Glucose and Fat Tolerance Tests Induce Differential Responses in Plasma Choline Metabolites in Healthy Subjects

Plasma choline shows associations with plasma glucose and lipids. We studied changes of choline metabolites after oral glucose tolerance test (OGTT) and fat tolerance test (OFTT). Eighteen healthy subjects (mean age 54.3 years; BMI 26.8 kg/m2) underwent 2 tests. First, OFTT (80 g fat) was applied and blood was collected at baseline and 4 h after OFTT. Seven days later, 75 g glucose was applied and blood was collected at baseline and 2 h after OGTT. Plasma concentrations of choline, betaine, trimethylamine N-oxide (TMAO), dimethylglycine, S-adenosylmethionine (SAM), lipids and glucose were measured. After OFTT, plasma choline declined (10.6 to 9.2 µmol/L; p = 0.004), betaine declined (33.4 to 31.7 µmol/L; p = 0.003), TMAO slightly increased (4.1 to 5.6 µmol/L; p = 0.105), glucose declined (5.39 to 4.98 mmol/L; p < 0.001), and triglycerides increased (1.27 to 2.53 mmol/L; p < 0.001). After OGTT, plasma choline increased (10.1 to 11.1 µmol/L; p < 0.001), TMAO declined (4.0 to 3.5 µmol/L; p = 0.029), dimethylglycine declined (2.0 to 1.7 µmol/L; p = 0.005), SAM declined (103 to 96 nmol/L; p = 0.041), but betaine, glucose, and SAM were unchanged. In conclusion, OFTT lowered plasma betaine and choline and caused heterogeneous changes in plasma TMAO. OGTT reduced the flow of methyl groups and plasma TMAO

Added Value of Tomoelastography for Characterization of Pancreatic Neuroendocrine Tumor Aggressiveness Based on Stiffness

Simple Summary: The prediction of pancreatic neuroendocrine tumor (PNET) aggressiveness is important for treatment planning. The aim of this study was to evaluate the diagnostic performance of magnetic resonance elastography (MRE) with tomoelastography postprocessing (tomoelastography) in differentiating PNET from healthy pancreatic tissue and to correlate PNET stiffness with aggressiveness using asphericity derived from positron emission tomography (PET) as reference. In this prospective study we showed in a group of 13 patients with PNET that tomoelastography detected PNET by increased stiffness (p < 0.01) with a high diagnostic performance (AUC = 0.96). PNET was positively correlated with PET derived asphericity (r = 0.81). Tomoelastography provides quantitative imaging markers for the detection of PNET and the prediction of greater tumor aggressiveness by increased stiffness. Abstract: Purpose: To evaluate the diagnostic performance of tomoelastography in differentiating pancreatic neuroendocrine tumors (PNETs) from healthy pancreatic tissue and to assess the prediction of tumor aggressiveness by correlating PNET stiffness with PET derived asphericity. Methods: 13 patients with PNET were prospectively compared to 13 age-/sex-matched heathy volunteers (CTR). Multifrequency MR elastography was combined with tomoelastography-postprocessing to provide high-resolution maps of shear wave speed (SWS in m/s). SWS of pancreatic neuroendocrine tumor (PNET-T) were compared with nontumorous pancreatic tissue in patients with PNET (PNET-NT) and heathy pancreatic tissue (CTR). The diagnostic performance of tomoelastography was evaluated by ROC-AUC analysis. PNET-SWS correlations were calculated with Pearson’s r. Results: SWS was higher in PNET-T (2.02 ± 0.61 m/s) compared to PNET-NT (1.31 ± 0.18 m/s, p < 0.01) and CTR (1.26 ± 0.09 m/s, p < 0.01). An SWS-cutoff of 1.46 m/s distinguished PNET-T from PNET-NT (AUC = 0.89; sensitivity = 0.85; specificity = 0.92) and a cutoff of 1.49 m/s differentiated pancreatic tissue of CTR from PNET-T (AUC = 0.96; sensitivity = 0.92; specificity = 1.00). The SWS of PNET-T was positively correlated with PET derived asphericity (r = 0.81; p = 0.01). Conclusions: Tomoelastography provides quantitative imaging markers for the detection of PNET and the prediction of greater tumor aggressiveness by increased stiffness

Expression of TRAIL, IP-10, and CRP in children with suspected COVID-19 and real-life impact of a computational signature on clinical decision-making: a prospective cohort study

Purpose We evaluated the host-response marker score “BV” and its components TRAIL, IP-10, and CRP in SARS-CoV-2 positive children, and estimated the potential impact on clinical decision-making. Methods We prospectively analyzed levels of TRAIL, IP-10, CRP, and the BV score, in children with suspected COVID19. Classifcation of infectious etiology was performed by an expert panel. We used a 5-point-questionnaire to evaluate the intention to treat with antibiotics before and after receiving test results. Results We screened 111 children, of whom 6 (5.4%) were positive for SARS-CoV-2. A total of 53 children were included for the exploratory analysis. Median age was 3.1 years (interquartile range [IQR] 1.3–4.3), and 54.7% (n=29) were girls. A viral and a bacterial biomarker pattern was found in 27/53 (50.9%) and 15/53 (28.3%), respectively. BV scores difered between COVID-19, children with other viral infections, and children with bacterial infections (medians 29.5 vs. 9 vs. 66; p=0.0006). Similarly, median TRAIL levels were diferent (65.5 vs. 110 vs. 78; p=0.037). We found no diferences in IP-10 levels (555 vs. 504 vs. 285; p=0.22). We found a concordance between physicians’ “unlikely intention to treat” children with a viral test result in most cases (n=19/24, 79.2%). When physicians expressed a “likely intention to treat” (n=15), BV test revealed 5 bacterial, viral, and equivocal scores each. Antibiotics were withheld in three cases (20%). Overall, 27/42 (64%) of pediatricians appraised the BV test positively, and considered it helpful in clinical practice. Conclusion Host-response based categorization of infectious diseases might help to overcome diagnostic uncertainty, support clinical decision-making and reduce unnecessary antibiotic treatment

Concentrations of Soluble Angiotensin Converting Enzyme 2 (sACE2) in Children and Adults with and without COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19) pandemic, leads to illness and death. Various risk factors for a severe course, such as higher age, male gender and pre-existing illnesses are known. However, pathophysiological risk factors are largely unclear. Notably, the mild course of disease in children is conspicuous. Angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2 and is a key enzyme in infection. Differences in the distribution of ACE2 can provide insights into different courses of COVID19. Our aim was to elucidate the role of ACE2 as a pathophysiological risk factor by measuring soluble ACE2 (sACE2) via ELISA in blood samples (lithium-heparin-plasma or serum) of 367 individuals including children and adults with and without COVID-19. sACE2-levels were compared between the groups according to age and sex. In adults and children with COVID-19, sACE2-concentrations are significantly higher compared to healthy individuals. sACE2-levels increase with age and are lower in children compared to adults with COVID-19. Sex doesn’t significantly influence sACE2- concentration. It remains unclear whether sACE2 concentrations increase because of the infection and what factors could influence this response. In conclusion, the increase of sACE2-concentration with age could indicate that ACE2 concentrations mirror increased COVID-19 severity

The Kynurenine Pathway Is Upregulated by Methyl-deficient Diet and Changes Are Averted by Probiotics

Scope Probiotics exert immunomodulatory effects and may influence tryptophan metabolism in the host. Deficiency of nutrients related to C1 metabolism might stimulate inflammation by enhancing the kynurenine pathway. This study used Sprague Dawley rats to investigate whether a methyl‐deficient diet (MDD) may influence tryptophan/kynurenine pathways and cytokines and whether probiotics can mitigate these effects. Methods and Results Rats are fed a control or MDD diet. Animals on the MDD diet received vehicle, probiotics (L. helveticus R0052 and B. longum R0175), choline, or probiotics + choline for 10 weeks (n = 10 per group). Concentrations of plasma kynurenine metabolites and the methylation and inflammatory markers in plasma and liver are measured. Results MDD animals (vs controls) show upregulation of plasma kynurenine, kynurenic acid, xanthurenic acid, 3‐hydroxyxanthranilic acid, quinolinic acid, nicotinic acid, and nicotinamide (all p < 0.05). In the MDD rats, the probiotics (vs vehicle) cause lower anthranilic acid and a trend towards lower kynurenic acid and picolinic acid. Compared to probiotics alone, probiotics + choline is associated with a reduced enrichment of the bacterial strains in cecum. The interventions have no effect on inflammatory markers. Conclusions Probiotics counterbalance the effect of MDD diet and downregulate downstream metabolites of the kynurenine pathway

Modulation of the sympathetic nervous system by renal denervation prevents reduction of aortic distensibility in atherosclerosis prone ApoE-deficient rats

Apolipoprotein E-deficient (ApoE(-/-)) rodents spontaneously develop severe hypercholesterolemia and increased aortic stiffness, both accepted risk factors for cardiovascular morbidity and mortality in humans. In patients with resistant hypertension renal denervation (RDN) may improve arterial stiffness, however the underlying mechanisms are incompletely understood. This study investigates the impact of RDN on aortic compliance in a novel atherosclerosis prone ApoE(-/-)-rat model.Methods Normotensive, 8 weeks old ApoE−/− and Sprague–Dawley (SD) rats were subjected to bilateral surgical RDN (n = 6 per group) or sham operation (n = 5 per group) and fed with normal chow for 8 weeks. Compliance of the ascending aorta was assessed by magnetic resonance imaging. Vasomotor function was measured by aortic ring tension recordings. Aortic collagen content was quantified histologically and plasma aldosterone levels were measured by enzyme-linked immunosorbent assay (ELISA).Results After 8 weeks, ApoE−/−-sham demonstrated a 58 % decrease in aortic distensibility when compared with SD-sham (0.0051 ± 0.0011 vs. 0.0126 ± 0.0023 1/mmHg; p = 0.02). This was accompanied by an impaired endothelium-dependent relaxation of aortic rings and an increase in aortic medial fibrosis (17.87 ± 1.4 vs. 12.27 ± 1.1 %; p = 0.006). In ApoE−/−-rats, RDN prevented the reduction of aortic distensibility (0.0128 ± 0.002 vs. 0.0051 ± 0.0011 1/mmHg; p = 0.01), attenuated endothelial dysfunction, and decreased aortic medial collagen content (12.71 ± 1.3 vs. 17.87 ± 1.4 %; p = 0.01) as well as plasma aldosterone levels (136.33 ± 6.6 vs. 75.52 ± 8.4 pg/ml; p = 0.0003). Cardiac function and metabolic parameters such as hypercholesterolemia were not influenced by RDN.Conclusion ApoE−/−-rats spontaneously develop impaired vascular compliance. RDN improves aortic distensibility and attenuated endothelial dysfunction in ApoE−/−-rats. This was associated with a reduction in aortic fibrosis formation, and plasma aldosterone levels

Modulation of the sympathetic nervous system by renal denervation prevents reduction of aortic distensibility in atherosclerosis prone ApoE-deficient rats

Apolipoprotein E-deficient (ApoE(-/-)) rodents spontaneously develop severe hypercholesterolemia and increased aortic stiffness, both accepted risk factors for cardiovascular morbidity and mortality in humans. In patients with resistant hypertension renal denervation (RDN) may improve arterial stiffness, however the underlying mechanisms are incompletely understood. This study investigates the impact of RDN on aortic compliance in a novel atherosclerosis prone ApoE(-/-)-rat model.Methods Normotensive, 8 weeks old ApoE−/− and Sprague–Dawley (SD) rats were subjected to bilateral surgical RDN (n = 6 per group) or sham operation (n = 5 per group) and fed with normal chow for 8 weeks. Compliance of the ascending aorta was assessed by magnetic resonance imaging. Vasomotor function was measured by aortic ring tension recordings. Aortic collagen content was quantified histologically and plasma aldosterone levels were measured by enzyme-linked immunosorbent assay (ELISA).Results After 8 weeks, ApoE−/−-sham demonstrated a 58 % decrease in aortic distensibility when compared with SD-sham (0.0051 ± 0.0011 vs. 0.0126 ± 0.0023 1/mmHg; p = 0.02). This was accompanied by an impaired endothelium-dependent relaxation of aortic rings and an increase in aortic medial fibrosis (17.87 ± 1.4 vs. 12.27 ± 1.1 %; p = 0.006). In ApoE−/−-rats, RDN prevented the reduction of aortic distensibility (0.0128 ± 0.002 vs. 0.0051 ± 0.0011 1/mmHg; p = 0.01), attenuated endothelial dysfunction, and decreased aortic medial collagen content (12.71 ± 1.3 vs. 17.87 ± 1.4 %; p = 0.01) as well as plasma aldosterone levels (136.33 ± 6.6 vs. 75.52 ± 8.4 pg/ml; p = 0.0003). Cardiac function and metabolic parameters such as hypercholesterolemia were not influenced by RDN.Conclusion ApoE−/−-rats spontaneously develop impaired vascular compliance. RDN improves aortic distensibility and attenuated endothelial dysfunction in ApoE−/−-rats. This was associated with a reduction in aortic fibrosis formation, and plasma aldosterone levels

Acanthocyte Sedimentation Rate as a Diagnostic Biomarker for Neuroacanthocytosis Syndromes: Experimental Evidence and Physical Justification

(1) Background: Chorea-acanthocytosis and McLeod syndrome are the core diseases among the group of rare neurodegenerative disorders called neuroacanthocytosis syndromes (NASs). NAS patients have a variable number of irregularly spiky erythrocytes, so-called acanthocytes. Their detection is a crucial but error-prone parameter in the diagnosis of NASs, often leading to misdiagnoses. (2) Methods: We measured the standard Westergren erythrocyte sedimentation rate (ESR) of various blood samples from NAS patients and healthy controls. Furthermore, we manipulated the ESR by swapping the erythrocytes and plasma of different individuals, as well as replacing plasma with dextran. These measurements were complemented by clinical laboratory data and single-cell adhesion force measurements. Additionally, we followed theoretical modeling approaches. (3) Results: We show that the acanthocyte sedimentation rate (ASR) with a two-hour read-out is significantly prolonged in chorea-acanthocytosis and McLeod syndrome without overlap compared to the ESR of the controls. Mechanistically, through modern colloidal physics, we show that acanthocyte aggregation and plasma fibrinogen levels slow down the sedimentation. Moreover, the inverse of ASR correlates with the number of acanthocytes (R 2 = 0.61, p = 0.004). (4) Conclusions: The ASR/ESR is a clear, robust and easily obtainable diagnostic marker. Independently of NASs, we also regard this study as a hallmark of the physical view of erythrocyte sedimentation by describing anticoagulated blood in stasis as a percolating gel, allowing the application of colloidal physics theory

Combined antibiotic stewardship and infection control measures to contain the spread of linezolid-resistant Staphylococcus epidermidis in an intensive care unit

Background The unrestricted use of linezolid has been linked to the emergence of linezolid-resistant Staphylococcus epidermidis (LRSE). We report the effects of combined antibiotic stewardship and infection control measures on the spread of LRSE in an intensive care unit (ICU). Methods Microbiological data were reviewed to identify all LRSE detected in clinical samples at an ICU in southwest Germany. Quantitative data on the use of antibiotics with Gram-positive coverage were obtained in defined daily doses (DDD) per 100 patient-days (PD). In addition to infection control measures, an antibiotic stewardship intervention was started in May 2019, focusing on linezolid restriction and promoting vancomycin, wherever needed. We compared data from the pre-intervention period (May 2018–April 2019) to the post-intervention period (May 2019–April 2020). Whole-genome sequencing (WGS) was performed to determine the genetic relatedness of LRSE isolates. Results In the pre-intervention period, LRSE were isolated from 31 patients (17 in blood cultures). The average consumption of linezolid and daptomycin decreased from 7.5 DDD/100 PD and 12.3 DDD/100 PD per month in the pre-intervention period to 2.5 DDD/100 PD and 5.7 DDD/100 PD per month in the post-intervention period (p = 0.0022 and 0.0205), respectively. Conversely, vancomycin consumption increased from 0.2 DDD/100 PD per month to 4.7 DDD/100 PD per month (p < 0.0001). In the post-intervention period, LRSE were detected in 6 patients (4 in blood cultures) (p = 0.0065). WGS revealed the predominance of one single clone. Conclusions Complementing infection control measures by targeted antibiotic stewardship interventions was beneficial in containing the spread of LRSE in an ICU

The Erythrocyte Sedimentation Rate and Its Relation to Cell Shape and Rigidity of Red Blood Cells from Chorea-Acanthocytosis Patients in an Off-Label Treatment with Dasatinib

Background: Chorea-acanthocytosis (ChAc) is a rare hereditary neurodegenerative disease with deformed red blood cells (RBCs), so-called acanthocytes, as a typical marker of the disease. Erythrocyte sedimentation rate (ESR) was recently proposed as a diagnostic biomarker. To date, there is no treatment option for affected patients, but promising therapy candidates, such as dasatinib, a Lyn-kinase inhibitor, have been identified. Methods: RBCs of two ChAc patients during and after dasatinib treatment were characterized by the ESR, clinical hematology parameters and the 3D shape classification in stasis based on an artificial neural network. Furthermore, mathematical modeling was performed to understand the contribution of cell morphology and cell rigidity to the ESR. Microfluidic measurements were used to compare the RBC rigidity between ChAc patients and healthy controls. Results: The mechano-morphological characterization of RBCs from two ChAc patients in an off-label treatment with dasatinib revealed differences in the ESR and the acanthocyte count during and after the treatment period, which could not directly be related to each other. Clinical hematology parameters were in the normal range. Mathematical modeling indicated that RBC rigidity is more important for delayed ESR than cell shape. Microfluidic experiments confirmed a higher rigidity in the normocytes of ChAc patients compared to healthy controls. Conclusions: The results increase our understanding of the role of acanthocytes and their associated properties in the ESR, but the data are too sparse to answer the question of whether the ESR is a suitable biomarker for treatment success, whereas a correlation between hematological and neuronal phenotype is still subject to verification