Weight change and lipoprotein particle concentration and particle size: a cohort study with 6.5-year follow-up

ObjectiveObesity and overweight are related to unfavourable lipoprotein subclass profiles. Here we studied the relation between weight change and lipoprotein particle concentrations and sizes in a general population cohort in a longitudinal setting.MethodsThe cohort included 683 adults with a 6.5-year follow-up. Lipoprotein particle subclasses and mean particle sizes of VLDL, LDL, and HDL were measured by nuclear magnetic resonance spectroscopy.ResultsDuring the follow-up period, a weight loss of at least 5% was associated with decreased particle concentrations of all apoB-containing subclasses and increased concentrations of large HDL particles. Coherently, weight gain (≥5%) was associated with increases in all apoB-containing subclasses and decreases in total and medium HDL particle concentrations. The relatively largest increase occurred for large HDL particle concentration (24.1%, 95% CI 15.8–32.5) in weight loss and for large VLDL particle concentration (33.0%, 19.6–46.4) in weight gain. Weight change correlated positively with changes in apoB-containing lipoprotein particle concentrations and also with the change in average VLDL particle size. Negative correlations were found between weight change and the change in average LDL (r = ?0.10) and HDL (r = ?0.32) particle size, but not between weight change and total HDL particle concentration.ConclusionModerate weight loss is related to favourable and weight gain to unfavourable changes in lipoprotein subclass profiles. These population level findings underline the importance of weight control as a modifier of cardiovascular risk factors.     

Laparoscopic Roux‐en‐Y gastric bypass surgery influenced pharmacokinetics of several drugs given as a cocktail with the highest impact observed for CYP1A2, CYP2C8 and CYP2E1 substrates

There is a lack of information about the changes in drug pharmacokinetics and cytochrome P450 (CYP) metabolism after bariatric surgery. Here, we investigated the effects of laparoscopic Roux‐en‐Y gastric bypass (LRYGB) surgery on pharmacokinetics of nine drugs given simultaneously which may reveal changes in the activities of the main CYPs. Eight obese subjects undergoing LRYGB received an oral cocktail containing nine drugs, substrates of various CYPs: melatonin (CYP1A2), nicotine (CYP2A6), bupropion (CYP2B6), repaglinide (CYP2C8), losartan (CYP2C9), omeprazole (CYP2C19/CYP3A4), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A). The 6‐hours pharmacokinetic profiles in serum and urine of each drug or corresponding metabolite as well as their metabolic ratios were compared before surgery with those at a median 1 year later. LRYGB exerted variable effects on the pharmacokinetics of these drugs. The geometric mean AUC_0‐6 (90% confidence interval) of melatonin, bupropion, repaglinide, chlorzoxazone and midazolam after LRYGB was 27 (19%‐41%), 54 (43%‐67%), 44 (29%‐66%), 160 (129%‐197%) and 74 (62%‐90%) of the pre‐surgery values, respectively. The pharmacokinetics of losartan, omeprazole and dextromethorphan did not change in response to surgery. Nicotine was not detected in serum, while geometric mean of AUC_0‐6 of its metabolite, cotinine, increased by 1.7 times after surgery. There were 3.6‐ and 1.3‐fold increases in the AUC ratios of 6‐hydroxymelatonin/melatonin and hydroxybupropion/bupropion, respectively. The cocktail revealed multiple pharmacokinetic changes occurring after LRYGB with the greatest effects observed for CYP1A2, CYP2C8 and CYP2E1 substrates. Future studies should be focused on CYP1A2, CYP2A6, CYP2C8 and CYP2B6 to clarify the changes in activities of these enzymes after LRYGB.     

Bioactive glass particulate filler composite: Effect of coupling of fillers and filler loading on some physical properties

Objectives

The aim of this study was to investigate the effect of silanization of biostable and bioactive glass fillers in a polymer matrix on some of the physical properties of the composite.

Methods

The water absorption, solubility, flexural strength, flexural modulus and toughness of different particulate filler composite resins were studied in vitro. Five different specimen groups were analyzed: A glass-free control, a non-silanized bioactive glass, a silanized bioactive glass, a non-silanized biostable glass and a silanized biostable glass groups. All of these five groups were further divided into sub-groups of dry and water-stored materials, both of them containing groups with 3 wt%, 6 wt%, 9 wt% or 12 wt% of glass particles (n = 8 per group). The silanization of the glass particles was carried out with 2% of gamma-3-methacryloxyproyltrimethoxysilane (MPS). For the water absorption and solubility tests, the test specimens were stored in water for 60 days, and the percentages of weight change were statistically analyzed. Flexural strength, flexural modulus and toughness values were tested with a three-point bending test and statistically analyzed.

Results

Higher solubility values were observed in non-silanized glass in proportion to the percentage of glass particles. Silanization, on the other hand, decreased the solubility values of both types of glass particles and polymer. While 12 wt% non-silanized bioactive glass specimens showed −0.98 wt% solubility, 12 wt% silanized biostable glass specimens were observed to have only −0.34 wt% solubility.The three-point bending results of the dry specimens showed that flexural strength, toughness and flexural modulus decreased in proportion to the increase of glass fillers. The control group presented the highest results (106.6 MPa for flexural strength, 335.7 kPA for toughness, 3.23 GPa for flexural modulus), whereas for flexural strength and toughness, 12 wt% of non-silanized biostable glass filler groups presented the lowest (70.3 MPa for flexural strength, 111.5 kPa for toughness). For flexural modulus on the other hand, 12 wt% of silanized biostable glass filler group gave the lowest results (2.57 GPa).

Significance

The silanization of glass fillers improved the properties of the glass as well as the properties of the composite. Silanization of bioactive glass may protect the glass from leaching at early stage of water storage.     

Effect of chlorhexidine and ethanol-wet bonding with a hydrophobic adhesive to intraradicular dentine

Purpose

To evaluate the effect of adjunctive application of ethanol-wet bonding and chlorhexidine (CHX) with a hydrophobic adhesive on bond durability of fibre posts to intraradicular dentine.

Methods

Ninety-six extracted human teeth with a single root and root canal were prepared for post placement after endodontic treatment. The teeth were randomly divided into four groups (n = 24) after etching and rinsing for rewetting: Group 1: water-wet bonding, Group 2: water-wet bonding with CHX, Group 3: ethanol-wet bonding and Group 4: ethanol-wet bonding with CHX. Teeth in Groups 1 and 2 were treated with either distilled water or distilled water with 2% CHX for 60 s; while teeth in Groups 3 and 4 were treated with either 100% ethanol or 100% ethanol with 2% CHX. Two coats of primer, followed by neat resin were applied and light-cured for 40 s. Fibre posts were luted to bonded root dentine using dual-cure resin cement. Bonded roots were subjected to push-out bond strength testing and interfacial nanoleakage evaluation after 24 h, 6 and 12 months of storage. Data were analyzed using 3-way ANOVA (rewetting solutions, time and post space regions) and SNK tests.

Results

Groups 3 and 4 showed significantly (p < 0.05) higher bond strengths and lower nanoleakage than Groups 1 and 2 after 12 months of ageing. Addition of 2% chlorhexidine to ethanol-wet bonding with a hydrophobic adhesive did not further improve the bonding of a fibre post to intraradicular dentine, when compared to ethanol-wet bonding alone after 12 months of ageing.

Clinical significance

Ethanol-wet bonding with a hydrophobic adhesive alone could improve the bond durability of fibre post to intraradicular dentine and therefore would increase the success rate of post and core restorations of endodontically treated teeth.     

Discovery and characterization of ORM‐11372, a novel inhibitor of the sodium‐calcium exchanger with positive inotropic activity

Background and PurposeThe lack of selective sodium–calcium exchanger (NCX) inhibitors has hampered the exploration of physiological and pathophysiological roles of cardiac NCX 1.1. We aimed to discover more potent and selective drug like NCX 1.1 inhibitor.Experimental ApproachA flavan series‐based pharmacophore model was constructed. Virtual screening helped us identify a novel scaffold for NCX inhibition. A distinctively different NCX 1.1 inhibitor, ORM‐11372, was discovered after lead optimization. Its potency against human and rat NCX 1.1 and selectivity against other ion channels was assessed. The cardiovascular effects of ORM‐11372 were studied in normal and infarcted rats and rabbits. Human cardiac safety was studied ex vivo using human ventricular trabeculae.Key ResultsORM‐11372 inhibited human NCX 1.1 reverse and forward currents; IC₅₀ values were 5 and 6 nM respectively. ORM‐11372 inhibited human cardiac sodium 1.5 (I _Na) and hERG K_V11.1 currents (I _hERG) in a concentration‐dependent manner; IC₅₀ values were 23.2 and 10.0 μM. ORM‐11372 caused no changes in action potential duration; short‐term variability and triangulation were observed for concentrations of up to 10 μM. ORM‐11372 induced positive inotropic effects of 18 ± 6% and 35 ± 8% in anaesthetized rats with myocardial infarctions and in healthy rabbits respectively; no other haemodynamic effects were observed, except improved relaxation at the lowest dose.Conclusion and ImplicationsORM‐11372, a unique, novel, and potent inhibitor of human and rat NCX 1.1, is a positive inotropic compound. NCX inhibition can induce clinically relevant improvements in left ventricular contractions without affecting relaxation, heart rate, or BP, without pro‐arrhythmic risk.