute kidney injury in rats
Clin Exp Pharmacol Physiol, 38 (2011), pp. 747-754
Y.M. Lee, J.W. Shin, E.H. Lee, Y. Moon, Y.J. Seo, J.Y. Kim, et al.
Protective effects of propofol against hydrogen peroxide-induced oxidative stress in human kidney proximal tubular cells
Korean J Anesthesiol, 63 (2012), pp. 441-446
P. Sanchez-Conde, J.M. Rodriguez-Lopez, J.L. Nicolas, F.S. Lozano, F.J. Garcia-Criado, C. Cascajo, et al.
The comparative abilities of propofol and sevoflurane to modulate inflammation and oxidative stress in the kidney after aortic cross-clamping
W.L. Chan, J.C. Leung, L.Y. Chan, K.Y. Tam, S.C. Tang, K.N. Lai
BMP-7 protects mesangial cells from injury by polymeric IgA
Kidney Int, 74 (2008), pp. 1026-1039
H. Yuzer, M.F. Yuzbasioglu, H. Ciralik, E.B. Kurutas, O.V. Ozkan, E. Bulbuloglu, et al.
Effects of intravenous anesthetics on renal ischemia/reperfusion injury
Ren Fail, 31 (2009), pp. 290-296
Z. Dogan, M.F. Yuzbasioglu, E.B. Kurutas, H. Yildiz, I. Coskuner, N. Senoglu, et al.
Thiopental improves renal ischemia-reperfusion injury
R. Almaas, O.D. Saugstad, D. Pleasure, T. Rootwelt
Effect of barbiturates on hydroxyl radicals, lipid peroxidation, and hypoxic cell death in human NT2-N neurons
K. Nishina, H. Akamatsu, K. Mikawa, M. Shiga, N. Maekawa, H. Obara, et al.
The inhibitory effects of thiopental, midazolam, and ketamine on human neutrophil functions
T. Yang, L. Zhuang, A.M. Rei Fidalgo, E. Petrides, N. Terrando, X. Wu, et al.
Xenon and sevoflurane provide analgesia during labor and fetal brain protection in a perinatal rat model of hypoxia-ischemia
PLoS One, 7 (2012), p. e37020
M. Fries, K.W. Nolte, M. Coburn, S. Rex, A. Timper, K. Kottmann, et al.
Xenon reduces neurohistopathological damage and improves the early neurological deficit after cardiac arrest in pigs
Crit Care Med, 36 (2008), pp. 2420-2426
P. Jia, J. Teng, J. Zou, Y. Fang, S. Jiang, X. Yu, et al.
Intermittent exposure to xenon protects against gentamicin-induced nephrotoxicity
D. Ma, T. Lim, J. Xu, H. Tang, Y. Wan, H. Zhao, et al.
Xenon preconditioning protects against renal ischemic-reperfusion injury via HIF-1alpha activation
H. Zhao, H.R. Watts, M. Chong, H. Huang, C. Tralau-Stewart, P.H. Maxwell, et al.
Xenon treatment protects against cold ischemia associated delayed graft function and prolongs graft survival in rats
Am J Transplant, 13 (2013), pp. 2006-2018
H. Zhao, X. Luo, Z. Zhou, J. Liu, C. Tralau-Stewart, A.J. George, et al.
Early treatment with xenon protects against the cold ischemia associated with chronic allograft nephropathy in rats
H. Zhao, J. Ning, S. Savage, H. Kang, K. Lu, X. Zheng, et al.
A novel strategy for preserving renal grafts in an ex vivo setting: potential for enhancing the marginal donor pool
FASEB J, 27 (2013), pp. 4822-4833
H. Zhao, A. Yoshida, W. Xiao, R. Ologunde, K.P. O'Dea, M. Takata, et al.
Xenon treatment attenuates early renal allograft injury associated with prolonged hypothermic storage in rats


text:
Never After
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RELEASE DATE: NOVEMBER 2009
PUBLISHER: Jove
Here, for the first time ever, are four stories based on the classic idea of the "faerie tale wedding"—except this time, the damsels aren't the ones in distress.
New York Times bestselling author Marjorie M. Liu tells the tale of a young princess who escapes betrothal to a warlord by entering a magical forest. But when an evil queen sends her on a quest to "The Tangleroot Palace" she faces dangers more perilous than marriage.
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The bonds of love…The bonds of matrimony…The bonds between husband and wife…
Some bonds are made to be broken.
New York Times bestselling author Laurell K. Hamilton spins a story of a princess who decides to take her own destiny in hand and rescue a pampered Prince Charming from an evil sorceress in "Can He Bake a Cherry Pie?"
A selkie on the run from a century-old broken marriage arrangement has finally found true love—only to have the darkness from her past return to threaten both her and her dearly beloved in USA Today bestselling author Yasmine Galenorn's "The Shadow of Mist."
When a princess refuses her boring betrothed, the king holds a competition to see who will win his daughter's hand. But in matters of the heart, is a winner truly worthy—or can a loser offer even more in national bestselling author Sharon Shinn's "The Wrong Bridegroom."
Weeks later, when she had a chance to put up her feet and savor a good hot cup of tea, Sally remembered something the gardener said, right before the old king told her that she had been sold in marriage.
"Only the right kind of fool is ever going to want you."
Sally, who was elbow deep in horse manure, blew a strand of red hair out of her eyes. "And?"
"Well," began the elderly woman, frowning—and then seemed to think better of what she was going to say, and crouched down beside her in the grass. "Here. Better let me."
They were both wearing leather gloves that were stiff as rawhide, sewn in tight patches to reach up past their elbows. Simple to clean if you let them sit in the sun until manure turned to dry flakes, easy to beat off with a stick. Sally, who did not particularly enjoy rooting through muck, was nonetheless pleased that the tannery had provided her with yet a new tool for her work in the garden.
"You know," Sally said, "when I told the stableboy to take care of my new roses, this is not what I meant."
The gardener made a noncommittal sound. "There were ravens in my dreams last night."
Sally finally felt something hard and stubbly beneath her fingers, and began clawing manure carefully away. "I thought we were talking about how only a fool would ever want me."
"All men are fools," replied the old woman absently, and then her frown deepened. "They were guarding a queen who wore a crown of horns."
It took Sally a moment to realize that she was speaking of the ravens in her dream again. "How odd."
"Not so odd if you know the right stories." The gardener shivered, and glanced over her shoulder—but not before her gaze lingered on Sally's hair. "Sabius is coming. Your father must want you."
Sally craned around, but the sun was in her eyes. All she could see was the blurry outline of a bowlegged man, stomping across the grass with his meaty fists swinging. She glanced down at herself, and then with a rueful little smile continued clearing debris away from her roses.
"Princess," said Sabius, well before his shadow fell over her. "Your father requests your . . . Oh, dear God."
The gardener bit her bottom lip and kept her head down, long silver braids swinging from beneath her straw hat. Sally, gazing with regret at the one little leaf she'd managed to expose, leaned backward and tugged until her arms slid free of the rawhide gloves—left sticking from the manure like two hollow branches. Her skin was pink and sweaty, her work apron brown with stains.
"Oh, dear God," said her father's manservant again; and turned his head, covering his mouth with a hairy, bare-knuckled hand better suited to brawling than to the delicately scripted letters he often sat composing for the king. He made a gagging sound, and squeezed shut his eyes.
"Er," said Sally, quite certain she didn't smell that bad. "What does my father want?"
Sabius, still indisposed, pointed toward the south tower. Sally considered arguing, but it was hardly worth the effort.
She shrugged off her apron and dropped it on the ground. Smoothing out her skirts—also rather stained, and patched with a quilt work of silk scrap from the seamstress's bin—she raised her brow at the gardener, who shook her head and returned to digging free the roses.
The king's study was on the southern side of the castle, directly below his bedchamber, which was accessible only through a hidden wall behind his desk that concealed a narrow stone staircase. Not that it was a secret. Everyone knew of its existence, what with the maids scurrying up and down in the mornings and evenings: cleaning, folding, dressing, doing all manner of maid, and maidenly, things that Sally did not want to know about.
Her father was just coming down the stairs when she entered his study; even more slowly than she had intended, having been stopped outside the kitchen by two of the cook's young apprentices from the village; who, in different ways, could not help but try to clean her up. First with scalding hot water and crushed lavender scrubbed into her face, loose hair tugged into a respectable braid; while the other girl fetched a fresh apron from the kitchen, which was not fine, and certainly not royal, but was clean and starched, and certainly in line with Sally's usual apparel. No use wasting fine gowns on long walks, or earth work, or even just reading in the library.
Her one concession to vanity was the amethyst pendant she wore against her skin; a teardrop long as her thumb, and held in a golden claw upon which half of a small wooden heart hung, broken jaggedly down the middle. Her mother's jewelry, and precious only for that reason.
"Salinda," said her father, and stopped, sniffing the air. "You smell as though you've been sleeping beneath a horse's ass."
"Do I?" she replied airily. "I hadn't noticed."
The old king frowned, looking over her clothing with a great deal more scrutiny than was usual. He was a barrel-chested man, tall and lean in most places, except for his gut and the wattle beneath his chin, which he tried vainly to hide with a coarse beard that was fading quickly from black to silver. He moved with a limp, due to an arrow shot recently into his hip.
Sally had been frightened for him—for as long as it had taken the old king to wake from the draught the doctor had poured down his throat in order to remove the bolt. His temper had been foul ever since. Everyone was avoiding him.
"Don't you have anything nicer to wear?" he asked, a peculiar tenseness in the way he studied her that made Sally instantly uneasy. "I pay for seamstresses."
"And I have fine clothing," she replied cautiously, as her father had never commented on her appearance, not once in seventeen years. "These are for everyday."
The old king made a small, dissatisfied sound, and limped past her to his desk. "I suppose you heard about the skirmish at old Bog Hill? Men died. More good men every day. Little weasel bastard Fartin throwing gold at mercenaries to test our borders. But"—and he smiled grimly—"I have a solution."
"Really," Sally said, suffering the most curious urge to run.
"Your darling mother, before we married, had a very dear friend who was given to one of those southern tribal types as part of a lucrative alliance. She bore a son. Who just so happens to be a very powerful man in need of a wife."
"Oh," Sally said.
Her father gave her a stern look. "And I suppose he's found one."
"Oh," Sally said again. "Oh, no."
"Fine man," replied the old king, but with a glittering unease in his eyes. "That Warlord fellow. You know.Him."
Sally stared, quite certain that bumblebees had just committed suicide in her ears. "Him. The Warlord. Who commands all the land south of the mountains to the sea; who leads a barbarian horde of nomadic horsemen so fierce, so vicious, so perverse in their torments, that grown men piddle themselves at the thought of even breathing the same air? That Warlord?"
"He does sound rather intimidating," said her father.
"Indeed," Sally replied sharply. "Have you lost your mind?"
"Amazingly, no." The old king rubbed his hip, and winced. "I haven't felt this proud of myself in years."
Sally closed her eyes, grabbing fistfuls of her skirt and squeezing. "I think I'm losing my mind." She had heard about the man for as long as she could remember. Warlord of this and that: colorfully descriptive names that were usually associated with pain, death, and destruction. Sally had vague memories of her mother speaking of him, as well, but only in association with his mother. He would have been a small child at the time, she thought. Nice and innocent; probably skinning dogs and plucking the wings off butterflies while suckling milk from his mother's teat.
"What in the world," she said slowly, fighting to control her temper, and rising horror, "could a man like that possibly want from a woman like me? He could have anyone. He probably has had everyone, given his reputation." Sally leaned forward, poking her father in the chest. "I will not do it. Absolutely not. You are sending me to a short, hard, miserable life. I'm ashamed of you."
Her father folded his arms over his chest. "Your mother's best friend was sent to that short, hard, miserable life—and she thrived. Your dear, late, lovely mother would not have lied about that." He turned and fumbled through the papers on his desk. "Now, here. The Warlord sent a likeness of himself."
Sally frowned, but leaned in for a good long stare. "He looks like a dirty fingerprint."
"Of course he doesn't," replied her father, squinting at the portrait. "You can see his eyes, right there."
"I thought those were his nostrils."
"Well, you're not going to be picky, are you? At least he has a face."
"Yes," Sally replied dryly. "What a miracle."
The king scowled. "Spoiled. I let you run wild, allow you teachers, books, a lifestyle unsuitable for any princess, and this is how you repay me. With sarcasm."
"You taught me how to think for myself. Which never seemed to bother you until now."
He slammed his fists onto the desk. "We are being overrun!"
His roar made her eardrums thrum. Sally shut her mouth, and fell backward into the soft cushions of a velvet armchair. Her knees were too weak to keep her upright. Terrible loneliness filled her heart, and sorrow—which she bottled up tight, refusing to let her father see.
The old king, as she stared at him, slumped with his arms braced against his desk. Staring at maps, and embroidered family crests that had been torn off the clothing of the fallen soldiers; and that now were scattered before him, some crusty with dried blood.
"We are being overrun," he said again, more softly. "I know how it starts. First with border incursions, and petty theft of livestock. Then villages ransacked, roads blocked. Blamed on vandals and simple thieves. Until one day you hear the thunder of footfall beyond the walls of your keep, and all that you were born to matters not at all."
He fixed her with a steely look. "I will not have that happen. Not for me, not for you. Not for any of the people who depend on us."
Sally swallowed hard. Perhaps she had been spoiled. Duty could not be denied. But when she looked at the small portrait of the man her father wanted her to marry, terrible, unbending disgust filled her—disgust and terror, and a gut-wrenching grief that made her want to howl with misery.
Married to that. Sent away from all she knew. Forced to give up her freedom. No matter how fondly her mother had spoken of her friend, that woman's son had a reputation that no sweet talk could alter. He was a monster.
The old king saw her looking at the Warlord's likeness, and held it out to her with grim determination. She did not take it, but continued to stare, feeling as though she were going to jump out of her skin.
"I can't tell anything from that," she said faintly. "His artist did a terrible job."
"Probably because he never sits still," replied her father sarcastically. "Or so I was told. I assume it's because he prefers to be out killing things."
Sally grimaced. "You're not seriously considering this?"
"Darling, sweet child; you golden lamb of my heart; my little chocolate knucklehead: I did consider, I have considered, and the deed is done. His envoy should be arriving within the week to inspect you for marriage, and sign the contracts."
"Oh, dear." Sally stared at her father, feeling as though she hardly knew him—quite certain that she did not.
And, since he was suddenly a stranger to her, she had no qualms in grabbing a nearby candle, and jamming it flame first into the tiny portrait he held in his hand. Hot wax sprayed. She nearly set his sleeve on fire. He howled in shock, dancing backward, and slammed his injured hip into the desk. He yelled even louder.
"And that," Sally said, shaken, "is how I feel about the matter."
CLOSE EXCERPT

redpajama_set_name: RedPajamaCommonCrawl


text:
package edu.cs4730.widgetdemo2;

import java.util.Random;

import android.app.PendingIntent;
import android.appwidget.AppWidgetManager;
import android.appwidget.AppWidgetProvider;
import android.content.Context;
import android.content.Intent;
import android.content.SharedPreferences;
import android.widget.RemoteViews;

public class Widgetd2Provider extends AppWidgetProvider {

    int randnum = 100;  //default value
    private static final String PREF_PREFIX_KEY = "appwidget_";

    @Override
    public void onUpdate(Context context, AppWidgetManager appWidgetManager, int[] appWidgetIds) {

        // if there may be multiple widgets active, so update all of them
        for (int appWidgetId : appWidgetIds) {
            updateAppWidget(context, appWidgetManager, appWidgetId);
        }
    }

    /**
     * do all the heavy lifting to update the widget here.
     */
    void updateAppWidget(Context context, AppWidgetManager appWidgetManager, int appWidgetId) {
        //first get the preference for this widget that is the top number.
        SharedPreferences preferences = context.getSharedPreferences("widgetDemo2", Context.MODE_PRIVATE);

        //Now get the preference for this widget, stored using it's id number.   The default value is 100, if not found.
        randnum = preferences.getInt(PREF_PREFIX_KEY + appWidgetId, 100);

        // Now create get the random number for it.
        int number = (new Random().nextInt(randnum));

        //finally update the widget view.
        RemoteViews remoteViews = new RemoteViews(context.getPackageName(), R.layout.widget_layout);
        //Log.w("WidgetExample", String.valueOf(number));
        // Set the text
        remoteViews.setTextViewText(R.id.update, String.valueOf(number));

        // Register an onClickListener
        Intent intent = new Intent(context, Widgetd2Provider.class);

        intent.setAction(AppWidgetManager.ACTION_APPWIDGET_UPDATE);

        //if I wanted every widget to update use this section and comment out the one below.
        //ComponentName thisWidget = new ComponentName(context, Example.class);
        //int[] ids = appWidgetManager.getAppWidgetIds(thisWidget);

        //if I want only this one to update, then use this code.
        int[] ids = {appWidgetId};

        intent.putExtra(AppWidgetManager.EXTRA_APPWIDGET_IDS, ids);
        PendingIntent pendingIntent;
        if (android.os.Build.VERSION.SDK_INT >= android.os.Build.VERSION_CODES.S) {
            pendingIntent = PendingIntent.getBroadcast(context, appWidgetId, intent, PendingIntent.FLAG_MUTABLE);
        } else {
            pendingIntent = PendingIntent.getBroadcast(context, appWidgetId, intent, PendingIntent.FLAG_UPDATE_CURRENT);
        }
        //where update is the view and is clickable.  That way, it the widget will update when clicked.
        //in this case get a new random number.
        remoteViews.setOnClickPendingIntent(R.id.update, pendingIntent);
        // Instruct the widget manager to update the widget
        appWidgetManager.updateAppWidget(appWidgetId, remoteViews);

    }

    @Override
    public void onDeleted(Context context, int[] appWidgetIds) {
        // When the user deletes the widget, delete the preference associated with it.
        //there maybe more then one, so loop.
        SharedPreferences.Editor editor = context.getSharedPreferences("widgetDemo2", Context.MODE_PRIVATE).edit();

        final int N = appWidgetIds.length;
        for (int i = 0; i < N; i++) {
            editor.remove(PREF_PREFIX_KEY + i);
        }

        editor.commit();  //finished, comment the preferences.
    }

    @Override
    public void onEnabled(Context context) {
        // Enter relevant functionality for when the first widget is created
        //in this case, nothing is necessary, since it is handled for every widget.
    }

    @Override
    public void onDisabled(Context context) {
        // Enter relevant functionality for when the last widget is disabled
        //it's all handled by the onDelete, so there is nothing here.
    }
}

redpajama_set_name: RedPajamaGithub


I love this place because of their quality furniture. I got the best beds for my little ones for the perfect price. They also included mattresses with one of them and they gave us a two year warranty on almost all items except for the night table. The staff is very polite and they took good care of us . I would definitely recommend this company to anyone looking for comfy yet affordable furniture.
I love this store for equipment and furniture. They have so many varieties and sets of baby furniture. Also countless strollers and carseats. I have found many things here I havent seen at other baby stores (ie babies r us).
This store caries almost anything that new moms and babies might need. It was the only store that carried the lilly padz and at the regular price. But some of the products are pricey.
Kiddytown Limited has not added any photos.
Looking for Children's Furniture pros in Ottawa?


The breach occurred in early January, though the department did not alert the public until Thursday.
Spokesman Robert Oakes said the agency does not know how many peoples' information was exposed. Oakes the agency ruled there was potential for the breach to impact at least 350,000 clients. Oregon's Identity Theft Protection Act requires agencies to alert the public when there is potential to cross that 350,000 threshold. A more specific number should be available in about two weeks, Oakes said.
Oakes said all 8,500 DHS employees have to go through training to protect against this sort of thing, which tells them to avoid anything questionable and provides resources they can seek if they fear an email could be a scheme. But this one was sophisticated he said.
Starting Friday, people who are worried their information was involved can call (800) 792-1750 or go to http://ide.myidcare.com/oregonDHS for help.


I agree that naps are a must for kids - and even adults some days!
Polynesian - This resort gets top marks in my book for easy access to both the Magic Kingdom and Epcot. The Magic Kingdom can be reached by boat or monorail, while Epcot is accessed by the Monorail. The Monorail to Epcot can be reached by using the resort monorail to the Ticket and Transportation Center and then transferring to the Epcot monorail or by walking to the Ticket and Transportation Center and then boarding the Epcot monorail.
Wilderness Lodge - If you're looking to spend the majority of your time in the Magic Kingdom, then the boat from the lodge to the park can be a great option. Transportation to the other parks is by bus.
Yacht & Beach Club and Boardwalk - these resorts are located between the International Gateway of Epcot and Hollywood Studios. Both parks can be accessed by walking or by boat.


Each month, Small Business Monthly's (SBM) Best in Business section features St. Louis area companies that won't settle for just good enough. Each month SBM poll their readers and ask them to help identify the best in the area in a particular industry.
In the December issue, which features the Best IT Firms in St. Louis, SSE received more than 200 nominations and was chosen as one of the top IT companies in St. Louis for 2010 by the readers of SBM. Since SBM began this award program in 2009, SSE has been recognized each year.
Therefore, when you call SSE to inquire about their services, know you can do so with assurance!


text:
Italian Holidays
Italian Property
Free tickets to A Place in the Sun Live
Italy's top five cheeses
Emilia-Romagna regional property guide
Homes in Emilia-Romagna
Meascia
Buy Italia
Reader's Photos
Italia! Mag
Buy Digital Version
Grand Tour Italy
Venice & Veneto
Published On: Thu, Jun 8th, 2017
Culture | By Italia Travel & Life
Our life in: Liguria
Max and Barbara Fenton from Nottinghamshire own a two-bed house on the edge of a small village in the hills of western Liguria. They spend a month there in summer, and make several one- or two-week visits throughout the rest of the year. What drew them to Italy, and to Liguria in particular?
"We're both keen walkers," Max explains, "and we've taken many holidays along pedestrian trails and hiking routes in France and Italy. About eight years ago we went on a series of long walks in Liguria – a region neither of us had ever been to before – and we fell in love with the place. The coast is stunning, obviously, with its pretty buildings and beaches, but we were especially taken by the beautiful old hill-villages and quiet woodlands inland. These were an absolute delight to explore on foot. Fragrant pines, flowering trees, sleepy village squares and elegant little churches. The air was so clean and fresh, we felt we wanted to walk forever. A couple of years later, when we thought about buying a house abroad, Liguria was the first thought for both of us."
"The house is on a hillside, in a village about 20 minutes' drive from the sea. We have a view through olive trees across a valley and off to the right we can see higher mountains rising beyond the hills. It's just about the quietest, calmest spot imaginable. The house is about 200 years old, made of dark local stone, and was a bit shabby when we bought it. It hadn't been lived in for several years. We had a bit of work done on the outside and a very good refurbishment done inside, and now it's really attractive and comfortable."
"We spend a lot of time out on the roof terrace – eating, reading, or just relaxing and enjoying the view. Because we have the extra bedroom, we often have Barbara's sister Wendy and her husband, Francis, out here to join us, and then the four of us usually sit out very late on the terrace after dinner and watch the stars. Sometimes one of us dozes off out there, it's so beautiful and peaceful. We just pop a blanket over them and toddle inside to bed."
"Having the coast within such easy reach is wonderful. It's always nice to go down to the beaches to swim and to wander in the buzzing holiday atmosphere of the resorts. But we feel most at home up here in the hills. The pace of life is slower, it's quieter, and the air feels fresher – perfumed with herbs and flowers and trees. I'd recommend Liguria to anyone. It gives you two different worlds in one small place."
Tags: Culture, Liguria, Travel
Winter in the Valle di Gran San Bernardo
Avoiding Bernini in Rome
Don't look now: Venice after dark
Now That's Amore: 3 Ways to Obtain Italian Dual Citizenship
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Events: June 2017
Summer brings festivals and events galore to Italy this month. June plays host to medieval football breaking out in Florence, light and...


text:
Intravenous aminophylline confers no benefit in acute asthma treated with intravenous steroids and inhaled bronchodilators
Aust N Z J Med. 1993 Aug;23(4):348-54. doi: 10.1111/j.1445-5994.1993.tb01434.x.
J Coleridge 1 , P Cameron, J Epstein, H Teichtahl
1 Western Hospital, Melbourne, Vic.
DOI: 10.1111/j.1445-5994.1993.tb01434.x
Background: The role of intravenous aminophylline in acute asthma is unclear despite meta-analysis of many studies comparing aminophylline with other bronchodilator therapies.
Aims: The aim of this study is to determine whether continuous aminophylline infusion confers any benefit in acute severe asthmatics treated with intravenous steroids and inhaled bronchodilators.
Methods: The study was randomised, double-blind and placebo-controlled. All patients received nebulised salbutamol (1 mL of 0.5%) and ipratropium bromide (1 mL of 0.025%) with glycol diluent (1 mL) at 0, two, four, six, eight and 12 hours, and six-hourly thereafter. In addition all patients were given intravenous hydrocortisone 250 mg six-hourly and oxygen to maintain normoxia. Aminophylline infusions were adjusted to maintain therapeutic levels. Peak expiratory flow rate (PEFR) was measured before and after nebulised bronchodilator on a two-hourly basis in the Emergency Department (ED) and six-hourly on the inpatient wards.
Results: Thirty-one patients were clinically sufficiently improved within 12 hours to be discharged home from the ED. The remaining 28 patients were admitted to the inpatient ward for a total trial duration of 48 hours. No significant difference was found between the placebo and treatment groups for measurements of PEFR, or for the duration of stay of the patients in hospital. The power of the study was 80% for a 25% to 33% difference at a 5% level of significance. Presentation values of PEFR and arterial blood gases did not predict which patients would require inpatient admission and which could be safely discharged home from the ED.
Aminophylline / administration & dosage*
Bronchodilator Agents / administration & dosage*
Double-Blind Method
Drug Therapy, Combination
Hydrocortisone / administration & dosage*
Infusions, Intravenous
Injections, Intravenous
Bronchodilator Agents


text:
Jukola Art Community
» Art Direction
Forced Perspective
Last Updated on Wed, 03 Oct 2018 | Art Direction
This is a practical technique for shooting a scene in a studio with less space than might be required. How can that happen? Isn't the size of a studio predetermined by the number of sets scheduled to occupy the space? Initially, it is. Then any number of things could happen: the schedule changes or a critical location is lost or an additional series of shots are added to forward the storytelling. At that point, a forced perspective set might be squeezed into the empty space previously occupied by a set already shot and wrapped.
The 1994 film Blown Away provides an example of forced perspective (Fig. 4-15). During the movie's exposition, this technique remains onscreen for two seconds before the shot changes. Here is the analysis:
Shot: The hero emerges from an upper floor stair landing as he runs into a hallway junction, pauses a moment to decide where to go, then exits through the door, camera right. The stationary camera pans from right to left, pauses, and pans briefly back to the right.
Scenery: The top section of a stair landing with window and translucent backing beyond leads up into an MIT hallway wall with a practical door leading into an office.
Technique and explanation: In the scene previously described, we are looking through the picture plane, noted as "P.P." in the plan drawing to several pair of pilasters and headers diminished in scale toward a back
Figure 4-15 Two forced-perspective sketches drawn by John Graysmark for Blown Away (2005).
wall that included a door with a translucent glass panel and a translucent transom. This picture plane was physically created by the closest set of pilasters and header to the camera. The floor of the hallway was purposely set on a steep slope, forcing the perspective through exaggeration. The "camera POV" noted in the section sketch below the plan sketch was fixed except for the minimal panning it did—watching this shot several times, one could estimate the fixed height of the camera lens at the same height as the translucent, glass paneled door at the far end of the forced perspective hallway. Lasting just a couple of seconds, this shot forwards the storytelling successfully via this highly believable and compelling technique.
This technique clearly uses forced perspective scenery as a 3D miniature glass painting. Seven decades earlier on a production of Monte Cristo (1922), a similar use of this technique extended the believability of a hallway that would otherwise be too costly to build. By forcing the linear perspective, the physical reality of scenery closest to the camera was distorted; the distortion continued rapidly as the distance was compressed. It is important to note from a design point of view that perspective detail on the built scenery tended to fall away as the eye of the viewer moved gradually down the force perspective hallway (Fig. 4-16). To push the illusion even further, an art director could insert a pale gray bobbinette into the width of the hallway somewhere just beyond the first 1/3 of the distance of the corri-
A hanging miniature is a partially-constructed model which is interposed between a full-scale set and the camera.
The finished composite. Note the false perspective which is produced by continuously varying the scale of the hanging miniature.
Figure 4-16 Hanging miniature built in forced perspective also acts as a 3D glass painting. Courtesy of Dr. Raymond Fielding.
dor. Backlighting a bit more intensely in the remainder of the corridor beyond the fine scrim forces the bobbinette to "go transparent" and creates a visual sense of atmospheric perspective. This technique is borrowed from the theater. Given this example, it is easy to use the phrase "trick-of-the-trade" to explain this and other techniques, but it is a misnomer. There is no trick involved, only careful, collaborative planning—calculated deception based on experience, yes, but no trickery.
If you have ever wanted the secrets to making your own film, here it is: Indy Film Insider Tips And Basics To Film Making. Have you ever wanted to make your own film? Is there a story you want to tell? You might even think that this is impossible. Studios make films, not the little guy. This is probably what you tell yourself. Do you watch films with more than a casual eye? You probably want to know how they were able to get perfect lighting in your favorite scene, or how to write a professional screenplay.
Filmmaking Stuff - How To Make, Market and Sell Your Movie
Photography Masterclass Online Course
Video Production Made Easy
Learn The Art Of Sketching
John Graysmark - Art Direction
Hanging Foreground Miniature
Traveling Mattes - Art Direction
Gate Matting - Art Direction
Specialty Props And Animatronics
makda
How to implement reverse forced perspective in 3d programs?
How to build in forced perspective, miniatures?
How to draw forced perspective production design?
iggi
How to draw false perspective?


There was money deducted from my account illegally. I have filed a complaint with the Better Business Bureau as well as filing fraud with my bank. These people are doing this without permission which is THEFT!!!


text:
Павло Григорович Суколенов (, місто Санкт-Петербург, тепер Російська Федерація — , місто Москва, Російська Федерація) — радянський діяч, секретар ЦК КП(б) Казахстану із кадрів, 1-й секретар Дзержинського районного комітету КПРС міста Москви.

Життєпис
Народився в родині закрійника. З вересня 1921 по липень 1922 року був наймитом і пастухом в станиці Брюховецькій Кубано-Чорноморської області.

З липня 1922 по червень 1927 року навчався в середній школі № 6 міста Краснодара. У 1927 році вступив до комсомолу. З червня по грудень 1927 року проживав у батьків у Ростові-на-Дону.

У грудні 1927 — серпні 1928 року — робітник Донської державної тютюнової фабрики в Ростові-на-Дону.

У серпні 1928 — грудні 1930 року — учень, модельник, у грудні 1930 — вересні 1931 року — культпрацівник клубу імені Мікояна, у вересні 1931 — вересні 1934 року — культпропорганізатор, секретар комітету ВЛКСМ Ростовської державної взуттєвої фабрики імені Мікояна.

У 1930 році закінчив шестимісячні курси із підготовки до вузу при Північно-Кавказькому державному університеті в Ростові-на-Дону.

Член ВКП(б) з жовтня 1931 року.

У 1934 році закінчив Ростовську школу радянського та партійного будівництва.

У вересні 1934 — вересні 1935 року — помічник начальника політичного відділу по комсомолу промислового радгоспу № 3 імені Сталіна Курганинського району Азово-Чорноморського краю.

У вересні 1935 — листопаді 1936 року — помічник начальника політичного відділу по комсомолу радгоспу «Індустрія» Київського району Північно-Донського округу Азово-Чорноморського краю.

У листопаді 1936 — лютому 1937 року — заступник голови фабрично-заводського комітету Донської державної тютюнової фабрики імені Рози Люксембург у Ростові-на-Дону.

У лютому — листопаді 1937 року — завідувач відділу керівних комсомольських органів Ростовського міського комітету ВЛКСМ.

У 1937 році закінчив Ростовський інститут масового заочного навчання.

У листопаді 1937 — травні 1938 року — інструктор із пропаганди Ростовського обласного комітету ВЛКСМ.

З травня по липень 1938 року — 2-й секретар, у липні — жовтні 1938 року — 1-й секретар Кіровського районного комітету ВКП(б) міста Ростов-на-Дону.

З жовтня 1938 по лютий 1939 року — слухач Вищої школи партійних організаторів при ЦК ВКП(б).

У лютому — квітні 1939 року — відповідальний організатор відділу керівних партійних органів ЦК ВКП(б).

У квітні 1939 — липні 1940 року — завідувач відділу комсомольських органів Управління кадрів ЦК ВКП(б).

У липні 1940 — серпні 1942 року — завідувач сектору організаційно-інструкторського відділу ЦК ВКП(б) у Москві.

У серпні 1942 — серпні 1943 року — завідувач організаційно-інструкторського відділу ЦК КП(б) Казахстану.

У серпні 1943 — 9 квітня 1944 року — секретар ЦК КП(б) Казахстану із кадрів.

У травні — листопаді 1944 року — заступник завідувача відділу кадрів Краснодарського крайового комітету ВКП(б).

У листопаді 1944 — квітні 1946 року — завідувач організаційно-інструкторського відділу Краснодарського крайового комітету ВКП(б).

У квітні 1946 — листопаді 1948 року — заступник завідувача відділу кадрів Курського обласного комітету ВКП(б).

У листопаді 1948 — лютому 1951 року — заступник начальника Головного управління організованого набору робітників Міністерства трудових резервів СРСР.

У лютому 1951 — жовтні 1952 року — секретар партійного комітету ВКП(б) Міністерства трудових резервів СРСР.

У жовтні 1952 — лютому 1955 року — 1-й секретар Дзержинського районного комітету КПРС міста Москви.

У лютому — грудні 1955 року — начальник управління із набору китайських робітників Головного управління трудових резервів при Раді міністрів СРСР.

У грудні 1955 — грудні 1959 року — начальник управління побутового і медичного обслуговування учнів Головного управління трудових резервів при Раді міністрів СРСР. Одночасно, в липні 1957 — грудні 1959 року — керівник радянської частини постійної радянсько-болгарської комісії із набору болгарських робітників для роботи на підприємствах, будівництвах і в радгоспах СРСР та їх трудовому навчанню.

У грудні 1959 — січні 1965 року — начальник відділу кадрів і технікумів Головного управління професійно-технічної освіти при Раді міністрів Російської РФСР.

У січні 1965 — лютому 1966 року — головний радник із професійно-технічної освіти в Об'єднаній Арабській Республіці в місті Каїрі.

У лютому — серпні 1966 року — начальник відділу кадрів і технікумів, у серпні 1966 — травні 1970 року — начальник відділу керівних та інженерно-педагогічних кадрів Державного комітету Ради міністрів Російської РФСР із професійно-технічної освіти.

З травня 1970 року — персональний пенсіонер у Москві.

Помер 29 жовтня 1990 року в Москві.

Примітки

Джерела
 Филиппов С. Руководители центральных органов ВКП(б) в 1934—1939 гг. Справочник.  : РОССПЭН, 2018.
 Ашимбаев Д. Кто есть Кто в Казахстане. Алматы, 2010
 Суколенов Павел Георгиевич

Члени КПРС

redpajama_set_name: RedPajamaWikipedia


text:
Brave Browser offers a host of features aimed at protecting your security and privacy on the web. For instance, it includes built-in blockers for ads, pop-ups, scripts, and third-party cookies. It even implements the HTTPS Everywhere extension, so you can ensure that your connections to sites are secure. The lightweight, minimal design looks great, too.
The library is an often-overlooked public resource (and some are modernizing quickly), but OverDrive brings it back into the fold with the newly redesigned, Libby. Supported by over 30,000 libraries worldwide, the app lets you access your local library's array of available ebooks and audiobooks. Use it to download titles, place holds on titles not yet available, and consume your borrowed content. The only requirement is a library card (or its digital equivalent). Droid Apps
All you need is to hold your Android device close to the source of the song, and after a few seconds, the app will accurately detect the song. Besides, you can also play songs and add them to Spotify playlists, buy songs in Google Play Music with one tap, connect your Facebook account, etc. If you are a musicophile, this Android app is a must-have for you.
Ever feel like there's just too much news to keep up with? Nwsty might well be the app for you. It's aimed at those who don't often read the news, and makes it easy to keep up with the daily headlines without spending too much time on them. Each day, you get six to 10 headlines in your digest that you can quickly and easily read in a matter of only a few minutes.
The very specific focus of F-Droid is to offer free and open source software (FOSS) Android apps. It's basic, but apps on the store are categorized, and the list is searchable. You'll find a big selection of free apps here, all of which promise no tracking, no ads, and no dependencies. It's worth checking out for free apps, especially if you support the open source movement. New Droid Apps
The Amazon-owned ComiXology —the iTunes of digital comics—offers a near-perfect combination of store and comic book reader in its wonderful Comics app. The free app transforms your Android smartphone or tablet into a digital long box that houses and syncs your purchases across multiple devices. Even better, the new Comixology Unlimited service lets you devour an ever-expanding catalog of titles for just $5.99 per month. Once you have the app downloaded, you should make sure to read our feature on digital comic books you should read right now.
Despite ups and downs in the quality of its library, Netflix dominates the world of streaming TV and movies. The service also creates its own—sometimes indispensable—content, including original comedies, cartoons, dramas, and documentaries. Some of the shows have become cultural phenomena, making Netflix a must-have. Shows such as Black Mirror, Stranger Things, and The Crown (the most expensive TV show ever made) are often the conversation topics of the day. You can even download select episodes to watch offline at your leisure.
There are a lot of apps out there that pay lip service to security and privacy, but Signal was built from the ground up with the goal of letting people easily communicate without having to worry about being overheard. The Signal app is a complete phone and SMS client replacement (though it works just fine as a standalone app, too) for sending and receiving encrypted calls and messages. A recent update has greatly improved the app's look and feel, proving that security and usability don't have to be at odds. Droid App
With NordVPN you can rest assured that no prying eyes will see your internet traffic. This app sports an excellent interface, a handy server selection tool, and hundreds of available VPN servers across the globe. NordVPN's signature feature is its assortment of specialized servers, which are optimized for activities like peer-to-peer downloading, video streaming, and access to Tor. Android App
Weather Underground combines a slick design with a focus on really useful weather information. We particularly like the ability to report weather conditions in your area and the extremely useful comparative forecasts that deftly show how conditions have changed since yesterday. With an accompanying set of useful widgets, it's the best weather app on Android.
Songkick is the bridge between the music in your digital collection and concerts in your area. Once installed, Songkick scans your device for tunes and then lets you see when and where your favorite artists are playing. If you see a show you're interested in, you can also purchase tickets all from within the app. Add multiple locations to Songkick to catch concerts when you're on the road. Droid App
If you're traveling within a major metropolitan area via either public transportation or personal vehicle, Citymapper can plan all your trip details. It has transit information for dozens of major U.S. cities and international hotspots in Europe, Asia, and Latin America. Further, it offers multiple transportation options for each city, so if you feel like taking the ferry to work one morning, there's nothing stopping you. Its top features include Commute, which lets you set up your daily travel to and from work, and an alert system that uses natural language to describe service delays or cancellations. New Droid Apps
Zocdoc makes it easy to research nearby doctors on your health insurance plan and book appointments from your phone. When you first sign up for the app, you can enter your insurance information manually or scan your card to get started. The app itself looks slick too, with a modern, bright design that makes the experience of scheduling visits less stressful. Zocdoc even saves your history of appointments and makes recommendations for future ones, so you can stay on top of your health history.
Hulu is an excellent app for watching movies and TV shows for free on Android. It's a free service that relies on ads, but there are some great shows available. You need to pay a subscription fee to access all of the content, but there is a range of excellent shows available without a subscription, including classic comedies such as Family Guy, Seinfeld and South Park. New Droid Apps
At first, Snapchat was a little dangerous, popular with the hip and the young, and utterly baffling to everyone else. With Snapchat, you quickly snap and exchange photos with one or several friends. The app also supports video snaps, as well as voice and video calling. The catch is that whatever you send will vanish after a few seconds. It's just a fun and ephemeral way to share the world around you. New updates make the service much easier to use, let you save old snaps, and build ongoing public stories. The more things change, the more they just turn into Facebook. Droid App
This app is geared toward those who are looking for a real relationship, rather than a quick hookup or short fling. Every day at noon, you get sent a prospective match based on a specific set of criteria. You can Like them or Pass on. If you like them, you'll be set up with icebreaker questions; if you pass, the app will learn your preferences and try again tomorrow. Droid Apps
This calorie counter and exercise tracker aims to help you lose weight the old-fashioned way—expending more calories than you take in. With its smart design and an extensive library of foods, it makes quickly logging the calories you take in and what you burn while exercising a snap. A barcode scanner makes it even easier to log that post-workout snack. This fitness app also plays nice with other such apps, so your data won't be tied up in just one place. MyFitnessPal won't give you a whole workout regimen, but it can make you more aware of your habits. PCMag has a full review of MyFitnessPal for the iPhone. Droid App
File browsing is something everyone inevitably has (or wants) to do, so you might as well do it with a capable, fantastic file browser. Solid Explorer is pretty much as good as it gets in the file explorer apps realm. It features Material Design, archiving support, support for the most popular cloud services, and even some more power user stuff like FTP, SFPT, WebDav, and SMB/CIFS support. It looks great, it's incredibly stable, and it just works well. There is a 14-day free trial with a $2.99 price tag at the end of it. This is, by far, the best file manager on Android for most people. Android App
Who needs Uber when so many cities offer world-class public transit? The Transit app shows mass transit options—including buses, ferries, and trains—and the estimated time of arrival in 87 cities in North American, Europe, and Australia. Here in New York, it even tells you how many bikes are parked at local Citi Bike stands. This app keeps you in the know no matter where your travels take you.
Here it is ladies and gentlemen. The crème de la crème. The Android apps that stand alone at the top of the pantheon. These apps have become ubiquitous with Android and if you're looking for good stuff it's assumed that you have some of this stuff already. There are a ton of amazing Android apps out there. However, their usefulness is usually limited to the habits of the people using them. These apps shouldn't have those problems. Everybody can use these. Without further delay, here are the best Android apps currently available! This is not a diamond-in-the-rough kind of list. You should be relatively familiar with all of these. New Droid Apps
Remember the bad old days of ordering food? You needed takeout menus, knowledge of the terrain ("will they even deliver out here?"), cash, and faith that the person jotting down your order got it right. Seamless takes care of all that, even letting you pay via credit card from your Android. The only drawback? It's not available in every city (or even every state), though it has expanded its range dramatically since it was first included on this list. Droid App
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text:
Еврідіка — дружина Орфея.
 Еврідіка — дочка Амфіарая.
 Еврідіка — дочка Адраста, дружина Іла, мати Лаомедонта ;
 Еврідіка — дочка Лакедемона й Спарти, дружина Акрісія, мати Данаї;
 Еврідіка — дружина немейського володаря Лікурга, мати Офельта, на честь якого були встановлені Немейські ігри;
 Еврідіка — дружина фіванського володаря Креонта;
 Еврідіка — одна з Данаїд.
 Еврідіка — дочка Клімена, дружина Нестора
 Еврідіка (* 355 до н. е.., † 336 до н. е..) — остання дружина македонського царя Філіпа II.

Див. також
 Еурідіче (значення)