Digestive lesions related to N.S.A.I.D. (epidemiology and prevention)]

The frequency of gastrointestinal ulcers and ulcers complications induced by non steroidal anti inflammatory drugs (NSAID) increases continuously. This is a major health problem, since 1.5% of general population (mostly elderly people) take regularly NSAID'S. NSAID'S gastropathy is asymptomatic in nearly 50% of cases, even in case of big gastric ulcer. A severe hemorrhage or a gastric perforation can occurred in the absence of previous symptoms. When the patient had epigastric symptoms during a treatment with NSAID'S, upper GI endoscopy is normal in 50% of cases. NSAID'S are ulcerogenic by decreasing the capacity of the gastric mucosa to produce prostaglandin (PG) and by weakening gastric mucosal barrier. H2 blockers are not effective to prevent such lesions. Elderly women, are at high risk of gastric mucosal lesions and complications. In a prospective study, it was shown that misoprostol was effective to reduce the rate of NSAID'S induced gastric and duodenal ulcers. Up to date, epidemiologic studies don't show any population group at no risk of NSAID'S induced gastric lesions. The actual problem, now, is to determine which groups of patients are at high risk of complication in order to clarify the indications of preventive treatment. Today, in France, it's believed that old patients, with organic pathology (respiratory, cardiac, hepatic or urinary) and/or using two or more NSAID'S are at high risk.     

Genomic Definition of Hypervirulent and Multidrug-Resistant Klebsiella pneumoniae Clonal Groups

Multidrug-resistant and highly virulent Klebsiella pneumoniae isolates are emerging, but the clonal groups (CGs) corresponding to these high-risk strains have remained imprecisely defined. We aimed to identify K. pneumoniae CGs on the basis of genome-wide sequence variation and to provide a simple bioinformatics tool to extract virulence and resistance gene data from genomic data. We sequenced 48 K. pneumoniae isolates, mostly of serotypes K1 and K2, and compared the genomes with 119 publicly available genomes. A total of 694 highly conserved genes were included in a core-genome multilocus sequence typing scheme, and cluster analysis of the data enabled precise definition of globally distributed hypervirulent and multidrug-resistant CGs. In addition, we created a freely accessible database, BIGSdb-Kp, to enable rapid extraction of medically and epidemiologically relevant information from genomic sequences of K. pneumoniae. Although drug-resistant and virulent K. pneumoniae populations were largely nonoverlapping, isolates with combined virulence and resistance features were detected.     

Intraoperative blood loss during decompressive craniectomy for intractable intracranial hypertension after severe traumatic brain injury in children

Purpose

There are no data available on the risk of intraoperative bleeding during decompressive craniectomy (DC) after traumatic brain injury (TBI) in children. The objectives of this study were to assess the risk of intraoperative bleeding during DC for intractable intracranial hypertension after TBI, to identify potential factors associated with the risk of bleeding during DC, and to assess the impact of DC on systemic and cerebral hemodynamics and on coagulation.

Methods

Twelve children were identified as having undergone DC after TBI from April 2009 to June 2013 in our center. Subjects were allocated into two groups according to the percentage of blood loss (IBL) during the intraoperative period (<or ≥50 % of the estimated blood volume (EBV)).

Results

The median IBL during DC was 49 [17–349] % of the EBV. Children with an IBL?≥?50 % of EBV had higher preoperative intracranial pressure (ICP) (p?=?0.03) and international normalized ratio (INR) (p?=?0.02) than those with an IBL?<?50 % of EBV. DC induced significant decreases in ICP (p?=?0.0005), mean arterial pressure (p?=?0.01), and a significant increase in norepinephrine flow rate (p?=?0.04) between the immediate pre- and postoperative periods.

Conclusions

DC allows a significant decrease in ICP after severe pediatric TBI but is a surgical procedure at a high risk of bleeding. High ICP and INR during the immediate preoperative period are the main factors associated with increased IBL during DC. Further studies are needed to confirm our results and to assess the impact of the amount of IBL on the postoperative survival and functional outcome.     

Multiplex PCR for Detection of Seven Virulence Factors and K1/K2 Capsular Serotypes of Klebsiella pneumoniae

A single multiplex PCR assay targeting seven virulence factors and the wzi gene specific for the K1 and K2 capsular serotypes of Klebsiella pneumoniae was developed and tested on 65 clinical isolates, which included 45 isolates responsible for community-acquired severe human infections. The assay is useful for the surveillance of emerging highly virulent strains.     

The use of external mesh reinforcement to reduce intimal hyperplasia and preserve the structure of human saphenous veins

The saphenous vein is the conduit of choice in bypass graft procedures. Haemodynamic factors play a major role in the development of intimal hyperplasia (IH), and subsequent bypass failure. To evaluate the potential protective effect of external reinforcement on such a failure, we developed an ex vivo model for the perfusion of segments of human saphenous veins under arterial shear stress. In veins submitted to pulsatile high pressure (mean pressure at 100 mmHg) for 3 or 7 days, the use of an external macroporous polyester mesh 1) prevented the dilatation of the vessel, 2) decreased the development of IH, 3) reduced the apoptosis of smooth muscle cells, and the subsequent fibrosis of the media layer, 4) prevented the remodelling of extracellular matrix through the up-regulation of matrix metalloproteinases (MMP-2, MMP-9) and plasminogen activator type I. The data show that, in an experimental ex vivo setting, an external scaffold decreases IH and maintains the integrity of veins exposed to arterial pressure, via increase in shear stress and decrease wall tension, that likely contribute to trigger selective molecular and cellular changes.     

New insights into the competition between antioxidant activities and pro-oxidant risks of rosmarinic acid

Direct and indirect antioxidant activities of rosmarinic acid (RA) based on HOO˙/CH₃OO˙ radical scavenging and Fe(iii)/Fe(ii) ion chelation were theoretically studied using density functional theory at the M05-2X/6-311++G(2df,2p) level of theory. First, four antioxidant mechanisms including hydrogen atom transfer (HAT), radical adduct formation (RAF), proton loss (PL) and single electron transfer (SET) were investigated in water and pentyl ethanoate (PEA) phases. Regarding the free radical scavenging mechanism, HAT plays a decisive role with overall rate coefficients of 1.84 × 10³ M⁻¹ s⁻¹ (HOO˙) and 4.49 × 10³ M⁻¹ s⁻¹ (CH₃OO˙) in water. In contrast to PL, RAF and especially SET processes, the HAT reaction in PEA is slightly more favorable than that in water. Second, the [Fe(iii)(H₂O)₆]³⁺ and [Fe(ii)(H₂O)₆]²⁺ ion chelating processes in an aqueous phase are both favorable and spontaneous especially at the O5, site-1, and site-2 positions with large negative Δ_rG⁰ values and great formation constant K_f. Finally, the pro-oxidant risk of RA⁻ was also considered via the Fe(iii)-to-Fe(ii) complex reduction process, which may initiate Fenton-like reactions forming reactive HO˙ radicals. As a result, RA⁻ does not enhance the reduction process when ascorbate anions are present as reducing agents, whereas the pro-oxidant risk becomes remarkable when superoxide anions are found. The results encourage further attempts to verify the speculation using more powerful research implementations of the antioxidant activities of rosmarinic acid in relationship with its possible pro-oxidant risks.

Direct and indirect antioxidant activities of rosmarinic acid (RA) based on HOO˙/CH₃OO˙ radical scavenging and Fe(iii)/Fe(ii) ion chelation were theoretically studied using density functional theory at the M05-2X/6-311++G(2df,2p) level of theory.     

Imeglimin population pharmacokinetics and dose adjustment predictions for renal impairment in Japanese and Western patients with type 2 diabetes

Imeglimin is an orally administered first‐in‐class drug to treat type 2 diabetes mellitus (T2DM) and is mainly excreted unchanged by the kidneys. The present study aimed to define the pharmacokinetic (PK) characteristics of imeglimin using population PK analysis and to determine the optimal dosing regimen for Japanese patients with T2DM and chronic kidney disease (CKD). Imeglimin plasma concentrations in Japanese and Western healthy volunteers, and patients with T2DM, including patients with mild to severe CKD with an estimated glomerular filtration rate (eGFR) greater than 14 ml/min/1.73 m² were included in a population PK analysis. PK simulations were conducted using a population PK model, and the area under concentration‐time curve (AUC) was extrapolated with power regression analysis to lower eGFR. The influence of eGFR, weight, and age on apparent clearance and of dose on relative bioavailability were quantified by population PK analysis. Simulations and extrapolation revealed that the recommended dosing regimen based on the AUC was 500 mg twice daily (b.i.d.) for patients with eGFR 15–45 ml/min/1.73 m², and 500 mg with a longer dosing interval was suggested for those with eGFR less than 15. Simulations revealed that differences in plasma AUCs between Japanese and Western patients at the same dose were mainly driven by a difference in the eGFR and that the plasma AUC after 1000 and 1500 mg b.i.d. in Japanese and Western patients, respectively, was comparable in the phase IIb studies. These results indicate suitable dosages of imeglimin in the clinical setting of T2DM with renal impairment.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Imeglimin is a first‐in‐class oral agent for the treatment of type 2 diabetes (T2DM) and is excreted unchanged into urine. A Japanese phase IIb study found that 1000 mg b.i.d. was optimal in Japanese population, and phase III studies confirmed significant glucose lowering effect. A Western phase IIb study found an optimal dose of 1500 mg b.i.d.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study addressed the key determinants of imeglimin pharmacokinetics (PKs), recommended doses for patients with renal impairment, and what drives the different optimal doses between Japanese and Western patients with T2DM.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Renal function significantly impacts imeglimin PKs. Recommended doses for patients with renal impairment have been proposed for exposure matching. Differences in estimated glomerular filtration rate (eGFR) comprised the key driver for different optimal doses at which estimated exposures were similar between Japanese and Western patients.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Doses of imeglimin could be reduced based on eGFR. Exposure responses seemed similar between Japanese and Western patients.     

Antioxidant and UV-radiation absorption activity of aaptamine derivatives – potential application for natural organic sunscreens

Antioxidant and UV absorption activities of three aaptamine derivatives including piperidine[3,2-b]demethyl(oxy)aaptamine (C1), 9-amino-2-ethoxy-8-methoxy-3H-benzo[de][1,6]naphthyridine-3-one (C2), and 2-(sec-butyl)-7,8-dimethoxybenzo[de]imidazo[4,5,1-ij][1,6]-naphthyridin-10(9H)-one (C3) were theoretically studied by density functional theory (DFT). Direct antioxidant activities of C1–C3 were firstly evaluated via their intrinsic thermochemical properties and the radical scavenging activity of the potential antioxidants with the HOO˙/HO˙ radicals via four mechanisms, including: hydrogen atom transfer (HAT), single electron transfer (SET), proton loss (PL) and radical adduct formation (RAF). Kinetic calculation reveals that HOO˙ scavenging in water occurs via HAT mechanism with C1 (k_app, 7.13 × 10⁶ M⁻¹ s⁻¹) while RAF is more dominant with C2 (k_app, 1.40 × 10⁵ M⁻¹ s⁻¹) and C3 (k_app, 2.90 × 10⁵ M⁻¹ s⁻¹). Antioxidant activity of aaptamine derivatives can be classified as C1 > C3 > C2. Indirect antioxidant properties based on Cu(i) and Cu(ii) ions chelating activity were also investigated in aqueous phase. All three studied compounds show spontaneous and favorable Cu(i) ion chelating activity with ΔG⁰ being −15.4, −13.7, and −15.7 kcal mol⁻¹, whereas ΔG⁰ for Cu(ii) chelation are −10.4, −10.8, and −2.2 kcal mol⁻¹ for C1, C2 and C3, respectively. In addition, all compounds show UVA and UVB absorption; in which the excitations are determined mostly as π–π* transition. Overall, the results suggest the potential applications of the aaptamines in pharmaceutics and cosmetics, i.e. as a sunscreen and antioxidant ingredient.

Antioxidant and UV absorption activities of three aaptamine derivatives were theoretically studied by density functional theory (DFT) and time-dependent density functional theory (TD-DFT).     

A Subset of Type I Conventional Dendritic Cells Controls Cutaneous Bacterial Infections through VEGFα-Mediated Recruitment of Neutrophils

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