Inflammation, not hyperhomocysteinemia, is related to oxidative stress and hemostatic and endothelial dysfunction in uremia

Inflammation, not hyperhomocysteinemia, is related to oxidative stress and hemostatic and endothelial dysfunction in uremia.BackgroundSeveral cardiovascular risk factors are present in patients with chronic renal failure (CRF), among which are systemic inflammation and hyperhomocysteinemia. Increased oxidative stress, endothelial activation/dysfunction, and coagulation activation are considered integral components of the inflammatory response, but have also been proposed as mediators of plasma homocysteine (tHcy)-induced cell damage. Using correlation analysis, we assessed the relative contributions of inflammation and hyperhomocysteinemia in the abnormal oxidative stress, endothelial activation/dysfunction, and hemostasis activation in patients with CRF.MethodsThe relationships of inflammatory proteins and tHcy with plasma markers of these processes were studied in 64 patients with CRF (serum creatinine 526 ± 319 μmol/L) on conservative treatment, comparing the results with healthy controls (N = 15 to 40, depending on the measured variable) of similar sex and age.ResultsPatients had significant increases in inflammatory cytokines (TNF-α and IL-8) and acute-phase proteins (C-reactive protein, fibrinogen and α1-antitrypsin). tHcy was increased in 87.5% of patients (mean = 27.1 μmol/L, range 6.5 to 118). Patients had significant increases in (1) indices of oxidative stress: TBARS (thiobarbituric acid-reactive species), a marker of lipid peroxidation and AOPP (advanced oxidation protein products), a marker of protein oxidation; (2) endothelial cell markers such as von Willebrand factor (vWF:Ag), soluble ICAM-1 and soluble thrombomodulin (sTM); (3) markers of intravascular thrombin generation: thrombin-antithrombin complexes (TAT) and prothrombin fragment F1+2 (PF1+2); and (4) indices of activation of fibrinolysis: plasmin-antiplasmin complexes (PAP), fibrin degradation products (FnDP) and fibrinogen degradation products (FgDP). tHcy was significantly correlated with plasma creatinine (r = 0.29, P < 0.018) and with serum folate (r = -0.38, P < 0.002). However, no significant correlations were observed between tHcy and TBARS, AOPP, vWF:Ag, sICAM-1, sTM, TAT, F1+2, sTF, PAP, FnDP, and FgDP. Conversely, acute-phase proteins showed significant, positive correlations with most markers of oxidative stress, endothelial dysfunction and hemostatic activation.ConclusionsSystemic inflammation, which is closely associated with augmented oxidative stress, endothelial cell dysfunction and hemostatic activation, emerges as a major cardiovascular risk factor in CRF. tHcy is unrelated to these events. Thus, alternative mechanisms through which hyperhomocysteinemia could predispose to vascular lesion and thrombotic events in CRF needs to be investigated

Post-veraison sunlight exposure induces MYB-mediated transcriptional regulation of anthocyanin and flavonol synthesis in berry skins of Vitis vinifera

Anthocyanins, flavan-3-ols, and flavonols are the three major classes of flavonoid compounds found in grape berry tissues. Several viticultural practices increase flavonoid content in the fruit, but the underlying genetic mechanisms responsible for these changes have not been completely deciphered. The impact of post-veraison sunlight exposure on anthocyanin and flavonol accumulation in grape berry skin and its relation to the expression of different transcriptional regulators known to be involved in flavonoid synthesis was studied. Treatments consisting of removing or moving aside the basal leaves which shade berry clusters were applied. Shading did not affect sugar accumulation or gene expression of HEXOSE TRANSPORTER 1, although in the leaf removal treatment, these events were retarded during the first weeks of ripening. Flavonols were the most drastically reduced flavonoids following shading and leaf removal treatments, related to the reduced expression of FLAVONOL SYNTHASE 4 and its putative transcriptional regulator MYB12. Anthocyanin accumulation and the expression of CHS2, LDOX, OMT, UFGT, MYBA1, and MYB5a genes were also affected. Other regulatory genes were less affected or not affected at all by these treatments. Non-transcriptional control mechanisms for flavonoid synthesis are also suggested, especially during the initial stages of ripening. Although berries from the leaf removal treatment received more light than shaded fruits, malvidin-3-glucoside and total flavonol content was reduced compared with the treatment without leaf removal. This work reveals that flavonol-related gene expression responds rapidly to field changes in light levels, as shown by the treatment in which shaded fruits were exposed to light in the late stages of ripening. Taken together, this study establishes MYB-specific responsiveness for the effect of sun exposure and sugar transport on flavonoid synthesis

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Population pharmacokinetics and dose simulation of vancomycin in critically ill patients during high-volume haemofiltration

This study aimed to describe the population pharmacokinetics of vancomycin in critically ill patients with refractory septic shock undergoing continuous venovenous high-volume haemofiltration (HVHF) and to define appropriate dosing for these patients. This was a prospective pharmacokinetic study in the ICU of a university hospital. Eight blood samples were taken over one vancomycin dosing interval. Samples were analysed by a validated liquid chromatography-tandem mass spectrometry assay. Non-linear mixed-effects modelling was used to describe the population pharmacokinetics. Dosing simulations were used to define therapeutic vancomycin doses for different HVHF settings. Nine patients were included (five male). The mean weight and SOFA score were 70 kg and 11, respectively. Mean HVHF settings were: blood flow rate, 240 mL/min; and haemofiltration exchange rate, 100 mL/kg/h. A linear two-compartment model with zero-order input adequately described the data. Mean parameter estimates were: clearance, 2.9 L/h; volume of distribution of central compartment (V1), 11.8 L; volume of distribution of peripheral compartment (V2), 18.0 L; and intercompartmental clearance, 9.3 L/h. HVHF intensity was strongly associated with vancomycin clearance (P < 0.05) and was a covariate in the final model. Simulations indicate that after a loading dose, vancomycin doses required for different HVHF intensities would be 750 mg every 12 h (q12 h) for 69 mL/kg/h, 1000 mg q12 h for 100 mL/kg/h and 1500 mg q12 h for 123 mL/kg/h. Continuous infusion would also be a valuable administration strategy. In conclusion, variable and much higher than standard vancomycin doses are required to achieve therapeutic concentrations during different HVHF settings