Systemic sclerosis (SSc) features autoimmunity, vasculopathy and tissue fibrosis. The renin-angiotensin and endothelin systems have been implicated in vasculopathy and fibrosis. A role for ...autoantibody-mediated receptor stimulation is hypothesised, linking three major pathophysiological features consistent with SSc.
Serum samples from 478 patients with SSc (298 in the study cohort and 180 from two further independent cohorts), 372 healthy subjects and 311 control-disease subjects were tested for antibodies against angiotensin II type 1 receptor (AT(1)R) and endothelin-1 type A receptor (ET(A)R) by solid phase assay. Binding specificities were tested by immunoprecipitation. The biological effects of autoantibodies in microvascular endothelial cells in vitro were also determined, as well as the quantitative differences in autoantibody levels on specific organ involvements and their predictive value for SSc-related mortality.
Anti-AT(1)R and anti-ET(A)R autoantibodies were detected in most patients with SSc. Autoantibodies specifically bound to respective receptors on endothelial cells. Higher levels of both autoantibodies were associated with more severe disease manifestations and predicted SSc-related mortality. Both autoantibodies exert biological effects as they induced extracellular signal-regulated kinase 1/2 phosphorylation and increased transforming growth factor β gene expression in endothelial cells which could be blocked with specific receptor antagonists.
Functional autoimmunity directed at AT(1)R and ET(A)R is common in patients with SSc. AT(1)R and ET(A)R autoantibodies could contribute to disease pathogenesis and may serve as biomarkers for risk assessment of disease progression.
Hypomagnesemia affects insulin resistance and is a risk factor for diabetes mellitus type 2 (DM2) and gestational diabetes mellitus (GDM). Two single nucleotide polymorphisms (SNPs) in the epithelial ...magnesium channel TRPM6 (V ¹³⁹³I, K ¹⁵⁸⁴E) were predicted to confer susceptibility for DM2. Here, we show using patch clamp analysis and total internal reflection fluorescence microscopy, that insulin stimulates TRPM6 activity via a phosphoinositide 3-kinase and Rac1-mediated elevation of cell surface expression of TRPM6. Interestingly, insulin failed to activate the genetic variants TRPM6(V ¹³⁹³I) and TRPM6(K ¹⁵⁸⁴E), which is likely due to the inability of the insulin signaling pathway to phosphorylate TRPM6(T ¹³⁹¹) and TRPM6(S ¹⁵⁸³). Moreover, by measuring total glycosylated hemoglobin (TGH) in 997 pregnant women as a measure of glucose control, we demonstrate that TRPM6(V ¹³⁹³I) and TRPM6(K ¹⁵⁸⁴E) are associated with higher TGH and confer a higher likelihood of developing GDM. The impaired response of TRPM6(V ¹³⁹³I) and TRPM6(K ¹⁵⁸⁴E) to insulin represents a unique molecular pathway leading to GDM where the defect is located in TRPM6.
Background
Sclerostin is a hormone contributing to the bone-vascular wall cross talk and has been implicated in cardiovascular events and mortality in patients with chronic kidney disease (CKD). We ...analyzed the relationship between sclerostin and mortality in renal transplant recipients.
Methods
600 stable renal transplant recipients (367men, 233 women) were followed for all-cause mortality for 3 years. Blood and urine samples for analysis and clinical data were collected at study entry. We performed Kaplan–Meier survival analysis and Cox regression models considering confounding factors such as age, eGFR, cold ischemia time, HbA1c, phosphate, calcium, and albumin. Optimal cut-off values for the Cox regression model were calculated based on ROC analysis.
Results
Sixty-five patients died during the observation period. Nonsurvivors (
n
= 65; sclerostin 57.31 ± 30.28 pmol/L) had higher plasma sclerostin levels than survivors (
n
= 535; sclerostin 47.52 ± 24.87 pmol/L) (
p
= 0.0036). Kaplan–Meier curve showed that baseline plasma sclerostin concentrations were associated with all-cause mortality in stable kidney transplant recipients (
p
= 0.0085, log-rank test). After multiple Cox regression analysis, plasma levels of sclerostin remained an independent predictor of all-cause mortality (hazard ratio, 1.011; 95% CI 1.002–1.020;
p
= 0.0137).
Conclusions
Baseline plasma sclerostin is an independent risk factor for all-cause mortality in patients after kidney transplantation.
Continuous renal replacement therapy is a standard treatment in critically ill patients with acute kidney injury. All CRRT techniques provide a high low‐molecular weight clearance but even with ...hemofiltration, clearance of middle molecules is low. We investigated whether a new super high‐flux hemofilter provides effective and sustained middle molecule clearance during citrate‐anticoagulated continuous venovenous hemodialysis for up to 72 h. We included 14 critically ill patients with AKI‐KDIGO‐III in a prospective observational trial. We measured/calculated blood and urine concentrations, clearances and sieving coefficients of eight molecules with molecular weights from 60 to 66 kDa, hemodynamic parameters and SAPS‐II scores. All filters were patent at 72 h. Clearance and sieving coefficients of small solutes were high and sustained over time, those for larger solutes decreased over 72 h but remained high enough to decrease blood concentrations of solutes up to 25 kDa. Albumin serum levels remained unaffected. Catecholamine doses and SAPS‐II scores decreased significantly. This new hemofilter may improve blood purification in critically ill patients with AKI.
Oxidation of PTH at methionine residues results in loss of biological activity. PTH may be oxidized in patients with renal disease. The aim of this study was to develop an assay considering oxidation ...of PTH. Oxidized hPTH was analyzed by high resolution nano-liquid chromatography coupled to ESI-FTT tandem mass spectrometry (nanoLC-ESI-FT-MS/MS) directly and after proteolytic cleavage. The oxidized hPTH(1-84) sample shows TIC-peaks at 18-20 min and several mass peaks due to mass shifts caused by oxidations. No significant signal for oxidized hPTH(1-84) species after removal of oxidized PTH molecules by a specific column with monoclonal antibodies (MAB) raised against the oxidized hPTH was detectable. By using this column in samples from 18 patients on dialysis we could demonstrate that measured PTH concentrations were substantially lower when considering oxidized forms of PTH. The relationship between PTH concentrations determined directly and those concentrations measured after removal of the oxidized PTH forms varies substantially. In some patients only 7% of traditionally measured PTH was free of oxidation, whereas in other patients 34% of the traditionally measured PTH was real intact PTH. In conclusion, a huge but not constant proportion of PTH molecules are oxidized in patients requiring dialysis. Since oxidized PTH is biologically inactive, the currently used methods to detect PTH in daily clinical practice may not adequately reflect PTH-related bone and cardiovascular abnormalities in patients on dialysis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Approximately 8 - 10 % of COVID-19 patients present with a serious clinical course and need for hospitalization, 8% of hospitalized patients need ICU-treatment. Currently, no causal therapy is ...available and treatment is purely supportive. The main reason for death in critically ill patients is acute respiratory failure. However, in a number of patients a severe hyperinflammatory response with excessively elevated proinflammatory cytokines causes vasoplegic shock resistant to vasopressor therapy. A new polystyrene-based hemoadsorber (CytoSorb®, Cytosorbents Inc., New Jersey, USA) has been shown to adsorb effectively cytokines and other middle molecular weight toxins this way reducing their blood concentrations. This has been routinely used in clinical practice in the EU for other conditions where a cytokine storm occurs and an observational study has just been completed on COVID-19 patients. We hypothesized that the extracorporeal elimination of cytokines in critically ill COVID-19 patients with suspected hyperinflammation and shock may stabilize hemodynamics and improve outcome. The primary endpoint is time until resolution of vasoplegic shock, which is a well implemented, clinically relevant endpoint in critical care studies.
Phase IIb, multicenter, prospective, open-label, randomized, 1:1 parallel group pilot study comparing the additional use of "CytoSorb" to standard of care without "CytoSorb".
Patients are recruited from the Intensive Care Units (ICUs) of 7 participating centers in Germany (approximately 10 ICUs). All patients aged 18- 80 with positive polymerase chain reaction (PCR) test for SARS-CoV-2, a C-reactive protein (CRP) ≥ 100 mg/l, a Procalcitonin (PCT) < 2 ng/l, and suspected cytokine storm defined via a vasoplegic shock (Norepinephrine > 0.2 μg/min/kg to achieve a Mean Arterial Pressure ≥ 65mmHg). Patients are included irrespective of indication for renal replacement therapy. Suspected or proven bacterial cause for vasoplegic shock is a contraindication.
Within 24 hours after meeting the inclusion criteria patients will be randomized to receive either standard of care or standard of care and additional "CytoSorb" therapy via a shaldon catheter for 3-7 days. Filter exchange is done every 24 hours. If patients receive antibiotics, an additional dose of antibiotics is administered after each change of "CytoSorb" filter in order to prevent underdosing due to "CytoSorb" treatment.
Primary outcome is time to resolution of vasoplegic shock (defined as no need for vasopressors for at least 8 hours in order to sustain a MAP ≥ 65mmHg) in days. Secondary outcomes are 7 day mortality after fulfilling the inclusion criteria, mortality until hospital discharge, Interleukin-6 (IL-6) measurement on day 1 and 3, need for mechanical ventilation, duration of mechanical ventilation, duration of ICU-stay, catecholamine dose on day 1/2/3 after start of "CytoSorb" and acute kidney injury.
An electronic randomization will be performed using the study software secuTrial® administered by the Clinical Study Center (CSC) of the Charité - Universitätsmedizin Berlin, Germany. Randomization is done in blocks by 4 stratified by including center.
The trial will be non-blinded for the clinicians and patients. The statistician will receive a blinded data set, so that all analyses will be conducted blinded.
As this is a pilot study with the goal to examine the feasibility of the study design as well as the intervention effect, no formal sample size calculation was conducted. A total number of approximately 80-100 patients is planned (40-50 patients per group). Safety assessment is done after the inclusion of each 10 patients per randomization group.
Please see the study protocol version from April 24 2020. Recruitment of patients is still pending.
The study was registered on April 27 2020 in the German Registry of Clinical Trials (DRKS) under the number DRKS00021447.
The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
Objective To compare maternal characteristics and obstetric outcomes of spontaneously conceived (SC) and after–fertility treatment (FT) twins. Design Retrospective study. Setting Single tertiary ...center (university hospital). Patient(s) All twin pregnancies (n = 1,239) delivered ≥24 weeks of gestation and classified by the mode of conception. Intervention(s) None. Main Outcome Measure(s) Maternal age, prematurity, preterm rupture of membranes (PROM), delivery mode, cervical insufficiency, preeclampsia/HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome, gestational diabetes, and postpartum hemorrhage. Result(s) Of 1,239 mothers evaluated, 34.4% received FT. We observed a continuous 3.2-year mean increase in maternal age over time in the FT population. The FT group had statistically significantly higher rates of women ≥35 years of age versus the SC group (37.6% vs. 22.9%). Mean maternal age (32.5 vs. 30.1 years) and the rates of cesarean delivery (72.3% vs. 63.9%), dichorionic twin prematurity (67.7% vs. 59.6%), postpartum hemorrhage (9.9% vs. 6%), PROM (2.3% vs. 0.6%), and cervical insufficiency (17.6% vs. 10%) were statistically significantly higher in the FT group. Preeclampsia/HELLP syndrome and gestational diabetes showed no significantly significant difference. Conclusion(s) Mothers of twins after FT were statistically significantly older and had higher rates of prematurity, cesarean delivery, and obstetric morbidity.
Abstract Background Systemic citrate accumulation is a complication of regional citrate anticoagulation (RCA) during continuous renal replacement therapy (CRRT). Our objective was to determine the ...incidence of clinical signs consistent with citrate accumulation in a large and representative cohort of intensive care unit patients undergoing RCA-CRRT. Methods Patients treated with RCA-CRRT during 2008-2010 were retrospectively analyzed. Decreased systemic ionized calcium (iCa), increased demand for calcium substitution, elevated total calcium to iCa ratio, and metabolic acidosis were evaluated as indicators for citrate accumulation. Results In the 3-year period, 1070 patients were treated with RCA–continuous venovenous hemodialysis. Metabolic signs of citrate accumulation occurred in 32 patients (2.99%, 64.5±14.0 years, 65.6% male, Acute Physiology and Chronic Health Evaluation score 34.2±9.7): systemic iCa decreased to 1.01±0.10 mmol/L with a simultaneous increase of the calcium substitution rate to 129%±26%, and the mean total calcium to iCa ratio increased to 2.51±0.54. All 32 patients had therapy-resistant shock with severe lactic acidosis (pH 7.20±0.11, lactate 136±61 mg/dL), indicating severe intracellular hypoxia. None of the patients survived. Conclusions The incidence of disarrangements consistent with citrate accumulation in patients undergoing RCA–continuous venovenous hemodialysis was low, taking place exclusively in patients with severe lactic acidosis due to multiorgan failure. This suggests that the appearance of citrate accumulation is secondary to a severe failure of cellular respiration.
Background:
Up to every fourth woman with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) suffers a clinically relevant relapse during pregnancy. High doses of steroids bear ...some serious risks, especially within the first trimester of pregnancy. Immunoadsorption (IA) is an effective and more selective treatment option in disabling MS relapse than plasma exchange. Data on the use of IA during pregnancy and breastfeeding are scarce.
Methods:
In this retrospective multicenter study, we analyzed the safety and efficacy of IA treatment in acute relapses during pregnancy or breastfeeding. The primary outcome parameter - change of acute relapse-related disability after IA - was assessed using Expanded Disability Status Scale (EDSS) and visual acuity (VA) measurements for patients with optic neuritis (ON).
Results:
A total of 24 patients were analyzed, 23 with relapsing–remitting MS, and 1 with NMOSD. Twenty patients were treated with IA during pregnancy. Four patients received IA postnatally during the breastfeeding period. Treatment was started at a mean 22.5 standard deviation (SD) 13.9 days after onset of relapse. Patients were treated with a series of 5.8 (mean, SD 0.7) IA treatments within 7–10 days. Sixteen patients received IA because of steroid-refractory relapse, eight were treated without preceding steroid pulse therapy. EDSS improved clinically relevant from 3.5 median, interquartile range (IQR) 2 before IA to 2.5 (median, IQR 1.1) after IA, p < 0.001. In patients with ON, VA improved in four out of five patients. Altogether, in 83% of patients, a rapid and marked improvement of relapse-related symptoms was observed after IA with either a decrease of ⩾1 EDSS grade or improvement in VA ⩾20%. No clinically relevant side effect was reported in 138 IA treatments.
Conclusions:
Tryptophan-IA was found to be effective and well tolerated in MS/NMOSD relapses, both as an escalation option after insufficient response to steroid pulse therapy and as first-line relapse treatment during pregnancy and breastfeeding.
Background/Aims: Gestational diabetes (GDM) might be associated with alterations in the metabolomic profile of affected mothers and their offspring. Until now, there is a paucity of studies that ...investigated both, the maternal and the fetal serum metabolome in the setting of GDM. Mounting evidence suggests that the fetus is not just passively affected by gestational disease but might play an active role in it. Metabolomic studies performed in maternal blood and fetal cord blood could help to better discern distinct fetal from maternal disease interactions. Methods: At the time of birth, serum samples from mothers and newborns (cord blood samples) were collected and screened for 163 metabolites utilizing tandem mass spectrometry. The cohort consisted of 412 mother/child pairs, including 31 cases of maternal GDM. Results: An initial non-adjusted analysis showed that eight metabolites in the maternal blood and 54 metabolites in the cord blood were associated with GDM. After Benjamini-Hochberg (BH) procedure and adjustment for confounding factors for GDM, fetal phosphatidylcholine acyl-alkyl C 32: 1 and proline still showed an independent association with GDM. Conclusions: This study found metabolites in cord blood which were associated with GDM, even after adjustment for established risk factors of GDM. To the best of our knowledge, this is the first study demonstrating an independent association between fetal serum metabolites and maternal GDM. Our findings might suggest a potential effect of the fetal metabolome on maternal GDM.
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