Peter Schreier

IMPORTANCE: Postoperative delirium (POD) is a multietiological condition and affects 20% of older surgical patients. It is associated with poor clinical outcome and increased mortality. OBJECTIVE: We aimed to develop and validate a risk prediction algorithm for POD based on a multimodal biomarker database exploiting preoperative data (predisposing factors) and procedural factors as well as perioperative molecular changes associated with POD (precipitating factors). DESIGN: BioCog is a prospective cohort study conducted from November 2014 to April 2017. Patients were followed up for seven postoperative days after surgery for POD. Gradient-boosted trees (GBT) with nested cross-validation was used for POD prediction. SETTING: Patients aged ≥65 years were enrolled at the anesthesiologic departments of two tertiary care centers. EXPOSURE: All patients underwent surgery with an expected duration of at least 60min. Clinical, neuropsychological, neuroimaging data and blood were collected and clinically well established as well as non-established biomarkers (e.g., gene expression profiling) were measured pre- and postoperatively. MAIN OUTCOME: POD according to DSM 5 until the seventh postoperative day RESULTS: 184 of 929 (20%) patients experienced POD. A GBT algorithm using both preoperative data, characteristics of the intervention and postoperative changes in laboratory parameters achieved the highest area under the curve (0.83, [0.79; 0.86]) with a Brier score of 0.12 (0.12; 0.13). CONCLUSIONS AND RELEVANCE: Models combining predisposing factors with precipitating factors predict POD best. Non-routine laboratory data provide useful information for POD risk prediction, providing relevant results for future studies on the molecular factors of POD. In addition, possibly relevant molecular mechanisms contributing to the development of POD were identified, mostly indicating a dysregulated postoperative immune response. This study constitutes the basis for future hypothesis-driven analyses or implementation of prediction expert system for clinical practice.

Infestation of crops by pathogenic fungi has continued to have a major impact by reducing yield and quality, emphasizing the need to identify new targets and develop new agents to improve methods of crop protection. Here we present Aurora kinase from the phytopathogenic fungus Ustilago maydis as a novel target for N-substituted diaminopyrimidines, a class of small-molecule kinase inhibitors. We show that Aurora kinase is essential in U. maydis and that diaminopyrimidines inhibit its activity in vitro. Furthermore, we observed an overall good correlation between in vitro inhibition of Aurora kinase and growth inhibition of diverse fungi in vivo. In vitro inhibition assays with Ustilago and human Aurora kinases indicate that some compounds of the N-substituted diaminopyrimidine class show specificity for the Ustilago enzyme, thus revealing their potential as selective fungicides.

In order to study the human intestinal transit of flavan-3-ol C-glycosides, several C-glycosyl derivatives were prepared by non-enzymatic reaction of (+)-catechin with α-D-glucose, α-D-galactose and α-D-rhamnose, respectively. In contrast to literature data, we propose that the reaction mechanism proceeds in analogy to the rearrangement of flavan-3-ols during epimerization under alkaline conditions. Four of the 12 synthesized flavan-3-ol C-glycosides were incubated under aerobic conditions at 37°C using saliva (2 min) and simulated gastric juice (3 h). To simulate human intestine, the C-glycosides were also incubated under anaerobic conditions at 37°C both in human ileostomy fluid (10 h) and colostomy fluid (24 h), respectively. The flavan-3-ol C-glycosides under study, i.e. (+)-epicatechin 8-C-β-D-glucopyranoside (1a), (+)-epicatechin 6-C-β-D-glucopyranoside (1d), (+)-catechin 6-C-β-D-galactopyranoside (2b), (+)-catechin 6-C-β-D-rhamnopyranoside (3b) were analyzed in the incubation samples by HPLC-DAD and HPLC-DAD-MS/MS. They were found to be stable in the course of incubation in saliva, simulated gastric juice and ileostomy fluid and underwent degradation in colostomy fluid. While the 6-C-β-D-glucopyranoside 1d was completely metabolized between 2 and 4 h, decomposition of the 6-C-β-D-galactopyranoside 2b reached only 16±2% within 4 h of incubation. Linear degradation rates of 1d and 2b in colostomy fluid differed significantly. As microbial metabolism of flavan-3-ols is known not to be influenced by the stereochemistry of the aglycon, varying degradation rates are ascribed to the effect of the sugar moiety. Based on these results we assume that flavan-3-ol C-glycosides pass through the upper gastrointestinal tract (oral cavity, stomach and small intestine) unmodified and are then metabolized by the colonic microflora.

Epidemiological studies suggest that nutritional antioxidants may reduce the incidence of neurodegenerative disorders and age-related cognitive decline. Specifically, protection against oxidative stress and inflammation has served as a rationale for promoting diets rich in vegetables and fruits. The present study addresses secretory phospholipase A₂ (sPLA₂) as a novel candidate effector of neuroprotection conferred by anthocyanins and anthocyanidins. Using a photometric assay, 15 compounds were screened for their ability to inhibit PLA₂. Of these, cyanidin, malvidin, peonidin, petunidin, and delphinidin achieved K _i values ≤18 μM, suggesting a modulatory role for berry polyphenols in phospholipid metabolism.

Health benefits associated with diets rich in anthocyanins are ascribed to multilevel biological activities including antioxidative and anti‐inflammatory effects. The present study addresses lipoxygenase inhibition as a mechanism by which anthocyanins may exert health promoting effects. The inhibitory potential of delphinidin (Dp), cyanidin (Cy), peonidin (Pn), and malvidin (Mv) glycosides, i.e., 3‐O‐glucosides, 3‐O‐galactosides, and 3‐O‐arabinosides as well as their aglycons was analyzed by using soybean lipoxygenase‐1 and human neutrophil granulocyte 5‐lipoxygenase. The determined IC₅₀ values comprised a wide range, i.e., from the sub‐μM level until practically no effect of inhibition (Mv and its glycosides). With IC₅₀ values of 0.43 and 0.49 μM Dp 3‐O‐glucoside (Dp3glc) and Dp 3‐O‐galactoside (Dp3gal) were found to be the most effective soybean lipoxygenase‐1 inhibitors; their strong inhibitory potential was also reflected by the IC₅₀ values determined for these anthocyanins in the 5‐lipoxygenase inhibition exhibiting 2.15 and 6.9 μM, respectively. As to the mechanism of inhibition, experiments carried out with lipoxygenase‐1 revealed the uncompetitive type. Considering the powerful inhibitory properties of Dp glycosides in relation to their currently known availability in human metabolism, in vivo prevention of inflammatory diseases by these anthocyanins could be envisaged.

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Recently, contamination of honey with pyrrolizidine alkaloids (PA) has been reported as potential health risk. Therefore, it was of interest to develop a reliable tool for selective and quantitative determination of PA in honey. Sample preparation of the novel method comprises strong cation exchange SPE (SCX‐SPE), followed by two reduction steps using zinc and LiAlH₄, as well as subsequent silylation. During this procedure the separated PA are converted into the necin backbone, the common structural feature of PA toxicity, which is analyzed by GC‐MS in the SIM mode. The procedure was validated using PA from extracts of Senecio vernalis as well as authentic PA standards including their corresponding N‐oxides. The PA content of honey samples was quantified with heliotrine as internal standard. The method was applied to generate a dataset in order to evaluate the potential risk of PA contamination especially for retail honeys available on the German/European market. No selection criteria in terms of floral or geographical origin were applied on the samples before analysis. In total, 216 commercially available floral honey samples were analyzed. Among them 19 samples contained PA, in the range of 0.019–0.120 μg/g, calculated as retronecine equivalents. The reported method facilitates the selective determination of PA without the need to identify each individual PA independently. The PA contamination of honey is expressed in terms of a single sum parameter and no background information such as foraged plants and pollen analysis is necessary. The LOQ is 0.01 ppm with a S/N of 7:1.

In order to study the human intestinal transit and metabolism of D‐galacturonic acid and amidated pectin a number of model experiments were carried out. Both substrates were incubated under aerobic conditions at 37°C using saliva (2 min) and simulated gastric juice (4 h). Under anaerobic conditions the substrates were incubated at 37°C using human ileostomy and colostomy fluids, each obtained from three different donors, for 10 and for 24 h, respectively. D‐Galacturonic acid, SCFA (acetic acid, propionic acid, and butyric acid), as well as methanol were analyzed photometrically after carbazole reaction, GC‐flame ionization detection (GC‐FID), and headspace solid‐phase microextraction GC/MS (HS‐SPME‐GC/MS), respectively. D‐Galacturonic acid and amidated pectin were found to be stable during incubations with saliva and simulated gastric juice, whereas both substrates underwent degradation in the course of human ileostomy and colostomy fluid incubations. D‐Galacturonic acid was practically completely decomposed within 10 h and SCFA, with acetic acid as the major representative, were formed up to 98% of the incubated substrate in colostomy effluent. The amidated pectin was only degraded in part, revealing stable amounts of 22–35% and 3–17% in ileostomy (after 10 h) and colostomy fluid (after 24 h), respectively. SCFA were generated up to 59% of the applied amidated pectin. In parallel, 19–60% and 52–67% of the available methyl ester groups were cleaved in the course of incubations with ileostomy and colostomy fluids, respectively. The results demonstrate for the first time that D‐galacturonic acid and amidated pectin are stable in human saliva and simulated gastric juice. The degradation of both compounds during incubation with ileostomy effluent is highlighted, providing evidence for a considerable metabolic potential of the small intestine.