Right ventricular and atrial strain in patients with advanced melanoma undergoing immune checkpoint inhibitor therapy.

AIMS: While immune checkpoint inhibitor (ICI) therapy significantly improves survival rates in advanced melanoma, ICI can evoke severe immune-related cardiovascular adverse events. Right ventricular (RV) dysfunction negatively impacts the outcomes in cardiovascular diseases and may be an early sign for overall cardiotoxicity. We aimed to assess RV function in melanoma patients undergoing ICI therapy using conventional echocardiographic and strain imaging techniques. METHODS AND RESULTS: We retrospectively examined 30 patients (40% women, age 59 ± 13 years) with advanced melanoma (stage III/IV) before and 4 weeks after the start of ICI therapy (follow-up at 39 ± 15 days); n = 15 of the patients received nivolumab, and n = 15 received the combination therapy nivolumab/ipilimumab. Two-dimensional echocardiography with assessment of RV longitudinal strain of the free wall (RV-LSFW) and assessment of right atrial (RA) strain from speckle tracking was performed at baseline and after the start of ICI therapy. Short-term ICI therapy caused a reduction of RV-LSFW (-25.5 ± 6.4% vs. -22.4 ± 4.3%, P = 0.002) and of RA strain during contraction phase (-10.6 ± 3.5% vs. -7.7 ± 3.1%, P = 0.001). Conventional parameters including tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), and pulmonary artery systolic pressure were not different between the two time points (TAPSE 26 ± 5 vs. 25 ± 5 mm, P = 0.125; FAC 38 ± 13% vs. 38 ± 14%, P = 0.750; and pulmonary artery systolic pressure 27 ± 10 vs. 25 ± 8 mmHg, P = 0.268). CONCLUSIONS: Analysis of RV and RA strain shows alterations even in a short-term follow-up, while changes in RV function are not visible by conventional RV parameters. Alterations in RV and RA strain could be early signs of cardiotoxicity and therefore should be assessed in patients undergoing ICI therapy.

ECG Scoring for the Evaluation of Therapy-Naïve Cancer Patients to Predict Cardiotoxicity.

OBJECTIVE: To evaluate a new electrocardiographic (ECG) score reflecting domains of electrical and structural alterations in therapy-naïve cancer patients to assess their risk of cardiotoxicity. METHODS: We performed a retrospective analysis of 134 therapy-naïve consecutive cancer patients in our two university hospitals concerning four ECG score parameters: Contiguous Q-waves, markers of left ventricular (LV) hypertrophy, QRS duration and JTc prolongation. Cardiotoxicity was assessed after a short-term follow-up (up to 12 months). RESULTS: Of all the patients (n = 25), 19% reached 0 points, 50% (n = 67) reached 1 point, 25% (n = 33) reached 2 points, 5% (n = 7) reached 3 points and 0.7% reached 4 or 5 points (n = 1 respectively). The incidence of cardiotoxicity (n = 28 [21%]) increased with the ECG score, with 0 points at 0%, 1 point 7.5%, 2 points 55%, 3 points 71% and ≥3 points 50%. In the ROC (Receiver operating curves) analysis, the best cut-off for predicting cardiotoxicity was an ECG score of ≥2 points (sensitivity 82%, specificity 82%, AUC 0.84, 95% CI 0.77-0.92, p < 0.0001) which was then defined as a high-risk score. High-risk patients did not differ concerning their age, LV ejection fraction, classical cardiovascular risk factors or cardiac biomarkers compared to those with a low-risk ECG score. CONCLUSION: ECG scoring prior to the start of anti-cancer therapies may help to identify therapy-naïve cancer patients at a higher risk for the development of cardiotoxicity.

Polymer-based spherical activated carbon - ultrafiltration (UF-PBSAC) for the adsorption of steroid hormones from water: Material characteristics and process configuration.

The European Union has proposed the value of 1 ng L-1 as a drinking water quality standard for estradiol. With conventional technologies only partially removing estradiol, the investigation of novel alternatives is more than ever required. Tagliavini and Schäfer proposed that the use of a thin activated carbon layer combined with a membrane is worth considering. In this work, the process was further advanced through a systematic investigation of the role of activated carbon size, activation and surface chemistry on the removal of estradiol. The use of smaller carbon particles allows reaching the ambitious target value of 1 ng L-1 in a millimetric layer. Further, adsorption kinetic enhancement by increasing the oxygen content on the carbon improves the removal from 96 to 99 % (for a layer of 2 mm) for OH-containing pollutants such as estradiol. High removal, together with low pressure and no by-product formation, are characteristics that make the UF-PBSAC a promising and competitive approach.

ECG Changes in Melanoma Patients Undergoing Cancer Therapy-Data From the ECoR Registry.

We aimed to evaluate whether therapy with immune checkpoint inhibitors (ICI) leads to changes in electrocardiogram (ECG) parameters in melanoma patients. We retrospectively examined 41 patients (46% women, age 61 ± 12years) with advanced melanoma (stage III/IV) before and during ICI treatment from our "Essen Cardio-oncology Registry" (ECoR). ECGs were analyzed before and 4-12 weeks after therapy started (follow-up, 90 ± 51 days). Heart rate, PR time, QRS duration and duration of the corrected QT (QTc) interval were recorded. QT dispersion (QTd) was calculated. Heart rate, PR time, QRS and QTc did not differ when comparing values before and after therapy started. QTd was prolonged after therapy started (32 ± 16 ms vs. 47 ± 19 ms, n = 41, p < 0.0001). Subgroup analyses revealed prolonged QTd in patients that received a combination immunotherapy with ipilimumab and nivolumab (31 ± 14 ms vs. 50 ± 14 ms, n = 21, p < 0.0001), while QTd in patients with anti-programmed death 1 (PD-1) inhibitor monotherapy did not change after therapy started. QTd is prolonged in patients under ICI combination therapy, potentially signaling an increased susceptibility to ventricular arrhythmias.

Troponins and Natriuretic Peptides in Cardio-Oncology Patients-Data From the ECoR Registry.

BACKGROUND: The long-term survival of cancer patients has significantly improved over the past years. Despite their therapeutic efficacy, various cancer therapies are associated with cardiotoxicity. Therefore, timely detection of cardiotoxic adverse events is crucial. However, the clinical assessment of myocardial damage caused by cancer therapy remains difficult. METHODS: This retrospective study was performed to evaluate the diagnostic value of cardiac troponin I (cTnI) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) for monitoring cancer therapy-induced cardiomyopathy. A total of 485 cancer patients referred to our cardio-oncology unit between July 2018 and January 2020 were selected from our Essen Cardio-oncology Registry (ECoR). We included patients with all types of cancer. Plasma concentrations of cTnI and NT-proBNP were measured by radioimmunoassay, and two-dimensional left ventricular ejection fraction (2D-LVEF), diastolic function, and global longitudinal strain (GLS) were measured by transthoracic echocardiography. In 116 patients, assessment was conducted before the induction of cancer therapy and during a short-term follow-up period; n = 42 of these were treated for malignant melanoma, and n = 42 with serial measurements were under treatment for breast cancer. RESULTS: In cross-sectional data, elevated NT-proBNP was associated with reduced LVEF and pathological GLS in the total cohort. A total of 116 patients had serial LVEF and biomarker measurements, and changes in NT-proBNP and troponin correlated with changes in LVEF during follow-up investigations. Similar to the total cohort, a subgroup of patients treated for malignant melanoma showed a correlation between the change in cTnI and the change in LVEF. In a subgroup analysis of patients undergoing breast cancer therapy, a correlation between the change in NT-proBNP and the change in LVEF could be detected. Thirty patients presented with chemotherapy-induced cardiomyopathy, defined as a significant LVEF decrease (> 10%) to a value below 50%. The number of patients with increased cTnI and NT-proBNP was significantly higher in patients with chemotherapy-induced cardiomyopathy than in patients without cardiotoxicity. Patients with positive cTnI and NT-proBNP were more likely to have a history of coronary heart disease, atrial fibrillation, and arterial hypertension. CONCLUSION: Our data suggest that cardiac biomarkers play an important role in the detection of cancer therapy-induced cardiotoxicity. Larger systematic assessment in prospective cohorts is mandatory.

Circulating macrophage migration inhibitory factor (MIF) in patients with heart failure.

BACKGROUND: Heart failure (HF) is characterized by impaired systolic ejection capacity and/or diastolic filling of the heart, leading to a multisystem disorder. Remote organ failure, systemic inflammation or pulmonary hypertension (PH) are hallmarks of the pathophysiological changes in HF. The Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is involved in a variety of cardiovascular and inflammatory diseases. Circulating MIF levels and their potential role as a disease marker in the different subgroups of HF have not been investigated yet. We here aimed to unravel a potential role of MIF in HF. METHODS AND RESULTS: MIF plasma levels were assessed in 249 consecutive patients with HF. MIF was detectable in all investigated subjects and showed no difference with regard to the nature of HF (preserved or reduced ejection fraction). Spearman correlation revealed an association with inflammatory biomarkers (white blood cell count r = 0.18, p = 0.005; c-reactive protein r = 0.20, p = 0.003). MIF was associated with higher pulmonary artery systolic pressure (PASP) as assessed by echocardiography (r = 0.23, p < 0.001). Log-transformed PASP was also independently associated with MIF in a multivariable linear regression model (p = 0.02). Follow-up (FU) data after 180 days revealed that patients with increased MIF values (in ng/ml) were more likely to reach the endpoint all-cause mortality (HR 1.01, 95% CI 1.004-1.02, p = 0.005, per unit change). CONCLUSION: MIF is detectable in the circulation of patients with HF and might be associated with clinical endpoints in HF, markers of inflammation and PH. These promising results should stimulate further research to elucidate the role of MIF in the multisystem disorder of HF.

Predictive potential of macrophage migration inhibitory factor (MIF) in patients with heart failure with preserved ejection fraction (HFpEF).

BACKGROUND: Prognostication in heart failure with preserved ejection fraction (HFpEF) is challenging and novel biomarkers are urgently needed. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that plays a crucial role in cardiovascular and various inflammatory diseases. Whether MIF is involved in HFpEF is unknown. METHODS AND RESULTS: Sixty-two patients with HFpEF were enrolled and followed up for 180 days. MIF plasma levels as well as natriuretic peptide (NP) levels were assessed. High MIF levels significantly predicted the combined end-point of all-cause death or hospitalization at 180 days in the univariate analysis (HR 2.41, 95% CI 1.12-5.19, p = 0.025) and after adjustment for relevant covariates in a Cox proportional hazard regression model (HR 2.35, 95% CI 1.05-5.27, p = 0.0374). Furthermore, MIF levels above the median were associated with higher pulmonary artery systolic pressure (PASP) as assessed by echocardiography (PASP 31 mmHg vs 48 mmHg in the low- and high-MIF group, respectively, p = 0.017). NPs significantly correlated with MIF in HFpEF patients (BNP p = 0.011; r = 0.32; NT-proBNP p = 0.027; r = 0.28). CONCLUSION: MIF was associated with clinical outcomes and might be involved in the pathophysiology of pulmonary hypertension in patients with HFpEF. These first data on MIF in HFpEF should stimulate further research to elucidate the role of this cytokine in heart failure. Trial registration NCT03232671.

Colonization With Multiresistant Bacteria: Impact on Ventricular Assist Device Patients.

BACKGROUND: Although the effect of infections with multidrug-resistant bacteria (MDRB) in left ventricular assist device (LVAD) recipients is well characterized, the influence of perioperative colonization on the development of infections in this patient cohort remains unknown. The study evaluated the effect of MDRB colonization on patient outcomes after LVAD implantation. METHODS: We retrospectively analyzed the microbiological screening studies of nasal, throat, wound, and rectal swabs in 82 consecutive patients who received an LVAD at our center between 2010 and 2015. Four categories of MDRB were determined: methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and Gram-negative bacterium resistant to three or four of four predefined pharmacologic categories of antibiotics. We also compared the long-term outcome of patients with and without colonization. RESULTS: There were 28 patients (34.1%) diagnosed as being colonized with at least 1 species of an MDRB. MDRB colonization was associated with the occurrence of fatal infections from any pathogen (MDRB positive, 63.2%; MDRB negative, 34.4%; p = 0.04) and fatal MDRB-specific infections (MDRB positive, 31.6%; MDRB negative, 6.3%; p = 0.04), significantly longer intensive care unit stay (p < 0.0001), and longer cumulative hospital stay (p = 0.04). CONCLUSIONS: Our study demonstrates that the colonization with MDRB is a highly prevalent risk factor for infection-associated death in the vulnerable LVAD population. Routine screening for MDRB before and after LVAD implantation should be considered to identify high-risk individuals and facilitate effective prevention of infectious complications.

Myocardial Expression of Macrophage Migration Inhibitory Factor in Patients with Heart Failure.

Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory protein and contributes to several different inflammatory and ischemic/hypoxic diseases. MIF was shown to be cardioprotective in experimental myocardial ischemia/reperfusion injury and its expression is regulated by the transcription factor hypoxia-inducible factor (HIF)-1α. We here report on MIF expression in the failing human heart and assess myocardial MIF in different types of cardiomyopathy. Myocardial tissue samples from n = 30 patients were analyzed by quantitative Real-Time PCR. MIF and HIF-1α mRNA expression was analyzed in myocardial samples from patients with ischemic (ICM) and non-ischemic cardiomyopathy (NICM) and from patients after heart transplantation (HTX). MIF expression was elevated in myocardial samples from patients with ICM compared to NICM. Transplanted hearts showed lower MIF levels compared to hearts from patients with ICM. Expression of HIF-1α was analyzed and was shown to be significantly increased in ICM patients compared to patients with NICM. MIF and HIF-1α mRNA is expressed in the human heart. MIF and HIF-1α expression depends on the underlying type of cardiomyopathy. Patients with ICM show increased myocardial MIF and HIF-1α expression.

Elevated MIF-2 levels predict mortality in critically ill patients.

PURPOSE: D-dopachrome tautomerase (MIF-2 or DDT) is a member of the macrophage migration inhibitory factor (MIF) superfamily and a close structural homolog to MIF. Circulating MIF-2 has been described to be elevated in patients suffering from sepsis, severe burn injury and after surgery. We sought to evaluate the prognostic value of MIF-2 in critically ill patients. METHODS: A total of 72 patients were studied upon admission to the medical intensive care unit (ICU). MIF and MIF-2 levels were assessed and compared to healthy controls. Clinical data, various laboratory parameters and mortality were assessed. RESULTS: We found significantly elevated levels of MIF-2 and MIF at admission to the ICU in critically ill patients compared to healthy controls. MIF-2 levels were associated with disease severity as measured by APACHE II scores. MIF-2 levels in ICU patients correlated with biomarkers reflecting organ damage, but were not influenced by acute or chronic kidney disease. Kaplan-Meier analysis revealed distinctly elevated mortality in patients with high plasma MIF-2 levels. CONCLUSIONS: MIF-2 levels are elevated in critically ill patients and linked to parameters of organ damage, supporting its value as a potential tool for the assessment of prognosis in critical illness.

Deep sedation Vs. general anesthesia in 232 patients undergoing percutaneous mitral valve repair using the MitraClip® system.

OBJECTIVES: To investigate in a series of 232 patients whether the MitraClip® procedure can be performed safely using deep sedation (DS) without general anesthesia (GA). BACKGROUND: Transcatheter mitral valve repair using the MitraClip® system is a safe and effective therapy for severe mitral regurgitation (MR) in patients who are at high operative risk or are unsuitable for surgery. For these patients, avoidance of GA might be beneficial. METHODS: Between 2011 and 2015, we performed 232 MitraClip® procedures for the treatment of severe MR. Of those, 76 procedures were performed using GA, while the remaining 156 procedures were performed using DS. RESULTS: Age, logistic EuroScore, severity of MR, left and right ventricular function, and renal function did not differ between the groups. The primary combined safety endpoint, which was defined as the occurrence of major adverse cardiac and cerebrovascular events, conversion to surgery, major vascular complications or pneumonia, did not differ between MitraClip® procedures performed using GA and MitraClip® procedures performed using DS. Intraprocedural conversion to GA was required in 2% of the patients in the DS group. There were no differences in procedural success or clinical outcome between the groups at the 3-month follow-up. Preparation time in the catheterization laboratory and intensive care unit (ICU) stay were shorter in the DS group compared to the GA group. CONCLUSION: The MitraClip® implantation performed using DS is as safe and effective as MitraClip® implantation performed using GA. © 2017 Wiley Periodicals, Inc.

MitraClip® Implantation Under Cerebral Protection: A Case Report.

MitraClip® implantation is commonly used in patients with severe mitral regurgitation (MR) and who are at high risk for surgical mitral valve repair. The occurrence of stroke or transient ischemic attack is a potential complication in patients undergoing MitraClip implantation, and incidences of up to 2.6% have been reported. Herein is reported the case of an 84-year-old woman with severe MR and a thin filamentous structure at the rim of the left atrial appendage of unknown etiology. Due to a high surgical risk, the heart team decided to perform endovascular mitral valve repair using the MitraClip procedure. In order to prevent stroke, the implantation procedure was performed using a cerebral protection system.

Renal replacement therapy neutralizes elevated MIF levels in septic shock.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is known to amplify the immune response in septic animal models. Few clinical data support this pro-inflammatory role in septic patients. Renal replacement therapy (RRT) as adjuvants in the complex therapy of sepsis has been proposed as a possible approach to eliminate elevated circulating cytokines. Since recent data suggest that MIF can be effectively removed from the circulating blood pool in patients with chronic kidney disease, we here aimed to investigate whether RRT in septic shock can lower plasma levels of this pro-inflammatory cytokine in septic shock patients. METHODS: An observational single-center study on an internist intensive care unit (ICU) was conducted. MIF plasma levels and mortality of n = 25 patients with septic shock were assessed with a previously validated method for reliable MIF values. The effect of continuous renal replacement therapy (CRRT) on daily MIF levels and mortality was assessed by comparing patients with and without need for CRRT due to acute kidney injury (AKI). RESULTS: MIF plasma levels in patients undergoing CRRT due to septic AKI were steadily decreased compared to those from patients without CRRT hinting at a MIF removal by hemodialysis. MIF release during ICU stay as assessed by MIFAUC was lower in patients undergoing CRRT, and Kaplan-Meier analysis revealed a distinctly lower mortality in patients undergoing CRRT. Analysis of daily MIF levels showed that patients who did not survive septic shock exhibited steadily higher MIF plasma levels and higher MIFAUC compared to those surviving sepsis. Low MIF levels were closely associated with improved survival. CONCLUSIONS: This is the first study investigating the effect of efficient MIF removal from the plasma pool of patients with septic shock. Reduction of high circulating MIF by CRRT therapy was accompanied by improved survival. Thus, targeted removal of MIF from the circulating blood pool might be a promising approach to reduce mortality in severe sepsis.

Impact of dietary nitrate on age-related diastolic dysfunction.

AIMS: Diastolic dysfunction is highly prevalent, and ageing is the main contributor due to impairments in active cardiac relaxation, ventriculo-vascular stiffening, and endothelial dysfunction. Nitric oxide (NO) affects cardiovascular functions, and NO bioavailability is critically reduced with ageing. Whether replenishment of NO deficiency with dietary inorganic nitrate would offer a novel approach to reverse age-related cardiovascular alterations was not known. METHODS AND RESULTS: A dietary nitrate supplementation was applied to young (6 month) and old (20 month) wild-type mice for 8 weeks and compared with controls. High-resolution ultrasound, pressure-volume catheter techniques, and isolated heart measurements were applied to assess cardiac diastolic and vascular functions. Cardiac manganese-enhanced magnetic resonance imaging was performed to study the effects of dietary nitrate on myocyte calcium handling. In aged mice with preserved systolic function, dietary nitrate supplementation improved LV diastolic function, arterial compliance, and coronary flow reserve. Mechanistically, improved cardiovascular functions were associated with an accelerated cardiomyocyte calcium handling and augmented NO/cyclic guanosine monophosphate/protein kinase G signalling, while enhanced nitrate reduction was related to age-related differences in the oral microbiome. CONCLUSION: Dietary inorganic nitrate reverses age-related LV diastolic dysfunction and improves vascular functions. Our results highlight the potential of a dietary approach in the therapy of age-related cardiovascular alterations.

MIF reflects tissue damage rather than inflammation in post-cardiac arrest syndrome in a real life cohort.

INTRODUCTION: Following successful resuscitation from cardiac arrest (CA), neurological impairment and other types of organ dysfunction cause significant morbidity and mortality-a condition termed post-cardiac arrest syndrome. Whole-body ischemia/reperfusion with oxygen debt activates immunologic and coagulation pathways increasing the risk of multiple organ failure and infection. We here examined the role of the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) in post-cardiac arrest syndrome. METHODS: MIF plasma levels of n=16 patients with return of spontaneous circulation (ROSC) after CA were assessed with a previously validated method and compared to markers of systemic inflammation and cellular damage. ICU patients without former CA and healthy volunteers served as controls. RESULTS: MIF levels in patients after ROSC were higher compared to those in healthy volunteers and ICU patients without CA. Kaplan-Meyer analysis revealed a distinctly elevated mortality since day one that further increased towards an elevated 60-days-mortality in patients with high plasma MIF. ROC curve identified plasma MIF as a predictor for mortality in patients after CA. Correlation with inflammatory parameters revealed that high MIF levels did not mirror post CA inflammatory syndrome, but distinctive cellular damage after ROSC as there were strong correlations with markers of cellular damage like LDH and GOT/GPT. CONCLUSION: High MIF levels were associated with elevated 60-days-mortality and high MIF predicted mortality after CA. We found a close relation between circulating MIF levels and cellular damage, but not with an inflammatory syndrome.

Targeted intracellular accumulation of macrophage migration inhibitory factor in the reperfused heart mediates cardioprotection.

S-nitrosation of macrophage migration inhibitory factor (MIF) has been shown to be cytoprotective in myocardial ischaemia/reperfusion (I/R) injury. Since the exact mechanism of action is unknown, we here characterise the cardioprotective effects of targeted intracellular accumulation of MIF in myocardial I/R injury. We used different in vivo, ex vivo and in vitro models of myocardial I/R and hypoxia/reoxygenation (H/R) injury to determine MIF levels by immunoblots and ELISA in different phases of reperfusion and reoxygenation, respectively. We discovered a rapid decrease of cardiac MIF that was specific to the early phase of reperfusion. Posttranslational modification of MIF via S-nitrosation--proofed by a modified version of the Biotin Switch Assay--prevented this rapid decrease, leading to a targeted intracellular accumulation of MIF in the early phase of reperfusion. Intracellular MIF accumulation preserved the intracellular ability of MIF to reduce oxidative stress as shown by hydrogen peroxide and aconitase activity measurements. Infarct size measurements by TTC staining showed an overall enhanced cardioprotective effect of this protein by reduction of reperfusion injury. In summary, we have unravelled a novel mechanism of MIF-mediated cardioprotection. Targeted intracellular accumulation of MIF by S-nitrosation may offer a novel therapeutic approach in the treatment of myocardial I/R-injury.

Filtration of Macrophage Migration Inhibitory Factor (MIF) in Patients with End Stage Renal Disease Undergoing Hemodialysis.

BACKGROUND: End stage renal disease (ESRD) patients are characterized by increased morbidity and mortality due to highest prevalence of cardiovascular disease. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that controls cellular signaling in human physiology, pathophysiology, and diseases. Increased MIF plasma levels promote vascular inflammation and development of atherosclerosis. We have shown that MIF is associated with vascular dysfunction in ESRD patients. Whether hemodialysis (HD) affects circulating MIF plasma levels is unknown. We here aimed to investigate whether HD influences the circulating MIF pool in ESRD patients. METHODS AND RESULTS: An observational single-center study was conducted. MIF plasma levels in ESRD patients were assessed before, during, and after a HD session (n = 29). Healthy age-matched volunteers served as controls to compare correlations of MIF plasma levels with inflammatory plasma components (n = 20). MIF removed from the circulating blood pool could be detected in the dialysate and allowed for calculation of totally removed MIF (MIF content in dialysate 219±4 µg/HD-session). MIF plasma levels were markedly decreased 2 hour after initiation of HD (MIF plasma level pre-HD 84.8±6 ng/ml to intra-HD 61.2±5 ng/ml p<0.001) and were replenished already 20 min after termination of HD to basal levels (intra-HD 61.2±5 ng/ml to post-HD 79.8±5 ng/ml, p<0.001). CONCLUSION: MIF is a dialyzable plasma component that is effectively filtrated during HD from the patient blood pool in large amounts. After removal of remarkable amounts of MIF during a single HD session, MIF plasma pool is early reconstituted after termination of HD from unknown sources.

How to dose powdered activated carbon in deep bed filtration for efficient micropollutant removal.

Direct addition of powdered activated carbon (PAC) to the inlet of a deep bed filter represents an energy- and space-saving option to remove organic micropollutants (OMPs) during advanced wastewater treatment or drinking water purification. In this lab-scale study, continuous dosing, preconditioning a filter with PAC and combinations thereof were investigated as possible dosing modes with respect to OMP adsorption efficiency. Continuous dosing resulted in decreasing effluent concentrations with increasing filter runtime due to adsorption onto accumulating PAC in the filter bed. Approximately constant removal levels were achieved at longer filter runtimes, which were mainly determined by the dose of fresh PAC, rather than the total PAC amount embedded. The highest effluent concentrations were observed during the initial filtration stage. Meanwhile, preconditioning led to complete OMP adsorption at the beginning of filtration and subsequent gradual OMP breakthrough. PAC distribution in the pumice filter was determined by the loss on ignition of PAC and pumice and was shown to be relevant for adsorption efficiency. Preconditioning with turbulent upflow led to a homogenous PAC distribution and improved OMP adsorption significantly. Combining partial preconditioning and continuous dosing led to low initial effluent concentrations, but ultimately achieved concentrations similar to filter runs without preconditioning. Furthermore, a dosing stop prior to the end of filtration was suitable to increase PAC efficiency without affecting overall OMP removals.

Modulation of circulating macrophage migration inhibitory factor in the elderly.

Aging increases the risk for cardiovascular morbidity and mortality. Chronic low-grade inflammation deteriorates vascular function, increases age-related vascular stiffness, and affects hemodynamics. The proinflammatory cytokine macrophage migration inhibitory factor (MIF) is a major mediator of atherosclerosis. Plasma MIF levels are associated with arterial stiffness, a hallmark of vascular aging. Preclinical studies show that blockade of MIF leads to atherosclerotic plaque regression. Nutritional approaches provide opportunities to counteract age-related inflammation. Following a chronic dietary supplementation with the micronutrient nitrate has been demonstrated to improve vascular stiffness. Whether dietary nitrate affects circulating MIF levels is not known. In a randomized placebo-controlled, double-blinded study, elderly subjects received a dietary nitrate supplementation for 4 weeks. Dietary nitrate led to a decrease in plasma MIF levels in the elderly and to an improvement in vascular functions. This was associated with a reduction in central systolic blood pressure. Our data show that supplementation with dietary nitrate is associated with a reduction of circulating MIF levels along with an improvement in vascular function. This supports the concept of dietary approaches to modulate age-related changes of vascular functions.

Age-related vascular gene expression profiling in mice.

Increasing age involves a number of detrimental changes in the cardiovascular system and particularly on the large arteries. It deteriorates vascular integrity and leads to increased vascular stiffness entailing hypertension with increased cardiovascular morbidity and mortality. The consequences of continuous oxidative stress and damages to biomolecules include altered gene expression, genomic instability, mutations, loss of cell division and cellular responses to increased stress. Many studies have been performed in aged C57BL/6 mice; however, analyses of the age-related changes that occur at a gene expression level and transcriptional profile in vascular tissue have not been elucidated in depth. To determine the changes of the vascular transcriptome, we conducted gene expression microarray experiments on aortas of adult and old mice, in which age-related vascular dysfunction was confirmed by increased stiffness and associated systolic hypertension. Our results highlight differentially expressed genes overrepresented in Gene Ontology categories. Molecular interaction and reaction pathways involved in vascular functions and disease, within the transforming growth factor-beta (TGF-ß) pathway, the renin-angiotensin system and the detoxification systems are displayed. Our results provide insight to an altered gene expression profile related to age, thus offering useful clues to counteract or prevent vascular aging and its detrimental consequences.