Ubiquitination of Mfn2 by MITOL may hamper ER mitochondria interactions selleck screening library at the mitochondria associated membranes [60]. MITOL has also been shown to ubiquitinate Drp1, hFis1, and mutant SOD1 [61]. Blocking the proteasome causes accumulation of intermembrane space proteins like EndonucleaseG (EndoG). Ubiquitination of these proteins occurs prior to import into the organelle as deletion of the mitochondrial targeting sequence does not affect ubiquitination. On proteasome inhibition, the intermembrane space protease Omi/Htra1 cleaves endoG acting as a backup mechanism of protein quality control in the mitochondria when the proteasomal system is malfunctioning [62]. Deubiquitinating enzymes like Ubiquitin-specific processing protease 16 (Ubp16) have also been discovered to be present on the mitochondrial outer membrane [63].

Though most of these are mitochondrial outer membrane proteins, many matrix resident proteins are also ubiquitinated by the cytosolic UPS. A recent proteomic study has identified a wide array of interactors for the cytosolic E3 ligase PARKIN; along with cytosolic and nuclear molecular partners, surprisingly, there are also proteins of the mitochondrial matrix [64]. How the proteasomal machinery gets access to the proteins residing inside the mitochondria remains uncertain. Whether the proteasomal components are recruited to the mitochondria or other ancillary proteins extract the membrane proteins from the mitochondrial membrane and transport them to the proteasome is unknown [57]. Recent reports indicate the presence of
AKI is defined as a sudden decrease in kidney function.

AKI is one of the serious conditions that affect the structure and function of kidneys. It is a broad clinical syndrome, including specific diseases affecting the kidney such as MM. Even a minor acute reduction in kidney function correlates to an adverse prognosis. A schematic view of the conceivable course of AKI has been proposed (Figure 2) [19]. AKI could be an important cause of CKD or ESRD. Therefore, early detection and treatment of AKI would improve outcomes. Two criteria of AKI, which were based on sCr and urine output, the Risk, Injury, Failure, Loss, End-Stage Renal Disease (RIFLE) [21] and Acute Kidney Injury Network (AKIN) [22] have been proposed and validated. Recently, severity of AKI staged by RIFLE criteria (OR = 2.

04 Failure stages versus Risk and Injury stage P = 0.06) has been reported as associated with marginally better long-term outcome in MM patients [23]. In 2012, the Kidney Disease: Improving Global Outcomes (KDIGO) AKI Guideline Work Group accepted the existing criteria for the diagnosis and staging of AV-951 AKI and proposed a single definition of AKI that should be useful for practice, research, and public health (Table 3) [20].

Figure 1Chemical structures of ionophore coccidiostats.In selleckchem Olaparib conclusion, to ensure safe and effective use of ionophores, the proper concentrations, precisely as stated in authorization documents, have to be applied. Therefore, the availability of analytical methodology for robust and reliable quantification of ionophores in animal feeding stuffs is essential for both official control and manufacturers’ quality control laboratories.A number of methods for the determination of ionophores in animal feed have been described. Because of the lack of chromophoric groups in their molecules, the derivatisation step is required when spectrophotometric detection is applied [2, 3]. Most of the available methods use postcolumn derivatisation with vanillin [4] or dimethylaminobenzaldehyde, DMAB [5]; such methods are sensitive and robust and require little sample preparation.

Lately, also the mass spectrometric detection has been applied in the determination of coccidiostats in feed [6]. Although MS-based methods can be both used for the reliable determination of single representative of ionophore family [7, 8] and to screen all authorized polyether antibiotics [9], this approach is not always available to routine laboratories because of high cost of purchase and maintenance of mass spectrometer. Also relatively high variation of results is observed due to lack of labelled internal standards.Some of the methods developed so far, using both postcolumn derivatisation/spectrophotometric detection and mass spectrometric approach, have been validated by interlaboratory comparisons and harmonized as international norms [10�C13].

Most of the routine laboratories performing analyses of feed stuffs for ionophore antibiotics follow these official documents. Nevertheless, none of the up-to-date methods enables the determination of all ionophores in single analytical run.The multianalyte protocols are more practical for the organization of laboratory work in terms of quality assurance and sample throughput. Therefore, we have decided to develop single protocol for the determination of all authorized ionophore coccidiostats based on the postcolumn derivatisation methodology, already successfully applied in the determination of monensin, narasin, and salinomycin [11].2. Material and Methods2.1. Chemicals and MaterialsMaduramicin ammonium (MAD), monensin sodium (MON), narasin from Streptomyces auriofaciens (NAR), and salinomycin sodium (SAL) were purchased from Sigma (Germany). Lasalocid A sodium (LAS) was obtained from Dr. Ehrenstorfer. Monensin methyl ester (MON-ME) and semduramicin sodium (SMD) were donated by EU-RL in Berlin. Methanol, HPLC grade, Dacomitinib was purchased from JT Baker (Germany). Methanol p.a.

One of the dynamic nonlinear inertia weights is represented by (18) and selleck Volasertib (19), while the other is represented by (20) and (21). They are meant to achieve tradeoff between exploration and exploitation:dn=dnmin?+(dnmax??dnmin?)(iteritermax?),(18)��=��min?+(��max??��min?)(iteritermax?)dn,(19)dn=dnmax??(dnmax??dnmin?)(iteritermax?),(20)��=��max??(��max??��min?)(iteritermax?)dn,(21)where dn is the dynamic nonlinear factor, �� is the inertia weight, ��max and ��min are the maximum and minimum values of ��, respectively, dnmax and dnmin are the maximum and minimum values of dn, respectively, and iter and itermax are the current iteration numbers and the maximum iteration number, respectively.

A dynamic logistic chaotic map in (4) was incorporated into the PSO variant inertia weight as shown in (23) to enrich searching behaviors and avoid being trapped into local optima:��=��max??(��max??��min?)(iteritermax?),(22)��=��+(1?��)Lmap,(23)where �� is the dynamic chaotic inertia weight adjustment factor, ��max and ��min are the maximum and minimum values of ��, respectively, and Lmap is the result of logistic chaotic map. In this variant, using (19) and (23) was labeled DLPSO1, while using (21) and (23) was captioned DLPSO2.For the purpose of achieving a balance between global exploration and local exploitation and also avoiding premature convergence, (19), (21), and (23) were mixed together to dynamically adjust the inertia weight of the variant as shown in Algorithm 4, where fi is the fitness value of particle i and favg is the average fitness value of the swarm.

Experiments and comparisons showed that the DLPSO2 outperformed several other well-known improved particle swarm optimization algorithms on many famous benchmark problems in all cases.Algorithm 43.7. DiscussionsLDIW-PSO is relatively simple to implement and fast in convergence. When [4] experimentally ascertained that LDIW-PSO is prone to premature convergence, especially when solving complex multimodal optimization problems, a new area of research was opened up for improvements on inertia weight strategies in PSO, and LDIW-PSO became a popular yard stick for many other variants.From the variants described previously, there are ample expectations that they should outperform LDIW-PSO judging by the various additional strategies introduced into the inertia weight strategies used by them.

For example, CDIW-PSO introduced chaotic optimization characteristic, REPSO introduced a combined effort of simulated annealing idea and fitness variance of particles, DAPSO introduced Anacetrapib a dynamic adaptive strategy based on swarm diversity function, APSO introduced an adaptive mutation to the particle positions and made the inertia weight dynamic based on the best global fitness, while DLPSO2 used different formulas coupled with chaotic mapping.

Smith et al. [26] have shown in young lambs, by using labeled albumin microspheres injected into carotid perfusion cannula, that relative coronary blood flow was significantly less than in the control group. Kato et al. [27] demonstrated references in puppies, that coronary arterial flow in VA ECMO with carotid arterial cannula decreased even proportionally to ECMO flow increase despite no significant changes in the mean or diastolic pressures in the ascending aorta. And most interestingly, Kamimura et al. [28], in neonatal dogs, proved the difference in coronary blood flow distributed from the proximal arterial cannula (1 cm above aortic valve) being significantly higher than that from the distal cannula (ostium of the brachiocephalic trunk).

He concludes that proximal arterial cannula appears necessary to provide sufficient oxygenated blood to the coronary circulation during V-A ECMO. However, animals in these three experimental protocols were not in cardiac arrest. We speculate that not only distance, but also the angle under which the outflow arterial cannula in FS approach is located, may play the role, causing prograde flow in aortic arch, thus underperfusing coronary arteries. These considerations are of critical importance in cardiogenic shock with persistent lung failure treated by peripheral ECMO to avoid coronary perfusion by poorly oxygenated blood ejected from the left ventricle.It has also been demonstrated that added pulsatility to continuous flow mechanical support improves organ perfusion in terms of blood flow, flow velocity in coronary artery [29,30], energy equivalent pressure and surplus hemodynamic energy, though not having influenced mean carotid pressure [31,32], and even improves a renal perfusion [33].

However, in most of these experiments, a central cannulation approach was used for both inflow and outflow cannulae. This surgical approach is usually not used in cardiac arrest patients [17,18]. We, therefore, investigated whether pulsatility represented by IABP might play a similar beneficial role also in peripheral configuration of FF vs. FS ECMO in the cardiac arrest model. Our results show that in this situation, IABP may have an unfavorable effect on macrocirculation in the FF configuration. We speculate that an intermittent aortic occlusion by the IABP balloon may diminish blood flow available for the aortic root (and thus for coronary arteries), more than for the aortic arch (and thus for the carotids).

These results are in accordance with a report by Sauren [34], where addition of IABP in severely hypotensive ECMO-treated animals was not beneficial; however, the animals were not in cardiac Carfilzomib arrest. On the other hand, the subclavian approach seems to be suitable for IABP assistance because the outflow cannula is located proximal to the IABP balloon. Drakos et al.

It is, however, more difficult to mutate multiple genes this way [10, 11].A BLAST search using the pyrG sequence Axitinib buy of A. oryzae S1 against the A. oryzae RIB40 genome database at the National Institute of Technology and Evaluation (NITE; http://www.bio.nite.go.jp/dogan) showed that pyrG is present as a single copy on chromosome 7 (contig SC011, location 2219667��2220565).In this study, a gene replacement cassette was constructed consisting of the native pyrG locus extending 1.5 to 2.0kb beyond the upstream and downstream termini of the pyrG coding region but lacking the open reading frame of the gene. Transformation of A. oryzae strain S1 with the gene replacement cassette generated 5-FOA-resistant uracil and uridine auxotrophs.

Putative pyrG��0 mutants were verified by comparing their growth on selective and nonselective media, PCR analyses of the pyrG region in the putative mutants and complementation with plasmids containing wild-type homologous and heterologous pyrG genes. Suitability of the pyrG��0 mutant as a host for heterologous protein production was assessed using strain GR6 harbouring a plasmid in which the pyrG and heterologous ��-galactosidase genes were integrated.2. Materials and Methods2.1. Fungus, Cultivation, and PlasmidsA. oryzae strain S1was obtained from the Fungal Stock Culture Collection of the Molecular Mycology Laboratory, School of Biosciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia. The fungus was maintained on a Potato Dextrose Agar (PDA; Difco, France) at 30��C and subcultured monthly.

Fungal cultivation was carried out by inoculating onto a fresh PDA plate. Cultures were incubated for 7 days at 30��C. Plasmid ANEp2 (Figure 1(a)) is a shuttle vector capable of autonomous replication in Aspergilla [12]. In addition to the pUC18 backbone ANEp2 carries the A. nidulans pyrG gene as a selectable marker, an expression cassette (GlaPr-lacA-GlaTt) that expresses an A. niger secreted ��-galactosidase, and the AMA1 sequence that supports autonomous replication in Aspergilli. ANEp2 was used to functionally test for complementation of uridine auxotrophy and reporter gene expression in an A. oryzae pyrG mutant. Plasmid pUC_pyrGAo containing the pyrG of the A. oryzae strain S1 was also used for complementation of uridine auxotrophy (Figure 1(b)) [13]. Escherichia coli strain DH5�� was used for DNA manipulation.

Figure 1Plasmids used for transformation. (a) Plasmid ANEp2 containing the pyrG gene of A. nidulans and a GlaPr-lacA-GlaTt chimera (b) plasmid pUC_pyrGAo containing pyrG (1,839bp) of A. oryzae strain S1.2.2. MediaPolypeptone dextrin (PD) medium containing 1.0% (w/v) polypeptone, 2.0% (w/v) glucose, 0.5% (w/v) KH2PO4, Brefeldin_A 0.1% (w/v) NaNO3, and 0.05% (w/v) MgSO4?7H2O was used for liquid cultivation of A. oryzae [14]. Czapek-Dox (CD) medium composed of 0.2% (w/v) NaNO3, 0.1% (w/v) K2HPO4, 0.05% (w/v) MgSO4?7H2O, 0.

According to previous Gefitinib reports [11-14,30], in no patient did a severe form of pontine myelinolysis develop. The cases of pontine myelinolysis reported linked to a fast increase in natremia were observed in patients with chronic hyponatremia [16] but not with infusion of HSS for posttraumatic ICH. In a description of HSS infusion in TBI children, no osmotic demyelination syndrome was seen on magnetic resonance imaging, even for natremia reaching 171 mmol/L [12].The main side effect reported in the present report was hyperchloremia. Excessive chloride infusion is a major factor with hyperchloremic acidosis. Thus, it is likely that hyperchloremic acidosis developed in TBI patients treated with continuous HSS infusion. Hyperchloremic acidosis increases the symptoms of postoperative ileus and induces biologic hemostasis perturbation [31].

To date, these complications are not evidence based in the ICU setting.Finally, a dose adaptation of HSS infusion with rigorous biologic monitoring may explain the lack of an uncontrolled metabolic disorder, except for a probable hyperchloremic acidosis, in our results.How to stop the infusion is of major importance to prevent a rebound of ICH, and few data are available. In the study by Qureshi et al. [11], half of the study population experienced a relapse of ICH at the end of the infusion. Interestingly, even with a likely residual barbiturate blood level, we did not report any rebound in ICP after stopping the infusion.

In the current algorithm, the slow tapering of continuous HSS treatment could have restored a normal brain osmolality without inducing a cerebral edema, as the dissipation of accumulated electrolytes and organic osmolytes takes place along with water repletion [6,28,32]. Finally, a slow reduction of the flow may be recommended in case of continuous HSS infusion.Several therapeutics have been tested for decreasing ICP in case of refractory ICH. Despite an improvement of the neurologic recovery in patients with moderate to severe TBI [33], moderate hypothermia may expose patients to intracranial bleeding as well as secondary infections [34] and is not currently recommended in patients with refractory ICH [5]. Surgical craniotomy is another option, but the optimal timing to perform this procedure remains controversial, and its efficiency to enhance neurologic recovery is still debated [18,35]. Regarding the absence of severe side effects with the current protocol, continuous controlled infusion of HSS may thus be an interesting alternative for the treatment of refractory ICH.Our study encountered limitations. First, the study had a retrospective design, and a randomized trial is necessary to confirm these results. Second, the external validity of this Dacomitinib single-center study may be limited.

Third, the status of the baseline proteinuria, presence of sepsis, and etiology of AKI were not identified. Recently, these variables were identified as important factors affecting short- and long-term prognosis after AKI [21,40,41]. In this study, we included all available demographic data and clinical information for analysis, but residual confounding might still exist to some extent due to unmeasured and unknown risk factors. Last, this retrospective observational study cannot prove that AKI plays a causal role in CKD progression or that aggressive follow-up after discharge would improve these long-term outcomes, as there was no pre-specified protocol for post-discharge care and SCr follow-up. Prospective studies with structured, multidisciplinary, follow-up medical care for AKI survivors are warranted to clarify this issue [42].ConclusionsThe present study demonstrated the gradual decline in kidney function after hospital discharge in critically ill patients with AKI, who did not require dialysis. Furthermore, there appeared to be an association between the deterioration of kidney function and long-term mortality. This finding underscores the need to explore the mechanisms that are responsible for the long-term consequences of an AKI. Additionally, there is a need for novel strategies that focus on retarding renal function deterioration and strengthening the continuous surveillance of kidney function in AKI survivors.Key messages? Long-term trajectories of kidney function after AKI in critically ill survivors are not well-defined, especially in those who have not received dialysis. This issue is possibly overlooked in post-discharge medical care.? A considerable portion of critically ill patients, who survived AKI that did not require dialysis, had CKD during long-term follow-up.? We revealed that there was a steady long-term decline in kidney function after hospital discharge. Therefore, we should not view AKI only as a self-limiting acute disease, but also as a long-lasting progressive disorder.? The mortality risk increased significantly in a graded manner with the decline in kidney function from baseline eGFR to advanced stages of CKD during the follow-up period.? We need to organize multidisciplinary medical care for critically ill AKI survivors to continually monitor kidney function after discharge. One potential modifiable factor to improve long-term survival of patients with AKI after discharge from hospital is to prevent the deterioration of their kidney function.

01 for IL-6) and IL-8, while all other individuals, www.selleckchem.com/products/17-DMAG,Hydrochloride-Salt.html including those with single mutations in either TLR4 or TIRAP/Mal had elevated cytokine levels at day 1 after diagnosis of pneumonia. Figure Figure11 shows cytokine values in patients of Group II on day 1 after diagnosis of VAP.Figure 1Impact of TIRAP/Mal or TLR4 polymorphisms or their combinations on circulating cytokine levels. Cytokine serum levels (pg/ml) were measured on day 1 after diagnosis of ventilator-associated pneumonia in Group II. Values are shown as median +/- 95% confidence …To investigate the influence of different genotypes on the cytokine induction pattern, monocytes from these patients were isolated and stimulated ex-vivo with LPS.

Concentrations of TNF-�� and IL-6 in cell supernatants of patients bearing the wild-type phenotype and of carriers of TIRAP/Mal or TLR4 polymorphisms showed an increase of cytokine levels. Individuals with a double mutation in TLR4 and TIRAP/Mal, however, exhibited a lack of inducibility for TNF-�� and IL-6 on day 1 after diagnosis (Figure (Figure2).2). Patients carrying no mutations or either TLR4 or TIRAP/Mal mutations showed a stronger induction of IL-6 following LPS-stimulation compared with patients with double mutations, although the difference did not reach statistical significance. Similar results were seen for TNF-�� although less pronounced. No differences in cytokine concentrations of monocyte supernatants between patients bearing the wild-type and carriers of polymorphisms were found on day 7 (data not shown).

Figure 2Impact of TIRAP/Mal or TLR4 polymorphisms or their combinations on monocyte release of IL-6 and TNF-�� following LPS-stimulation. Monocytes were isolated from patients on day 1 after diagnosis of ventilator-associated pneumonia. Cells were then …Influence of genotypes on cytokine release following cardiac surgeryA third group of patients was then examined to distinguish between a predominately sterile inflammatory stimulation as compared with the stimulus towards immune cells by bacterial ligands. The patients studied following cardiac surgery were all of Caucasian descent. Patient characteristics of this cohort and the matched patients are shown in Tables S1, S2 and S5 in Additional file 1. There were no statistically significant differences in the cytokine levels following surgery over the study period between the subgroups (Figure (Figure3).

3). The postoperative course was not related to cytokine levels in these patients (data not shown). Interestingly, patients receiving cardiac surgery exhibited markedly higher levels of IL-6 following the procedure in all studied genotypes as compared with patients suffering from infection approximately 24 hours Batimastat following the insult. Although the results were obtained by different cytokine-detection assays there seem to be different mechanisms responsible for the release of cytokines in operated patients.Figure 3Time-dependent cytokine release in cardiac surgery patients.

Monocyte alterations, during for example, can decrease phagocytosis, inflammatory cytokine expression, and antigen presentation because of the loss of mHLA-DR expression. Lymphocyte anergy and apoptosis can ensue [3,37-39]. These changes together may increase susceptibility to infection, which in turn could provoke multiple organ failure and death.Diminished mHLA-DR expression has been proposed as a reliable biomarker of immunosuppression in ICU patients. Today, it is the most reliable marker and is used in most of the studies about ICU-acquired immunosuppression. More specifically, it has been shown to be a predictor of septic complications in several conditions, including surgical interventions, sepsis, burns, stroke, and pancreatitis [11,40-48]. Immunosuppression has long been postulated as a concomitant of trauma [37,49,50].

In regard to mHLA-DR, the pioneering work of Polk and colleagues [50] reported in 1986 revealed an association between the development of sepsis and low mHLA-DR expression. Subsequently, mHLA-DR expression was assessed as a predictor of sepsis in several series of severely injured patients [15,17,18,20,39,51-53]. A major limitation of these studies is that they were conducted over a 20-year period, during which time case management and methodologies for measurement of mHLA-DR expression have evolved, thereby complicating interpretation and comparison of the findings of these studies.In the present cohort, incidence of sepsis was 35% and the mortality rate for the entire study was 6%.

Though apparently high, these values are in concordance with those of a previous epidemiologic study by Osborn and colleagues [2], in which incidence rates of sepsis were 42% for moderate injury (defined as an ISS of between 15 and 29) and 39% for severe injury (ISS of up to 30). Another epidemiologic study in trauma patients reported a low sepsis incidence, but most of the patients presented with mild injury (ISS of less than 15: 67.7%) and no brain injury [54], the latter of which is known to be a risk factor for developing pneumonia [55-58]. In our cohort, septic patients presented more trauma brain injury than the non-septic patients did, and this is in concordance with the literature.The present study showed an overall reduction in mHLA-DR expression in trauma patients. Most importantly, in injured patients with an uneventful outcome, mHLA-DR expression returned to normal within a week.

In contrast, in patients who developed infection, mHLA-DR levels remained low or fell even lower.It would appear that the steepness of the slope of mHLA-DR recovery AV-951 is a more significant indicator than the levels attained at a given point in time. Indeed, the incidence of sepsis was significantly greater in the group with a slope of less than 1.2 (days 3 and 4/days 1 and 2).

DRS was the chairman of the ABC Faculty and is a member of the ABC-Trauma Faculty, which are selleck inhibitor both managed by Physicians World Europe GmbH, Mannheim, Germany and sponsored by unrestricted educational grants from Novo Nordisk Health Care AG, Zurich, Switzerland and CSL Behring GmbH, Marburg, Germany. In the past 5 years, DRS has received honoraria or travel support for consulting or lecturing from the following companies: Abbott AG, Baar, Switzerland, AMGEN GmbH, Munich, Germany, AstraZeneca AG, Zug, Switzerland, Bayer (Schweiz) AG, Z��rich, Switzerland, Baxter AG, Volketswil, Switzerland, Baxter S.p.A., Roma, Italy, B. Braun Melsungen AG, Melsungen, Germany, Boehringer Ingelheim (Schweiz) GmbH, Basel, Switzerland, Bristol-Myers-Squibb, Rueil-Malmaison Cedex, France and Baar, Switzerland, CSL Behring GmbH, Hattersheim am Main, Germany and Berne, Switzerland, Curacyte AG, Munich, Germany, Ethicon Biosurgery, Sommerville, NJ, USA, Fresenius SE, Bad Homburg v.

d.H., Germany, Galenica AG, Bern, Switzerland (including Vifor SA, Villars-sur-Glane, Switzerland), GlaxoSmithKline GmbH & Co. KG, Hamburg, Germany, Janssen-Cilag AG, Baar, Switzerland, Janssen-Cilag EMEA, Beerse, Belgium, Merck Sharp & Dohme-Chibret AG, Opfikon-Glattbrugg, Switzerland, Novo Nordisk A/S, Bagsv?rd, Denmark, Octapharma AG, Lachen, Switzerland, Organon AG, Pf?ffikon/SZ, Switzerland, Oxygen Biotherapeutics, Costa Mesa, CA, Pentapharm GmbH (now tem Innovations GmbH), Munich, Germany, ratiopharm Arzneimittel Vertriebs-GmbH, Vienna, Austria, Roche Pharma (Schweiz) AG, Reinach, Switzerland, Schering-Plough International, Inc.

, Kenilworth, NJ, USA, Vifor Pharma Deutschland GmbH, Munich, Germany, Vifor Pharma ?sterreich GmbH, Vienna, Austria, and Vifor (International) AG, St Gallen, Switzerland.AcknowledgementsSupport and manuscript preparation was provided by Physicians World Europe GmbH (Mannheim, Germany) supported by an unrestricted grant from CSL Behring GmbH (Marburg, Germany).
In recent years, our knowledge of the characteristics of patients who are admitted to critical care with sepsis, severe sepsis, or septic shock has greatly advanced thanks to the findings of numerous observational studies [1-6]. There is wide Entinostat variation in the incidence of sepsis and severe sepsis in the intensive care unit (ICU) setting, with reported rates ranging from 20% to 80%, and reported mortality of 20% to 50% [1-6]. Septic shock, defined as a state of acute circulatory failure characterized by persistent hypotension unexplained by other causes, despite adequate fluid resuscitation [7], affects between 10% and 30% of patients managed in the ICU [1,3,4,8-10], and its incidence is increasing [3].