Outcomes of Preventive Embolization of the Inferior Mesenteric Artery during Endovascular Abdominal Aortic Aneurysm Repair.

PURPOSE: To evaluate the impact of preemptive inferior mesenteric artery (IMA) embolization on outcomes of endovascular abdominal aortic aneurysm (AAA) repair (EVAR). MATERIALS AND METHODS: From January 2015 to July 2017, all patients undergoing elective EVAR or fenestrated EVAR (F-EVAR) for asymptomatic AAA in a single tertiary hospital were retrospectively included. Three groups of patients were defined: patients with a patent IMA who underwent embolization during EVAR/F-EVAR (group 1), those with a patent IMA who did not undergo embolization during EVAR/F-EVAR (group 2), and those with a chronically occluded IMA (group 3). Preoperative aortic morphology, demographics, and procedural details were recorded. Aneurysmal growth (≥5 mm), reintervention, and overall mortality rates were analyzed using multivariate proportional hazard multivariate modeling. Propensity scores were constructed, and inverse probability weighting was applied to a new set of multivariate analyses to perform a sensitivity analysis. RESULTS: A total of 266 patients (male, 95% [n = 249]) with a median age of 70 (65-77) years were included, with F-EVAR procedures comprising 87 (32.7%) of the interventions. There were 52, 142, and 72 patients in groups 1, 2, and 3, respectively. Changes in aneurysmal sac size did not differ between groups, nor did overall survival or reintervention rates at 24 months. IMA embolization was not identified as an independently protective factor for aneurysmal growth during follow-up (relative risk [RR] = 2.82/mm [0.96-8.28], P = .060), whereas accessory renal arteries (RR = 5.07/mm [1.72-14.96], P = .003) and a larger preoperative aneurysmal diameter (RR = 1.09/mm [1.03-1.15], P = .004) were independent risk factors for sac enlargement. CONCLUSIONS: Preventive embolization of the IMA during EVAR or F-EVAR did not promote aneurysmal sac shrinking or decrease the reintervention rate at 2-year follow-up.

Exposure of South Korean Population to 5G Mobile Phone Networks (3.4-3.8 GHz).

As industrialized countries race to install and deploy 5G networks, some countries have taken the lead and already have operational 5G networks in place. South Korea is among these. In this study, we measured exposure to electromagnetic fields in South Korea to evaluate the relative contribution of 5G as compared with other frequencies such as 2G, 3G, and 4G. Results show that the emission of 5G contributes about 15% to total telecommunications emissions. The highest levels were observed in the vicinity of 5G antennas and remain below the limits set by the International Commission on Non-Ionizing Radiation Protection (ICNIRP). © 2021 Bioelectromagnetics Society.

Glucose-based spiro-oxathiazoles as in vivo anti-hyperglycemic agents through glycogen phosphorylase inhibition.

The design of glycogen phosphorylase (GP) inhibitors targeting the catalytic site of the enzyme is a promising strategy for a better control of hyperglycaemia in the context of type 2 diabetes. Glucopyranosylidene-spiro-heterocycles have been demonstrated as potent GP inhibitors, and more specifically spiro-oxathiazoles. A new synthetic route has now been elaborated through 1,3-dipolar cycloaddition of an aryl nitrile oxide to a glucono-thionolactone affording in one step the spiro-oxathiazole moiety. The thionolactone was obtained from the thermal rearrangement of a thiosulfinate precursor according to Fairbanks' protocols, although with a revisited outcome and also rationalised with DFT calculations. The 2-naphthyl substituted glucose-based spiro-oxathiazole 5h, identified as one of the most potent GP inhibitors (Ki = 160 nM against RMGPb) could be produced on the gram-scale from this strategy. Further evaluation in vitro using rat and human hepatocytes demonstrated that compound 5h is a anti-hyperglycaemic drug candidates performing slightly better than DAB used as a positive control. Investigation in Zucker fa/fa rat model in acute and subchronic assays further confirmed the potency of compound 5h since it lowered blood glucose levels by ∼36% at 30 mg kg-1 and ∼43% at 60 mg kg-1. The present study is one of the few in vivo investigations for glucose-based GP inhibitors and provides data in animal models for such drug candidates.

Apoptosis of tumor-infiltrating T lymphocytes: a new immune checkpoint mechanism.

Immunotherapy based on checkpoint inhibitors is providing substantial clinical benefit, but only to a minority of cancer patients. The current priority is to understand why the majority of patients fail to respond. Besides T-cell dysfunction, T-cell apoptosis was reported in several recent studies as a relevant mechanism of tumoral immune resistance. Several death receptors (Fas, DR3, DR4, DR5, TNFR1) can trigger apoptosis when activated by their respective ligands. In this review, we discuss the immunomodulatory role of the main death receptors and how these are shaping the tumor microenvironment, with a focus on Fas and its ligand. Fas-mediated apoptosis of T cells has long been known as a mechanism allowing the contraction of T-cell responses to prevent immunopathology, a phenomenon known as activation-induced cell death, which is triggered by induction of Fas ligand (FasL) expression on T cells themselves and qualifies as an immune checkpoint mechanism. Recent evidence indicates that other cells in the tumor microenvironment can express FasL and trigger apoptosis of tumor-infiltrating lymphocytes (TIL), including endothelial cells and myeloid-derived suppressor cells. The resulting disappearance of TIL prevents anti-tumor immunity and may in fact contribute to the absence of TIL that is typical of "cold" tumors that fail to respond to immunotherapy. Interfering with the Fas-FasL pathway in the tumor microenvironment has the potential to increase the efficacy of cancer immunotherapy.

Effects of Nigella sativa seeds (black cumin) on insulin secretion and lipid profile: A pilot study in healthy volunteers.

It has been claimed that Nigella sativa seeds (NSS), also known as black cumin, have antidiabetic and lipid-lowering properties. Our pilot study investigated the effects of powdered NSS on insulin secretion and lipid profile in healthy male volunteers. We conducted a double-blind, randomized, placebo-controlled 4-week trial in 30 subjects, receiving NSS powder (1 g/day) or placebo orally (15 subjects/group). Insulin secretion as determined by the hyperglycaemic clamp technique, insulin sensitivity as well as cholesterol and triglycerides serum concentrations, were measured before and after treatment. NSS powder administration was clinically well tolerated. It did not modify fasting glycaemia and insulinaemia, and was ineffective on glucose-induced insulin secretion and insulin sensitivity. No significant changes on serum lipids were observed after treatment in any treatment groups, nor between the two treatment groups. However, in the treated group only, there was a significant correlation between total cholesterol change after treatment and its baseline level (r = -0.71, P = 0.006, n = 13), and between low-density lipoprotein (LDL) cholesterol change after treatment and its baseline level (r = -0.74, P = 0.004, n = 13). No such correlations were found for high-density lipoprotein (HDL) cholesterol, and for triglycerides. These results do not confirm any NSS effect on glucose regulation; however, they suggest that NSS powder may be of interest in lowering lipid concentrations in hyperlipidaemic subjects.

Evidence of Wolframite-Type Structure in Ultrasmall Nanocrystals with a Targeted Composition MnWO4.

Here, we report a study of white-ochre powders with targeted composition MnWO4 prepared via a coprecipitation method. Through X-ray total scattering combined with pair distribution function analysis and Rietveld refinement of X-ray diffraction data, we find that their crystal structure is similar to that of bulk-MnWO4, despite a mean crystallite size of 1.0-1.6 nm and a significant deviation of the average chemical composition from MnWO4. The chemical formula derived from elemental and thermogravimetric analyses is Mn0.8WO3.6(OH)0.4·3H2O. X-ray absorption and magnetic susceptibility measurements show that Mn and W have the same oxidation states as in MnWO4. No magnetic ordering or spin glass or superparamagnetic behavior is observed above 2 K, unlike in the case of MnWO4 nanocrystals having a mean size higher than 10 nm.

A family of metal-dependent phosphatases implicated in metabolite damage-control.

DUF89 family proteins occur widely in both prokaryotes and eukaryotes, but their functions are unknown. Here we define three DUF89 subfamilies (I, II, and III), with subfamily II being split into stand-alone proteins and proteins fused to pantothenate kinase (PanK). We demonstrated that DUF89 proteins have metal-dependent phosphatase activity against reactive phosphoesters or their damaged forms, notably sugar phosphates (subfamilies II and III), phosphopantetheine and its S-sulfonate or sulfonate (subfamily II-PanK fusions), and nucleotides (subfamily I). Genetic and comparative genomic data strongly associated DUF89 genes with phosphoester metabolism. The crystal structure of the yeast (Saccharomyces cerevisiae) subfamily III protein YMR027W revealed a novel phosphatase active site with fructose 6-phosphate and Mg(2+) bound near conserved signature residues Asp254 and Asn255 that are critical for activity. These findings indicate that DUF89 proteins are previously unrecognized hydrolases whose characteristic in vivo function is to limit potentially harmful buildups of normal or damaged phosphometabolites.

Prevalence of Antipsychotic-Treated Patients in a Cohort of Adult Addicted Patients.

PURPOSE: The objective of this cross-sectional study was to describe and estimate the prevalence of antipsychotics (AP) in a cohort of addicted patients, and to compare the profiles of addictive patients receiving AP or not. METHODS: We included all adult patients seen at the addiction care center of Montpellier University Hospital, between January 1, 2015, and March 31, 2015. Demographic, clinical, and therapeutic data were collected from the patients' medical records. RESULTS: During the study period, 415 patients were included, with a mean age of 38 ± 10 years. They were mostly men (73.3%), French (54.9%), and unemployed (61.8%). Among the study population, 93 patients (patients treated with AP [trAP], 22.4%) were treated by 111 different AP, mainly cyamemazine (29.0% of treated patients), aripiprazole (20.4%), olanzapine (17.2%), and quetiapine (16.1%), mostly in monotherapy (80.6%) and by oral route (93.2% of AP). Psychiatric history was more frequent in trAP than in those without AP (untrAP) (55.9% vs 35.4% respectively; P < 0.001). Professional activity tended to be less frequent in patients with AP (25.3% vs 38.9%, P = 0.08).When compared with untrAP, trAP consumed more amphetamine (10.8% vs 4.4%; P = 0.02) and tended to consume less opiates (7.5% vs 14.9%; P = 0.06); the consumptions of cannabis (43.0% vs 35.7%; P = 0.20) and cocaine (22.6% vs 16.8%; P = 0.20) were not statistically different.Opiate maintenance therapy was reported in 63.7% of trAP and 68.4% of untrAP (P = 0.41): it consisted of methadone (trAP, 60.3% vs untrAP, 56.5%) and buprenorphine (trAP, 39.7% vs untrAP, 43.5%). CONCLUSIONS: The concomitant management of psychiatric and substance use disorders in the same center may explain the high prevalence of trAP in this study. Cannabis and psychostimulants may have been used in these patients as self-medication for mental disease-related symptoms or adverse effects of APs.

Success of tardive electroconvulsive therapy sessions after loxapine-induced malignant syndrome in the context of very poor metabolisation.

We report the success of tardive electroconvulsive therapy in a case of loxapine malignant syndrome with catatonia. Loxapine and its metabolites were measured in biological samples by liquid chromatography coupled to tandem mass spectrometry. Genes were studied by sequencing and quantitative polymerase chain reaction (PCR). Plasmatic drug concentrations showed a supratherapeutic concentration of loxapine with a very low 8-hydroxyloxapine/loxapine ratio (range from 0.32 to 0.66, normal value>2 for 100mg) and a very long elimination half-life of loxapine (half-life>140h, normal value from 1 to 4hours). We tried to explain this kinetics by exploring the main pharmacogenes implicated in the metabolism of loxapine. No genetic abnormality for CYP1A2 was observed. The study of associated treatments showed the potential contribution of valproate. Pharmacokinetics and pharmacogenetics investigations revealed a blockade of the CYP1A2 metabolic pathway without genetic abnormalities, probably due to valproate co-medication. Toxicological monitoring of loxapine and its metabolites helped to explain the persistence of symptoms and to adapt the therapeutic management.

Structure and activity of the Cas3 HD nuclease MJ0384, an effector enzyme of the CRISPR interference.

Clustered regularly interspaced short palindromic repeats (CRISPRs) and Cas proteins represent an adaptive microbial immunity system against viruses and plasmids. Cas3 proteins have been proposed to play a key role in the CRISPR mechanism through the direct cleavage of invasive DNA. Here, we show that the Cas3 HD domain protein MJ0384 from Methanocaldococcus jannaschii cleaves endonucleolytically and exonucleolytically (3'-5') single-stranded DNAs and RNAs, as well as 3'-flaps, splayed arms, and R-loops. The degradation of branched DNA substrates by MJ0384 is stimulated by the Cas3 helicase MJ0383 and ATP. The crystal structure of MJ0384 revealed the active site with two bound metal cations and together with site-directed mutagenesis suggested a catalytic mechanism. Our studies suggest that the Cas3 HD nucleases working together with the Cas3 helicases can completely degrade invasive DNAs through the combination of endo- and exonuclease activities.

[Abuse Liability of Quetiapine (Xeroquel®)]. / Évaluation du potentiel d'abus et de dépendance de la quétiapine (Xeroquel®).

OBJECTIVE: In recent years, there have been several reports in the literature concerning the misuse and abuse of quetiapine. The aim of this study was to review the data reported to the French Network of the Addictovigilance Centers as well as the published data. METHODS: Epidemiological data from the studies of French network addictovigilance centers (spontaneous notifications, suspicious presciptions suggesting possible abuse [ ordonnances suspectes indicateur d'abus possibles, OSIAP], observatory of illegal psychotropic substances or delivered substances diverted from their medicinal use survey [observation des produits psychotropes illicites ou détournées de leur utilisation médicamenteuse, OPPIDUM], deaths related to medication and substance abuse survey [décès en relation avec l'abus de médicaments et de substances, DRAMES]) were analyzed between 2011 and 2014. All cases of abuse and dependence with quetiapine in PubMed were reviewed using the MeSH terms "quetiapine," "substances abuse," and "dependence", until October 2014. RESULTS: The analysis of the literature has identified 21 cases of abuse related to quetiapine, mainly in men (85.7%), with a history of substance abuse (76%). The main route of administration was oral but other routes were also reported (intravenous, intranasal). The main reason for abuse was sedation and anxiolytic. Other characteristics of quetiapine abuse include amplification or even simulation of psychotic symptoms to obtain quetiapine, an increased dose and the existence of street names. The French addictovigilance network reported few cases of abuse with quetiapine. DISCUSSION-CONCLUSION: The pharmacological mechanism of abuse of quetiapine is not fully understood. However, several arguments are in favor of the abuse liability of quetiapine. Despite the recent availability of quetiapine in France, there have been some isolated signals of abuse. Therefore, it seems important to inform prescribers on the risk of misuse of quetiapine and also of some other antipsychotics.

The Legionella pneumophila kai operon is implicated in stress response and confers fitness in competitive environments.

Legionella pneumophila uses aquatic protozoa as replication niche and protection from harsh environments. Although L. pneumophila is not known to have a circadian clock, it encodes homologues of the KaiBC proteins of Cyanobacteria that regulate circadian gene expression. We show that L. pneumophila kaiB, kaiC and the downstream gene lpp1114, are transcribed as a unit under the control of the stress sigma factor RpoS. KaiC and KaiB of L. pneumophila do not interact as evidenced by yeast and bacterial two-hybrid analyses. Fusion of the C-terminal residues of cyanobacterial KaiB to Legionella KaiB restores their interaction. In contrast, KaiC of L. pneumophila conserved autophosphorylation activity, but KaiB does not trigger the dephosphorylation of KaiC like in Cyanobacteria. The crystal structure of L. pneumophila KaiB suggests that it is an oxidoreductase-like protein with a typical thioredoxin fold. Indeed, mutant analyses revealed that the kai operon-encoded proteins increase fitness of L. pneumophila in competitive environments, and confer higher resistance to oxidative and sodium stress. The phylogenetic analysis indicates that L. pneumophila KaiBC resemble Synechosystis KaiC2B2 and not circadian KaiB1C1. Thus, the L. pneumophila Kai proteins do not encode a circadian clock, but enhance stress resistance and adaption to changes in the environments.

A review of current information and communication technologies: can they be used to assess apathy?

BACKGROUND: Neuropsychiatric symptoms, such as apathy, have an important impact on the quality of life of both patients diagnosed with dementia and their caregivers and represent a strong predictor of progression of the illness. Current clinical assessment methods risk bias resulting from the assessor's subjectivity, pointing to a need for additional objective and systematic assessment tools. Therefore, the use of information and communication technologies (ICT) such as actigraphy and automatized video monitoring are of interest in addition to current assessment methods. AIM: The goal of this study is to give an overview of current assessment tools for apathy in clinical practice and new approaches to assessment methods with the help ICT. METHODS: This study was conducted with the use of narrative literature overview. RESULTS: There is evidence that apart from the currently used assessment methods for apathy, new ICT approaches could provide clinicians with valuable additional information for an earlier detection and therefore more accurate diagnosis of apathy. CONCLUSIONS: There are no ICT techniques specifically designed for the assessment of apathy, but nevertheless several techniques seem to be promising and deserve more study.

Psychological and physiological effects of bupropion compared to methylphenidate after prolonged administration in healthy volunteers (NCT00285155).

PURPOSE: Bupropion is largely used as an antidepressant and smoking cessation therapy. The aim of this work was to compare pharmacodynamic properties of bupropion and the amphetamine-like methylphenidate after sustained administration in humans. METHODS: Twelve male volunteers completed this randomized, double-blind, placebo controlled, cross-over study. Bupropion and methylphenidate were administered separately for initial half-dose 6-day periods (150 and 10 mg respectively) followed by full-dose 8-day periods (300 and 20 mg respectively). Outcomes were subjective feelings, cognitive performances, autonomic and physiological parameters. RESULTS: Data are expressed as mean(SEM). After repeated administration, bupropion, like methylphenidate, decreased asthenia-fatigue [44(3.2) and 42(3.7), respectively vs. 53(4.1) for placebo; p = 0.034], despite an impairment of sleep onset [-4.3(3.32) and -1.9(3.76), respectively vs. +7.5(3.69); p = 0.016]. Both drugs increased resting diastolic blood pressure [67.9(1.23) and 65.7(0.98), respectively vs. 62.5(1.42) mm Hg; p = 0.001], body temperature [36.5(0.12) and 36.5(0.14) vs. 36.3(0.10) °C; p = 0.037] and decreased body weight [-0.7(0.23) and -0.6(0.22), respectively vs. +0.2(0.27) kg; p = 0.038]. No significant change could be observed on cognitive functions, appetite and energy consumption. CONCLUSION: Although it may not share all the properties of stimulant drugs, the effect profile of bupropion presents a number of similarities with that of methylphenidate over a 2-week treatment period.

Nonviral delivery of small interfering RNA into pancreas-associated immune cells prevents autoimmune diabetes.

The development of small interfering RNA (siRNA) for the treatment of human disorders has been often hampered by their low transfection efficiency in vivo. In order to overcome this major drawback, various in vivo siRNA transfection methods have been developed. However, their capacity to transfect immune or insulin-producing ß-cells within the pancreas for the treatment of autoimmune diabetes remains undetermined. We found that lipid- or polyethylenimine-based delivery agents were efficient to address siRNA molecules within pancreas-associated antigen-presenting cells (APCs) (but not ß-cells) and particularly a CD11b(+) cell population comprising both CD11b(+)CD11c(neg) macrophages and CD11b(+)CD11c(+) dendritic cells. However, the route of administration and the carrier composition greatly affected the transfection efficacy. Therapeutically, we showed that early (starting at 6-week-old) short-course treatment with lipid/Alox15-specific siRNA complex promoted long-term protection from type 1 diabetes (T1D) in wild-type (WT) nonobese diabetic (NOD) mice. Alox15 downregulation in pancreas-associated CD11b(+) cells significantly upregulated a variety of costimulatory molecules and particularly the programmed death 1 ligand 1 (PD-L1) pathway involved in tolerance induction. Concomitantly, we found that regulatory T cells were increased in the pancreas of lipid/Alox15 siRNA-treated NOD mice. Collectively, our data provide new insights into the development of siRNA-based therapeutics for T1D.

Structure and activity of the cold-active and anion-activated carboxyl esterase OLEI01171 from the oil-degrading marine bacterium Oleispira antarctica.

The uncharacterized α/ß-hydrolase protein OLEI01171 from the psychrophilic marine bacterium Oleispira antarctica belongs to the PF00756 family of putative esterases, which also includes human esterase D. In the present paper we show that purified recombinant OLEI01171 exhibits high esterase activity against the model esterase substrate α-naphthyl acetate at 5-30°C with maximal activity at 15-20°C. The esterase activity of OLEI01171 was stimulated 3-8-fold by the addition of chloride or several other anions (0.1-1.0 M). Compared with mesophilic PF00756 esterases, OLEI01171 exhibited a lower overall protein thermostability. Two crystal structures of OLEI01171 were solved at 1.75 and 2.1 Å resolution and revealed a classical serine hydrolase catalytic triad and the presence of a chloride or bromide ion bound in the active site close to the catalytic Ser148. Both anions were found to co-ordinate a potential catalytic water molecule located in the vicinity of the catalytic triad His257. The results of the present study suggest that the bound anion perhaps contributes to the polarization of the catalytic water molecule and increases the rate of the hydrolysis of an acyl-enzyme intermediate. Alanine replacement mutagenesis of OLEI01171 identified ten amino acid residues important for esterase activity. The replacement of Asn225 by lysine had no significant effect on the activity or thermostability of OLEI01171, but resulted in a detectable increase of activity at 35-45°C. The present study has provided insight into the molecular mechanisms of activity of a cold-active and anion-activated carboxyl esterase.

Rotation of non-spherical micro-particles by amplitude modulation of superimposed orthogonal ultrasonic modes.

Contactless rotation of non-spherical particles has been modeled and experimentally achieved using ultrasonic manipulation. For this purpose an acoustic radiation torque was generated by a time-varying pressure field resulting in a change of orientation of the potential well. The rotation method is based on amplitude modulation of two orthogonal ultrasonic modes. The force potential field has been used to evaluate the different modes and actuations to achieve rotation. Experiments have been performed in micro devices with copolymer particles and glass fibers at frequencies in the megahertz range. A continuous rotation was successfully demonstrated and the method allowed to stop the rotation at arbitrary angular positions.

New formulation of methadone for opioid dependence in France: acceptability and diversion/misuse liability.

BACKGROUND: A new formulation of methadone as capsules is marketed in France since 2008. Few data are available on the patient acceptability and the risk of misuse of this new formulation. METHODS: To assess the patient acceptability after the switch methadone syrup/capsules and the diversion/misuse liability of the methadone capsule, a study through an anonymous questionnaire was conducted between March 2011 and May 2012 in two methadone centers of the region. RESULTS: Forty-one patients (men 75.6%) participated, with a median age of 37 years [IQR: 33-43 years]. The median duration of syrup methadone maintenance therapy was 1 year [IQR: 1-3 years]. A majority of patients (80.5%) described side-effects due to the syrup formulation. Median daily dose at the switch to methadone capsules was 75 mg [IQR: 42-105 mg]. Six patients described differences in the pharmacologic effect between the two formulations. Concerning the diversion and misuse liability of methadone capsules, 26.8% of patients reported that the medication was available at the "street market". Three patients have tried to solubilize and eight have tried to snooze it. CONCLUSION: All patients recognize the contribution of this new formulation concerning the use, side-effects and transport. None of them returned to the syrup.

Structure and activity of the Saccharomyces cerevisiae dUTP pyrophosphatase DUT1, an essential housekeeping enzyme.

Genomes of all free-living organisms encode the enzyme dUTPase (dUTP pyrophosphatase), which plays a key role in preventing uracil incorporation into DNA. In the present paper, we describe the biochemical and structural characterization of DUT1 (Saccharomyces cerevisiae dUTPase). The hydrolysis of dUTP by DUT1 was strictly dependent on a bivalent metal cation with significant activity observed in the presence of Mg2+, Co2+, Mn2+, Ni2+ or Zn2+. In addition, DUT1 showed a significant activity against another potentially mutagenic nucleotide: dITP. With both substrates, DUT1 demonstrated a sigmoidal saturation curve, suggesting a positive co-operativity between the subunits. The crystal structure of DUT1 was solved at 2 Å resolution (1 Å=0.1 nm) in an apo state and in complex with the non-hydrolysable substrate α,ß-imido dUTP or dUMP product. Alanine-replacement mutagenesis of the active-site residues revealed seven residues important for activity including the conserved triad Asp87/Arg137/Asp85. The Y88A mutant protein was equally active against both dUTP and UTP, indicating that this conserved tyrosine residue is responsible for discrimination against ribonucleotides. The structure of DUT1 and site-directed mutagenesis support a role of the conserved Phe142 in the interaction with the uracil base. Our work provides further insight into the molecular mechanisms of substrate selectivity and catalysis of dUTPases.