Citrate confers less filter-induced complement activation and neutrophil degranulation than heparin when used for anticoagulation during continuous venovenous haemofiltration in critically ill patients

Background: During continuous venovenous haemofiltration (CVVH), regional anticoagulation with citrate may be superior to heparin in terms of biocompatibility, since heparin as opposed to citrate may activate complement (reflected by circulating C5a) and induce neutrophil degranulation in the filter and myeloperoxidase (MPO) release from endothelium. Methods. No anticoagulation (n = 13), unfractionated heparin (n = 8) and trisodium citrate (n = 17) regimens during CVVH were compared. Blood samples were collected pre- and postfilter; C5a, elastase and MPO were determined by ELISA. Additionally, C5a was also measured in the ultrafiltrate. Results: In the heparin group, there was C5a production across the filter which most decreased over time as compared to other groups (P = 0.007). There was also net production of elastase and MPO across the filter during heparin anticoagulation (P = 0.049 or lower), while production was minimal and absent in the no anticoagulation and citrate group, respectively. During heparin anticoagulation, plasma concentrations of MPO at the inlet increased in the first 10 minutes of CVVH (P = 0.024). Conclusion: Citrate confers less filter-induced, potentially harmful complement activation and neutrophil degranulation and less endothelial activation than heparin when used for anticoagulation during continuous venovenous haemofiltration in critically ill patients

The plasma level and biomarker value of neutrophil gelatinase-associated lipocalin in critically ill patients with acute kidney injury are not affected by continuous venovenous hemofiltration and anticoagulation applied

Introduction: Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury (AKI), and levels reflect severity of disease in critically ill patients. However, continuous venovenous hemofiltration (CVVH) may affect plasma levels by clearance or release of NGAL by activated neutrophils in the filter, dependent on the anticoagulation regimen applied. We therefore studied handling of NGAL by CVVH in patients with AKI.Methods: Immediately before initiation of CVVH, prefilter blood was drawn. After 10, 60, 180, and 720 minutes of CVVH, samples were collected from pre- and postfilter (in- and outlet) blood and ultrafiltrate. CVVH with the following anticoagulation regimens was studied: no anticoagulation in case of a high bleeding tendency (n = 13), unfractionated heparin (n = 8), or trisodium citrate (n = 21). NGAL levels were determined with enzyme-linked immunosorbent assay (ELISA).Results: Concentrations of NGAL at inlet and outlet were similar, and concentrations did not change over time in any of the anticoagulation groups; thus no net removal or production of NGAL occurred. Concentrations of NGAL at inlet correlated with disease severity at initiation of CVVH and at the end of a CVVH run. Concentrations of NGAL in the ultrafiltrate were lower with citrate-based CVVH (P = 0.03) and decreased over time, irrespective of anticoagulation administered (P < 0.001). The sieving coefficient and clearance of NGAL were low and decreased over time (P < 0.001).Conclusions: The plasma level and biomarker value of NGAL in critically ill patients with AKI are not affected by CVVH, because clearance by the filter was low. Furthermore, no evidence exists for intrafilter release of NGAL by neutrophils, irrespective of the anticoagulation method applied

Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling

Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPKα(Thr172) and CREB-1(Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000 ppm) or control chow. Functionally, celecoxib inhibited TNF-α-induced NF-κB p65(Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1β-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs

Maladaptive personality traits in adolescence: Psychometric properties of the Personality Diagnostic Questionnaire-4+

AbstractThe Personality Diagnostic Questionnaire-4+ (PDQ-4+) is a self-report used for the assessment of personality disorder traits, however, its psychometric characteristics have yet to be tested in community samples of adolescents. The main goal was to analyze the psychometric properties of the PDQ-4+ scores in a large sample of non-clinical adolescents (N=1,443; M=15.9 years; SD=1.2). The PDQ-4+ scores showed adequate psychometric properties. Reliability of the subscales, incorporating a Likert-type 5-point response format, ranged from .62 to .85. The study of the internal structure at item level revealed that the PDQ-4+ subscales were essentially one-dimensional. Analysis of the internal structure at the subscale level by means of exploratory factor analysis and exploratory structural equation modeling yielded a possible three-dimensional solution. The PDQ-4+ subscales correlated moderately with emotional and behavioural variables measured by the Strengths and Difficulties Questionnaire. The results have clear implications for the understanding of maladaptive personality traits in adolescents

Citrate anticoagulation versus systemic heparinisation in continuous venovenous hemofiltration in critically ill patients with acute kidney injury: A multi-center randomized clinical trial

Introduction: Because of ongoing controversy, renal and vital outcomes are compared between systemically administered unfractionated heparin and regional anticoagulation with citrate-buffered replacement solution in predilution mode, during continuous venovenous hemofiltration (CVVH) in critically ill patients with acute kidney injury (AKI).Methods: In this multi-center randomized controlled trial, patients admitted to the intensive care unit requiring CVVH and meeting inclusion criteria, were randomly assigned to citrate or heparin. Primary endpoints were mortality and renal outcome in intention-to-treat analysis. Secondary endpoints were safety and efficacy. Safety was defined as absence of any adverse event necessitating discontinuation of the assigned anticoagulant. For efficacy, among other parameters, survival times of the first hemofilter were studied.Results: Of the 139 patients enrolled, 66 were randomized to citrate and 73 to heparin. Mortality rates at 28 and 90 days did not differ between groups: 22/66 (33%) of citrate-treated patients died versus 25/72 (35%) of heparin-treated patients at 28 days, and 27/65 (42%) of citrate-treated patients died versus 29/69 (42%) of heparin-treated patients at 90 days (P = 1.00 for both). Renal outcome, i.e. independency of renal replacement therapy 28 days after initiation of CVVH in surviving patients, did not differ between groups: 29/43 (67%) in the citrate-treated patients versus 33/47 (70%) in heparin-treated patients (P = 0.82). Heparin was discontinued in 24/73 (33%) of patients whereas citrate was discontinued in 5/66 (8%) of patients (P &#60; 0.001). Filter survival times were superior for citrate (median 46 versus 32 hour

Trash-Talking: Competitive Incivility Motivates Rivalry, Performance, and Unethical Behavior

Trash-talking increases the psychological stakes of competition and motivates targets to outperform their opponents. In Studies 1 and 2, participants in a competition who were targets of trash-talking outperformed participants who faced the same economic incentives, but were not targets of trash-talking. Perceptions of rivalry mediate the relationship between trash-talking and effort-based performance. In Study 3, we find that targets of trash-talking were particularly motivated to punish their opponents and see them lose. In Study 4, we identify a boundary condition, and show that trash-talking increases effort in competitive interactions, but incivility decreases effort in cooperative interactions. In Study 5, we find that targets of trash-talking were more likely to cheat in a competition than were participants who received neutral messages. In Study 6, we demonstrate that trash-talking harms performance when the performance task involves creativity. Taken together, our findings reveal that trash-talking is a common workplace behavior that can foster rivalry and motivate both constructive and destructive behavior

Successful Reversal of Acute Kidney Failure by Ultrasound-Accelerated Thrombolysis of an Occluded Renal Artery

Purpose. To describe the treatment of renal artery thrombosis with ultrasound-accelerated thrombolysis and discuss the management of prolonged renal ischemia. Case. A 76-year-old patient with a single functional kidney, mild chronic renal impairment, and a recent history of endovascular repair of a thoracoabdominal aneurysm with an aortic branch graft presented with acute flank pain, anuria, and renal failure. The side branch from the aortic stent graft to his single, right, functional kidney appeared to be completely thrombosed. Symptoms had started after cessation of oral anticoagulants because of a planned mastectomy for breast cancer. After identification of the occlusion, ultrasound-accelerated thrombolysis was started 19 hours after the onset of anuria. Angiography, 4 hours after beginning of therapy, already showed partial dissolution of the thrombus and angiographic control after 18 hours showed complete patency of the renal artery side branch. Despite a long period of ischemia, renal function was completely recovered. Conclusion. In patients with acute renal ischemia due to thrombosis of the renal artery, complete recovery of function can be achieved with ultrasound-accelerated thrombolysis, even after prolonged periods of ischemia

Tumor Ulceration Does Not Fully Explain Sex Disparities in Melanoma Survival among Adolescents and Young Adults

Hypertension in kidney transplant recipients (KTRs) is a risk factor for cardiovascular mortality and graft loss. Data on the prevalence of hypertension and uncontrolled hypertension (uHT) in paediatric and young adult KTRs are scarce. Also, it is unknown whether 'transition' (the transfer from paediatric to adult care) influences control of hypertension. We assessed the prevalence of hypertension and uHT among Dutch paediatric and young adult KTRs and analysed the effects of transition. Additionally, we made an inventory of variations in treatment policies in Dutch transplant centres. Cross-sectional and longitudinal national data from living KTRs a parts per thousand currency sign30 years of age (a parts per thousand yen1-year post-transplant, eGFR > 20 mL/min) were extracted from the 'RICH Q' database, which comprises information about all Dutch KTRs <19 years of age, and the Netherlands Organ Transplant Registry database for adult KTRs (a parts per thousand yen18-30 years of age). We used both upper-limit blood pressure (BP) thresholds for treatment according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. uHT was defined as a BP above the threshold. A questionnaire on treatment policies was sent to paediatric and adult nephrologists at eight Dutch transplant centres. Hypertension and uHT were more prevalent in young adult KTRs (86.4 and 75.8%) than in paediatric KTRs (62.7 and 38.3%) according to the KDIGO definition. Time after transplantation was comparable between these groups. Longitudinal analysis showed no evidence of effect of transition on systolic BP or prevalence of uHT. Policies vary considerably between and within centres on the definition of hypertension, BP measurement and antihypertensive treatment. Average BP in KTRs increases continuously with age between 6 and 30 years. Young adult KTRs have significantly more uHT than paediatric KTRs according to KDIGO guidelines. Transition does not influence the prevalence of uHT

Determinants of Outcome in Non-Septic Critically Ill Patients with Acute Kidney Injury on Continuous Venovenous Hemofiltration

Background/Aims: In view of ongoing controversy, we wished to study whether patient characteristics and/or continuous venovenous hemofiltration (CVVH) characteristics contribute to the outcome of non-septic critically ill patients with acute kidney injury (AKI). Methods: We retrospectively studied 102 consecutive patients in the intensive care unit (ICU) with non-septic AKI needing CVVH. Patient and CVVH characteristics were evaluated. Primary outcome was mortality up to day 28 after CVVH initiation. Results: Forty-four patients (43%) died during the 28-day period after the start of CVVH. In univariate analyses, non-survivors had more often a cardiovascular reason for ICU admission, greater disease acuity/severity and organ failure, lower initial creatinine levels, less use of heparin and more use of bicarbonate-based substitution fluid. The latter two can be attributed to high lactate levels and bleeding tendency in non-survivors necessitating withholding lactate-buffered fluid and heparin, respectively, according to our clinical protocol. In multivariate analyses, mortality was predicted by disease severity, use of bicarbonate-based fluids and lack of heparin, while initial creatinine and CVVH dose did not contribute. Conclusion: The outcome of non-septic AKI in need of CVVH is more likely to be determined by underlying or concurrent, acute and severe disease rather than by CVVH characteristics, including timing and dose

PIRCHE-II Is Related to Graft Failure after Kidney Transplantation

Individual HLA mismatches may differentially impact graft survival after kidney transplantation. Therefore, there is a need for a reliable tool to define permissible HLA mismatches in kidney transplantation. We previously demonstrated that donor-derived Predicted Indirectly ReCognizable HLA Epitopes presented by recipient HLA class II (PIRCHE-II) play a role in de novo donor-specific HLA antibodies formation after kidney transplantation. In the present Dutch multi-center study, we evaluated the possible association between PIRCHE-II and kidney graft failure in 2,918 donor–recipient couples that were transplanted between 1995 and 2005. For these donors–recipients couples, PIRCHE-II numbers were related to graft survival in univariate and multivariable analyses. Adjusted for confounders, the natural logarithm of PIRCHE-II was associated with a higher risk for graft failure [hazard ratio (HR): 1.13, 95% CI: 1.04–1.23, p = 0.003]. When analyzing a subgroup of patients who had their first transplantation, the HR of graft failure for ln(PIRCHE-II) was higher compared with the overall cohort (HR: 1.22, 95% CI: 1.10–1.34, p &lt; 0.001). PIRCHE-II demonstrated both early and late effects on graft failure in this subgroup. These data suggest that the PIRCHE-II may impact graft survival after kidney transplantation. Inclusion of PIRCHE-II in donor-selection criteria may eventually lead to an improved kidney graft survival