Essential phospholipids impact cytokine secretion and alter lipid-metabolizing enzymes in human hepatocyte cell lines.

BACKGROUND: Essential phospholipids (EPL) are hepatoprotective. METHODS: The effects on interleukin (IL)-6 and -8 secretion and on certain lipid-metabolizing enzymes of non-cytotoxic concentrations of EPL (0.1 and 0.25 mg/ml), polyenylphosphatidylcholine (PPC), and phosphatidylinositol (PtdIns) (both at 0.1 and 1 mg/ml), compared with untreated controls, were assessed in human hepatocyte cell lines (HepG2, HepaRG, and steatotic HepaRG). RESULTS: Lipopolysaccharide (LPS)-induced IL-6 secretion was significantly decreased in HepaRG cells by most phospholipids, and significantly increased in steatotic HepaRG cells with at least one concentration of EPL and PtdIns. LPS-induced IL-8 secretion was significantly increased in HepaRG and steatotic HepaRG cells with all phospholipids. All phospholipids significantly decreased amounts of fatty acid synthase in steatotic HepaRG cells and the amounts of acyl-CoA oxidase in HepaRG cells. Amounts of lecithin cholesterol acyltransferase were significantly decreased in HepG2 and HepaRG cells by most phospholipids, and significantly increased with 0.1 mg/ml PPC (HepaRG cells) and 1 mg/ml PtdIns (steatotic HepaRG cells). Glucose-6-phosphate dehydrogenase activity was unaffected by any phospholipid in any cell line. CONCLUSIONS: EPL, PPC, and PtdIns impacted the secretion of pro-inflammatory cytokines and affected amounts of several key lipid-metabolizing enzymes in human hepatocyte cell lines. Such changes may help liver function improvement, and provide further insights into the EPL's mechanism of action.

Analysis of the microbial content of probiotic products commercialized worldwide and survivability in conditions mimicking the human gut environment.

Introduction: Probiotics are living microorganisms that, when administered in adequate amounts, confer a health benefit on the host. Adequate number of living microbes, the presence of specific microorganisms, and their survival in the gastrointestinal (GI) environment are important to achieve desired health benefits of probiotic products. In this in vitro study, 21 leading probiotic formulations commercialized worldwide were evaluated for their microbial content and survivability in simulated GI conditions. Methods: Plate-count method was used to determine the amount of living microbes contained in the products. Culture-dependent Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry and culture-independent metagenomic analysis through 16S and 18S rDNA sequencing were applied in combination for species identification. To estimate the potential survivability of the microorganisms contained in the products in the harsh GI environment, an in vitro model composed of different simulated gastric and intestinal fluids was adopted. Results: The majority of the tested probiotic products were concordant with the labels in terms of number of viable microbes and contained probiotic species. However, one product included fewer viable microbes than those displayed on the label, one product contained two species that were not declared, and another product lacked one of the labeled probiotic strains. Survivability in simulated acidic and alkaline GI fluids was highly variable depending on the composition of the products. The microorganisms contained in four products survived in both acidic and alkaline environments. For one of these products, microorganisms also appeared to grow in the alkaline environment. Conclusion: This in vitro study demonstrates that most globally commercialized probiotic products are consistent with the claims described on their labels with respect to the number and species of the contained microbes. Evaluated probiotics generally performed well in survivability tests, although viability of microbes in simulated gastric and intestinal environments showed large variability. Although the results obtained in this study indicate a good quality of the tested formulations, it is important to stress that stringent quality controls of probiotic products should always be performed to provide optimal health benefits for the host.

Essential phospholipids decrease apoptosis and increase membrane transport in human hepatocyte cell lines.

BACKGROUND: Essential phospholipids (EPL) have hepatoprotective effects across many liver diseases/conditions. The impact of EPL on hepatocyte function in vitro was investigated. METHODS: Effects of noncytotoxic concentrations of EPL (0.1 and 0.25 mg/ml), and its constituents, polyenylphosphatidylcholine (PPC) and phosphatidylinositol (PI) (both at 0.1 and 1 mg/ml), on membrane fluidity, apoptosis and extracellular transport versus controls were investigated in human hepatocyte cell lines (HepG2, HepaRG, steatotic HepaRG).  RESULTS: Significantly increased membrane fluidity occurred with all 3 phospholipids (PLs) in HepG2 cultures, and with PI (1 mg/ml) in steatotic HepaRG cells. Significantly decreased tamoxifen-induced apoptosis was observed in HepG2 cells with EPL, PPC and PI. Breast cancer resistance protein (BCRP) activity was significantly increased by EPL and PI in HepG2 cells. Multidrug resistance-associated protein 2 (MRP-2) activity was unaffected by any PL in HepG2 cells, and significantly increased by EPL, PI and PPC (1 mg/ml) in HepaRG cells, and by PI (1 mg/ml) in steatotic HepaRG cells. Bile salt export protein (BSEP) activity in HepG2 cells and steatotic HepaRG cells was significantly increased by EPL (0.25 mg/ml), and PPC (both concentrations), but not by PI. The PLs had no effects on HepaRG cell BSEP activity. P-glycoprotein (P-GP) activity was significantly increased by all compounds in HepG2 cells. PI (1 mg/ml) significantly increased P-GP activity in HepaRG and steatotic HepaRG cells. CONCLUSIONS: EPL, PPC, and PI increased hepatocyte membrane fluidity, decreased apoptosis and increased hepatocellular export, all of which may improve liver function. These in-vitro investigations provide valuable insights into the mechanism of action of EPL.

Reduced Self-Perception of Fatigue after Intake of Panax ginseng Root Extract (G115®) Formulated with Vitamins and Minerals-An Open-Label Study.

BACKGROUND: Unexplained fatigue is a common complaint. When underlying disease causes have been eliminated, lifestyle measures and supplementation can be indicated. Elaborating on clinical findings that G115®, a dry extract from the root of Panax ginseng, combined with vitamins and minerals could alleviate fatigue, this open label study aimed at assessing its effect on perceived fatigue and energy. METHODS: Healthy adults self-reporting fatigue (n = 103) completed the Multidimensional Fatigue Inventory questionnaire. They rated their perceptions of mental and physical fatigue, energy, performance, and stress at baseline and 15, 30, 60 and 90 days after a daily intake of 40 mg G115® formulated with vitamins and minerals. RESULTS: Compared with baseline values, mean self-perception of general fatigue was reduced by -7.55 units [95% CI: -8.44; -6.66] (-41.8%, p < 0.0001) at 90 days. All assessed perception ratings (mental and physical fatigue, reduced activity and motivation, performance, and stress) were significantly and steadily improved from two weeks after supplementation up to study's end. Overall satisfaction with the ability of the product to reduce fatigue reached 85% at Day 90. CONCLUSION: Daily intake with G115® extract formulated with vitamins and minerals suggests an improvement of self-perception of fatigue and energy in a fatigued adult population.

Effect of magnesium and vitamin B6 supplementation on mental health and quality of life in stressed healthy adults: Post-hoc analysis of a randomised controlled trial.

Magnesium status and vitamin B6 intake have been linked to mental health and/or quality of life (QoL). In an 8-week Phase IV randomised controlled study in individuals with low magnesemia and severe/extremely severe stress but who were otherwise healthy, greater stress reduction was achieved with magnesium combined with vitamin B6 than with magnesium alone. We present a previously unreported secondary analysis of the effect of magnesium, with and without vitamin B6, on depression, anxiety, and QoL. Adults with Depression Anxiety Stress Scales (DASS-42) stress subscale score >18 were randomised 1:1 to magnesium + vitamin B6 combination (Magne B6® ; daily dose 300 and 30 mg, respectively) or magnesium alone (Magnespasmyl® ; daily dose 300 mg). Outcomes included changes from baseline in DASS-42 depression and anxiety scores, and QoL (Short Form-36 Health Survey). DASS-42 anxiety and depression scores significantly improved from baseline to week 8 with both treatments, particularly during the first 4 weeks. Improvement in QoL continued over 8 weeks. Participants' perceived capacity for physical activity in daily life showed greater improvement with magnesium + vitamin B6 than magnesium alone (Week 4). In conclusion, magnesium supplementation, with or without vitamin B6, could provide a meaningful clinical benefit in daily life for individuals with stress and low magnesemia.

Kinetics of Intestinal Presence of Spores Following Oral Administration of Bacillus clausii Formulations: Three Single-Centre, Crossover, Randomised, Open-Label Studies.

BACKGROUND AND OBJECTIVE: Probiotics are live microorganisms that may provide benefits including the prevention of gastrointestinal disorders and other diseases. Enterogermina is a probiotic mix of spores from four strains of Bacillus clausii (O/C, T, N/R and SIN), available in several oral formulations. The objective of this analysis was to evaluate and compare the kinetic profiles of different formulations of Enterogermina-vial [E4 once daily (OD) and E2 twice daily (BID)], capsule [EC2 three times daily (TID)], oral powder for suspension (ES6 OD) and oral powder not requiring suspension (E6 OD) from two studies from 2012 (EUDRACT 2010-024497-19 and 2010-023187-41) and one study from 2016 (EUDRACT 2015-003330-27). METHODS: B. clausii spores were counted in homogenised faecal samples (results expressed as counts per gram) or after culture at 37 °C for 24-36 h (results expressed as colony-forming units). Kinetics were assessed by area under the concentration-time curve (AUC), maximum concentration (Cmax), time to maximum concentration (Tmax) and spore presence/persistence. RESULTS: In total, 22 subjects in each of the 2012 studies and 30 subjects in the 2016 study were randomised (mean age 25.0-33.8 years across studies). The mean (±SD) absolute faecal spore counts (in millions) expressed as AUC per hour were 270.7 ± 147.7 (E2 BID) and 213.8 ± 60.2 (E4 OD) in 2012 EGKINETIC4, 312.7 ± 218.0 (EC2 TID) and 319.0 ± 221.1 (ES6 OD) in 2012 EGKINETIC6, and 212.6 ± 118.0 (E6 OD) and 293.2 ± 247.2 (ES6 OD) in 2016 EGKINETIC6OP. The kinetic profiles of the different formulations of Enterogermina were similar, with superimposable AUC and daily curve profiles in each study up to the 8th day post dose. B. clausii spore presence/persistence in the intestine of healthy volunteers did not differ between the two formulations within each of the three studies. Enterogermina was well tolerated across all formulations and studies. CONCLUSION: These results show different formulations of Enterogermina had similar kinetic profiles within each study; however, they also showed that probiotics could be associated with high variability. The European Medicines Agency guidelines are the current bioequivalence reference, although only the Tmax parameter is used for high variability drugs. Due to the specific kinetics of probiotics, new parameters of bioequivalence could be necessary, considering, for example, variability via a parameter such as AUC. TRIAL REGISTRATION: EUDRACT 2010-024497-19, 2010-023187-41 and 2015-003330-27.

A novel digital approach to describe real world outcomes among patients with constipation.

Understanding day-to-day variations in symptoms and medication management can be important in describing patient centered outcomes for people with constipation. Patient Generated Health Data (PGHD) from digital devices is a potential solution, but its utility as a tool for describing experiences of people with frequent constipation is unknown. We conducted a virtual, 16-week prospective study of individuals with frequent constipation from an online wellness platform that connects mobile consumer digital devices including wearable monitors capable of passively collecting steps, sleep, and heart rate data. Participants wore a Fitbit monitoring device for the study duration and were administered daily and monthly surveys assessing constipation symptom severity and medication usage. A set of 38 predetermined day-level behavioral activity metrics were computed from minute-level data streams for steps, sleep and heart rate. Mixed effects regression models were used to compare activity metrics between constipation status (irregular or constipated vs. regular day), medication use (medication day vs. non-medication day) and the interaction of medication day with irregular or constipation days, as well as to model likelihood to treat with constipation medications based on daily self-reported symptom severity. Correction for multiple comparisons was performed with the Benjamini-Hochberg procedure for false discovery rate. This study analyzed 1540 enrolled participants with completed daily surveys (mean age 36.6 sd 10.0, 72.8% female, 88.8% Caucasian). Of those, 1293 completed all monthly surveys and 756 had sufficient Fitbit data density for analysis of activity metrics. At a daily-level, 22 of the 38 activity metrics were significantly associated with bowel movement or medication treatment patterns for constipation. Participants were measured to have fewer steps on irregular days compared to regular days (-200 steps, 95% CI [-280, -120]), longer periods of inactivity on constipated days (9.1 min, 95% CI [5.2, 12.9]), reduced total sleep time on irregular and constipated days (-2.4 min, 95% CI [-4.3, -0.4] and -4.0 min, 95% CI [-6.5, -1.4], respectively). Participants reported greater severity of symptoms for bloating, hard stool, difficulty passing, and painful bowel movements on irregular, constipation and medication days compared to regular days with no medication. Interaction analysis of medication days with irregular or constipation days observed small increases in severity compared to non-medication days. Participants were 4.3% (95% CI 3.2, 5.3) more likely to treat with medication on constipated days versus regular. No significant increase in likelihood was observed for irregular days. Daily likelihood to treat increased for each 1-point change in symptom severity of bloating (2.4%, 95% CI [2.0, 2.7]), inability to pass (2.2%, 95% CI [1.4, 3.0]) and incomplete bowel movements (1.3%, 95% CI [0.9, 1.7]). This is the first large scale virtual prospective study describing the association between passively collected PGHD and constipation symptoms and severity at a day-to-day granularity level. Constipation status, irregular or constipated, was associated with a number of activity metrics in steps and sleep, and likelihood to treat with medication increased with increasing severity for a number of constipation symptoms. Given the small magnitude of effect, further research is needed to understand the clinical relevance of these results. PGHD may be useful as a tool for describing real world patient centered experiences for people with constipation.

Safety and Tolerability of Insulin Aspart Biosimilar SAR341402 Versus Originator Insulin Aspart (NovoLog) When Used in Insulin Pumps in Adults with Type 1 Diabetes: A Randomized, Open-Label Clinical Trial.

Background: The aim was to assess the safety and tolerability of the insulin aspart biosimilar/follow-on product SAR341402 (100 U/mL solution; SAR-Asp) and originator insulin aspart (100 U/mL; NN-Asp; NovoLog®) self-administered through an insulin pump. Materials and Methods: This randomized, open-label, 2 × 4-week crossover study enrolled 45 adults with type 1 diabetes (T1D). Participants were randomized 1:1 to the treatment sequence SAR-Asp/NN-Asp or NN-Asp/SAR-Asp. The basal and prandial insulin doses were individually titrated. The primary outcome was the number of participants with at least one infusion set occlusion (infusion set change due to failure-to-correct hyperglycemia [plasma glucose ≥250 mg/dL] by insulin pump bolus) during the 4-week treatment. The main secondary outcome was the number of participants with at least one episode of unexplained hyperglycemia (regardless of correction by an insulin pump bolus without apparent material defect, medical, dietary, insulin dosing reason, or pump problem). Results: The number of participants reporting ≥1 infusion set occlusion were similar between treatments: 14/43 on SAR-Asp (33 events) and 12/43 on NN-Asp (24 events). The estimated difference in infusion set occlusion risk for SAR-Asp versus NN-Asp was 4.1% (95% confidence interval: -9.3% to 17.4%). The number of participants with ≥1 episode of unexplained hyperglycemia was similar between treatments (31/43 on SAR-Asp [154 events]; 32/43 on NN-Asp [175 events]). Hypoglycemia, treatment-emergent adverse events, hypersensitivity, and injection site reactions were similar between treatments. Conclusions: SAR-Asp and NN-Asp were well tolerated and had similar infusion set occlusions over a 4-week period in insulin pump users with T1D.

[Estimating emergency hospital admissions to gauge short-term effects of air pollution: evaluation of health data quality]. / Estimation des hospitalisations en urgence pour mesurer les effets à court terme de la pollution atmosphérique : qualité des données issues du PMSI.

The study of the short-term effects and health impact of air pollution is carrier out by the ERPURS regional surveillance program which utilizes hospitalization data obtained from the French hospital information system (PMSI) to determine these links. This system does not permit the distinction between emergency hospital admissions from scheduled ones, which cannot be related to short term changes in air pollution levels. This study examines how scheduled admissions affect the quality of the health indicators used to estimate air pollution effects. This indicator is compared to three new emergency hospitalisation indicators reconstructed based on data from the public hospitals in Paris, partly from the PMSI data and partly with data from an on-line emergency network that regroups all of the computerized emergency services. According to the pathology, scheduled admissions present a difficulty which affects the capacity to highlight the weakest risks with any precision.