Is There a FADS2-Modulated Link between Long-Chain Polyunsaturated Fatty Acids in Plasma Phospholipids and Polyphenol Intake in Adult Subjects Who Are Overweight?

Dietary polyphenols promote cardiometabolic health and are linked with long-chain polyunsaturated fatty acids in plasma phospholipids (LC-PUFA). The FADS2 polymorphisms are associated with LC-PUFA metabolism and overweight/obesity. This 4-week study examined the link between polyphenol intake, FADS2 variants (rs174593, rs174616, rs174576) and obesity in 62 overweight adults (BMI ≥ 25), allocated to consume 100 mL daily of either: Aronia juice, a rich source of polyphenols, with 1177.11 mg polyphenols (expressed as gallic acid equivalents)/100 mL (AJ, n = 22), Aronia juice with 294.28 mg polyphenols/100 mL (MJ, n = 20), or nutritionally matched polyphenol-lacking placebo as a control (PLB, n = 20). We analyzed LC-PUFA (% of total pool) by gas chromatography and FADS2 variants by real-time PCR. Four-week changes in LC-PUFA, BMI, and body weight were included in statistical models, controlling for gender and PUFA intake. Only upon AJ and MJ, the presence of FADS2 variant alleles affected changes in linoleic, arachidonic, and eicosapentaenoic acid (EPA). Upon MJ treatment, changes in EPA were inversely linked with changes in BMI (β= −0.73, p = 0.029) and weight gain (β= −2.17, p = 0.024). Only in subjects drinking AJ, the link between changes in EPA and anthropometric indices was modified by the rs174576 variant allele. Our results indicate the interaction between FADS2, fatty acid metabolism, and polyphenol intake in overweight subjects.     

Validation of low-cost models for minimal invasive surgery training of congenital diaphragmatic hernia and esophageal atresia

BackgroundMinimal invasive surgery (MIS) is increasingly used for the correction of congenital diaphragmatic hernia (CDH) and esophageal atresia (EA). It is important to master these complex procedures, preferably preclinically, to avoid complications. The aim of this study was to validate recently developed models to train these MIS procedures preclinically.MethodsTwo low cost, reproducible models (one for CDH and one for EA) were validated during several pediatric surgical conferences and training sessions (January 2017–December 2018), used in either the LaparoscopyBoxx or EoSim simulator. Participants used one or both models and completed a questionnaire regarding their opinion on realism (face validity) and didactic value (content validity), rated on a five-point-Likert scale.ResultsOf all 60 participants enrolled, 44 evaluated the EA model. All items were evaluated as significantly better than neutral, with means ranging from 3.7 to 4.1 (p < 0.001). The CDH model was evaluated by 48 participants. All items scored significantly better than neutral (means 3.5–3.9, p < 0.001), with exception of the haptics of the simulated diaphragm (mean 3.3, p = 0.054). Both models were considered a potent training tool (means 3.9).ConclusionThese readily available and low budget models are considered a valid and potent training tool by both experts and target group participants.Type of studyProspective study.Level of evidenceLevel II.     

TrkC Is Essential for Nephron Function and Trans-Activates Igf1R Signaling

BackgroundInjury to kidney podocytes often results in chronic glomerular disease and consecutive nephron malfunction. For most glomerular diseases, targeted therapies are lacking. Thus, it is important to identify novel signaling pathways contributing to glomerular disease. Neurotrophic tyrosine kinase receptor 3 (TrkC) is expressed in podocytes and the protein transmits signals to the podocyte actin cytoskeleton.MethodsNephron-specific TrkC knockout (TrkC-KO) and nephron-specific TrkC-overexpressing (TrkC-OE) mice were generated to dissect the role of TrkC in nephron development and maintenance.ResultsBoth TrkC-KO and TrkC-OE mice exhibited enlarged glomeruli, mesangial proliferation, basement membrane thickening, albuminuria, podocyte loss, and aspects of FSGS during aging. Igf1 receptor (Igf1R)–associated gene expression was dysregulated in TrkC-KO mouse glomeruli. Phosphoproteins associated with insulin, erb-b2 receptor tyrosine kinase (Erbb), and Toll-like receptor signaling were enriched in lysates of podocytes treated with the TrkC ligand neurotrophin-3 (Nt-3). Activation of TrkC by Nt-3 resulted in phosphorylation of the Igf1R on activating tyrosine residues in podocytes. Igf1R phosphorylation was increased in TrkC-OE mouse kidneys while it was decreased in TrkC-KO kidneys. Furthermore, TrkC expression was elevated in glomerular tissue of patients with diabetic kidney disease compared with control glomerular tissue.ConclusionsOur results show that TrkC is essential for maintaining glomerular integrity. Furthermore, TrkC modulates Igf-related signaling in podocytes.     

Fear of hypoglycemia,a game changer during physical activity in type 1 diabetes mellitus patients

Hypoglycemia limits optimal glycemic management of patients with type 1 diabetes mellitus (T1DM). Fear of hypoglycemia (FoH) is a significant psychosocial consequence that negatively impacts the willingness of T1DM patients to engage in and profit from the health benefits of regular physical activity (e.g., cardiometabolic health, improved body composition, cardiovascular fitness, quality of life). Technological advances, improved insulin regimens, and a better understanding of the physiology of various types of exercise could help ameliorate FoH. This narrative review summarizes the available literature on FoH in children and adults and tools to avoid it.     

Analysis of time‐to‐event for observational studies: Guidance to the use of intensity models

This paper provides guidance for researchers with some mathematical background on the conduct of time‐to‐event analysis in observational studies based on intensity (hazard) models. Discussions of basic concepts like time axis, event definition and censoring are given. Hazard models are introduced, with special emphasis on the Cox proportional hazards regression model. We provide check lists that may be useful both when fitting the model and assessing its goodness of fit and when interpreting the results. Special attention is paid to how to avoid problems with immortal time bias by introducing time‐dependent covariates. We discuss prediction based on hazard models and difficulties when attempting to draw proper causal conclusions from such models. Finally, we present a series of examples where the methods and check lists are exemplified. Computational details and implementation using the freely available R software are documented in Supplementary Material. The paper was prepared as part of the STRATOS initiative.     

Near-fatal cerebellar swelling caused by acute multifocal cerebellar necrosis.

We report a case of acute near-fatal cerebellar swelling, which was accompanied by multifocal cerebellar necrosis. Acute, near-fatal cerebellar swelling is a rare problem thought to be of parainfectious aetiology. Initiation by multifocal cerebellar necrosis has not been reported so far with this disorder.     

Phase I pharmacological and bioavailability study of oral diflomotecan (BN80915), a novel E-ring-modified camptothecin analogue in adults with solid tumors.

PURPOSE: Diflomotecan (BN80915) is an E-ring modified camptothecin analogue that possesses greater lactone stability in plasma compared with other topoisomerase I inhibitors, a potential advantage for antitumor activity. As with other camptothecins, oral administration has pharmacological and clinical advantages. This Phase I study was performed to assess the feasibility of the administration of oral diflomotecan, to determine the maximum-tolerated, dose its bioavailability, and to explore the pharmacokinetics. EXPERIMENTAL DESIGN: An initial i.v. bolus was administered to assess the bioavailability of diflomotecan. Fourteen days later, diflomotecan was administered p.o. once daily for 5 days to adult patients with solid malignant tumors and repeated every 3 weeks. BN80915 and its open lactone form BN80942 were measured. RESULTS: Twenty-two patients entered the study and received a total of 57 cycles of oral diflomotecan at flat dose levels of 0.10, 0.20, 0.27, and 0.35 mg. The main toxicity was hematological, but some patients experienced alopecia, mild gastrointestinal toxicity, and fatigue. At the 0.35-mg dose level, 2 of 4 patients experienced dose-limiting toxicity comprising grade 3 thrombocytopenia with epistaxis and febrile neutropenia in 1 patient and uncomplicated grade 4 neutropenia lasting for >7 days in another. Toxicity was acceptable at the 0.27-mg dose level at which dose-limiting toxicities were observed in 3 of 12 patients (grade 4 neutropenia > 7 days, complicated by fever in 1 patient but without other signs of infection). After two cycles of diflomotecan, 6 patients had disease stabilization, which was maintained in 2 patients for 9 months and >1 year, respectively. Diflomotecan pharmacokinetics were linear over the dose range studied. Systemic exposure correlated with the fall in WBC counts. The mean oral bioavailability (+/-SD) was 72.24 +/- 59.2% across all dose levels. Urinary excretion of BN80915 was very low. CONCLUSIONS: The recommended oral diflomotecan dose for Phase II studies is 0.27 mg/day x 5 every 3 weeks. This regimen is convenient and generally well tolerated with a favorable pharmacokinetic profile and high but variable bioavailability.     

Joint effect of commercial preparations of Stevia rebaudiana Bertoni and sodium monoketocholate on glycemia in mice.

A study was made of the combined effect of two commercial products of Stevia rebaudiana Bertoni and sodium monoketocholate (mkc) on blood glucose concentration in mice. One group of animals was treated four days with mkc, 4 mg/kg, s.c., second with 200 mg/kg, i.p., of Stevita (Stevita Co, INC, Arlington, Texas) (stevia), third with 20 mg/kg, i.p., of Clear Steviosides Liquid (Stevita Co, INC, Herbal supplement, Brazil) (stevioside), fourth with the combination of stevia and mkc, and the fifth with stevisode and mkc. Blood glucose concentration was measured before treatment, after the first and fourth dose, as well as after subjecting animals to glucose-tolerance test (500 mg/kg, p.o.) or provoking glycemia by injecting adrenaline (0.2 mg/kg, s.c.). It was found that one dose of stevioside combined with mkc caused a significant increase of glycemia with respect of mkc alone and control (10.80:7.90:8.01). However, when repeated four days, the same pretreatment resulted in a significant decrease of glycemia compared with single-dose pretreatment (10.80:7.20). The increase in glycemia with the mice that received four doses of stevioside and mkc and then were subjected to glucose-tolerance test was significantly lower compared to that in mice that were pretreated four days only with mkc before receiving glucose (6.33:7.80). Analogous difference was observed between the animals given mkc alone and mkc plus stevioside after injecting adrenaline (13.33:10.54). As for the interaction of mkc and stevia it was found that the combined pretreatment yielded lower values of glycemia compared with that measured after treatment with stevia alone (6.40:7.82).