ero Les élections seront-elles l’étincelle qui mettra le feu au Burundi ? By feedproxy.google.com Published On :: Wed, 03 Jun 2015 22:00:00 GMT Tous les éléments d’une confrontation violente sont en place en Burundi. En observant les derniers développements, il semble que les éléments qui ont conduit par le passé à des massacres et à une longue guerre civile au début des années 1990 se remettent en place. Full Article
ero Cameroon: The Threat of Religious Radicalism By feedproxy.google.com Published On :: Thu, 03 Sep 2015 09:56:00 GMT Religious intolerance is a growing but seriously underestimated risk in Cameroon, both between and inside the major faiths. To halt the spread of violent extremism in the country, Cameroon needs to bring all sects into a new social compact and within the bounds of a charter for religious tolerance. Full Article
ero Cameroon’s Rising Religious Tensions By feedproxy.google.com Published On :: Mon, 07 Sep 2015 22:00:00 GMT The image of Cameroon as an island of peace amidst regional turmoil ended in 2013, when Boko Haram’s violence first crossed the Nigerian border. The militant group is affiliated with so-called Islamic State or Daesh, and even renamed itself Islamic State in West Africa earlier this year. But the brutal form of African jihadism it represents is hardly a result of the Islamic State’s rise in Iraq and Syria. In fact, it is in part a consequence of Africa’s changing religious landscape – not least in Cameroon. Full Article
ero Cameroun : au-delà de Boko Haram, la menace insidieuse du radicalisme religieux By feedproxy.google.com Published On :: Wed, 16 Sep 2015 22:00:00 GMT L’image de havre de paix dans une région en proie aux conflits dont bénéficiait le Cameroun a volé en éclats depuis l’irruption de Boko Haram en 2013 au nord du pays. Ce mouvement, devenu l’Etat islamique en Afrique de l’Ouest en mars 2015, revendique son affiliation à Daech. Néanmoins, l’apparition brutale et sanglante de ce djihadisme africain est moins liée à l’essor de Daech en Irak et en Syrie qu’aux bouleversements du paysage religieux de l’Afrique en général et du Cameroun en particulier. Full Article
ero Burundi: A Dangerous Third Term By feedproxy.google.com Published On :: Fri, 20 May 2016 10:03:00 GMT The current political crisis has reopened the wounds of Burundi’s past. Hardliners now dominant in the government brutally stifle dissent, fuel ethnic hatred, and undermine the Arusha accord that framed Burundi’s peace for the past decade. The international community should push toward real dialogue, and prepare to intervene if violence escalates. Full Article
ero Impact of KPC-production and high-level meropenem resistance on all-cause mortality of ventilator-associated pneumonia in association with Klebisella pneumoniae [Clinical Therapeutics] By aac.asm.org Published On :: 2020-03-23T08:47:35-07:00 Objectives: Carbapenemase-producing Enterobacterales and specifically KPC-producing Klebsiella pneumoniae (KPC-Kp) are rapidly spreading worldwide. The prognosis of ventilator-associated pneumonia (VAP) caused by KPC-producing Klebsiella pneumoniae (KPC-Kp) is not well known. Our study tries to assess whether ventilator-associated pneumonia caused by a KPC-Kp strain is associated with higher all-cause mortality than if caused by carbapenem-susceptible isolates.Study design and methods: This is a retrospective cohort study of patients with VAP due to K. pneumoniae from a 35-bed polyvalent Intensive Care Unit in a university hospital (> 40,000 annual admissions) between January 2012 and December 2016. Adjusted multivariate analysis was used to study the association of KPC-Kp with 30-day all-cause mortality (Cox regression).Results. We analyze 69 cases of K. pneumoniae VAP of which 39 were produced by a KPC-Kp strain with high-level resistance to meropenem (MIC > 16 mg/mL). All-cause mortality at 30 days was 41% in the KPC-Kp group (16/39) and 33.3% in the carbapenem-susceptible cases (10/30). KPC-Kp etiology was not associated with higher mortality when controlled for confounders (adjusted hazard ratio [lsqb]HR[rsqb] 1.25; 95% CI: 0.46–3.41). Adequate targeted therapy (HR 0.03; 95% CI: <0.01–0.23) was associated with all-cause mortality.Conclussion. Assuming the limitations due to the available sample size, the prognosis of VAP caused by KPC-Kp is similar to VAPs caused by carbapenem-susceptible K. pneumoniae when appropriate treatment is used. Full Article
ero Complex response of the CpxAR two-component system to {beta}-lactams on antibiotic resistance and envelop homeostasis in Enterobacteriaceae [Mechanisms of Resistance] By aac.asm.org Published On :: 2020-03-30T10:04:32-07:00 The Cpx stress response is widespread among Enterobacteriaceae. We have previously reported a mutation in cpxA in a multidrug resistant strain of Klebsiella aerogenes isolated from a patient treated with imipenem. This mutation yields to a single amino acid substitution (Y144N) located in the periplasmic sensor domain of CpxA. In this work, we sought to characterize this mutation in Escherichia coli by using genetic and biochemical approaches. Here, we show that cpxAY144N is an activated allele that confers resistance to β-lactams and aminoglycosides in a CpxR-dependent manner, by regulating the expression of the OmpF porin and the AcrD efflux pump, respectively. We also demonstrate the intimate interconnection between Cpx system and peptidoglycan integrity on the expression of an exogenous AmpC β-lactamase by using imipenem as a cell wall active antibiotic or inactivation of penicillin-binding proteins. Moreover, our data indicate that the Y144N substitution abrogates the interaction between CpxA and CpxP and increase phosphotransfer activity on CpxR. Because the addition of a strong AmpC inducer such as imipenem is known to causes abnormal accumulation of muropeptides (disaccharide-pentapeptide, N-acetylglucosamyl-1,6-anhydro-N-acetylmuramyl-l-alanyl-d-glutamy-meso-diaminopimelic-acid-d-alanyl-d-alanine) in the periplasmic space, we propose these molecules activate the Cpx system by displacing CpxP from the sensor domain of CpxA. Altogether, these data could explain why large perturbations to peptidoglycan caused by imipenem lead to mutational activation of the Cpx system and bacterial adaptation through multidrug resistance. These results also validate the Cpx system, in particular the interaction between CpxA and CpxP, as a promising therapeutic target. Full Article
ero The Impact of Intrinsic Resistance Mechanisms on Potency of QPX7728, a New Ultra-Broad-Spectrum Beta-lactamase Inhibitor of Serine and Metallo Beta-Lactamases in Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii. [Mechanisms of Resis By aac.asm.org Published On :: 2020-03-30T10:04:32-07:00 QPX7728 is an ultra-broad-spectrum boronic acid beta-lactamase inhibitor that demonstrates inhibition of key serine and metallo beta-lactamases at a nano molar range in biochemical assays with purified enzymes. The broad-spectrum inhibitory activity of QPX7728 observed in biochemical experiments translates into enhancement of the potency of many beta-lactams against strains of target pathogens producing beta-lactamases. The impact of bacterial efflux and permeability on inhibitory potency were determined using isogenic panels of KPC-3 producing isogenic strains of K. pneumoniae and P. aeruginosa and OXA-23-producing strains of A. baumannii with various combinations of efflux and porin mutations. QPX7728 was minimally affected by multi-drug resistance efflux pumps in either Enterobacteriaceae, or in non-fermenters such as P. aeruginosa or A. baumannii. In P. aeruginosa, the potency of QPX7728 was further enhanced when the outer membrane is permeabilized. The potency of QPX7728 in P. aeruginosa is not affected by inactivation of the carbapenem porin OprD. While changes in OmpK36 (but not OmpK35) reduced the potency of QPX7728 (8-16-fold), QPX7728 (4 μg/ml) nevertheless completely reversed KPC-mediated meropenem resistance in strains with porin mutations, consistent with a lesser effect of these mutations on the potency of QPX7728 compared to other agents. The ultra-broad-spectrum beta-lactamase inhibition profile combined with enhancement of the activity of multiple beta-lactam antibiotics with varying sensitivity to the intrinsic resistance mechanisms of efflux and permeability indicate QPX7728 is a useful inhibitor for use with multiple beta-lactam antibiotics. Full Article
ero MgrB inactivation is responsible for acquired resistance to colistin in Enterobacter hormaechei subsp. steigerwaltii [Mechanisms of Resistance] By aac.asm.org Published On :: 2020-04-06T08:49:26-07:00 Multidrug resistant strains belonging to the Enterobacter cloacae complex (ECC) group, and especially those belonging to clusters C-III, C-IV and C-VIII, have increasingly emerged as a leading cause of healthcare-associated infections, with colistin used as one of the last line of treatment. However, colistin-resistant ECC strains have emerged. The aim of this study was to prove that MgrB, the negative regulator of PhoP/PhoQ two-component regulatory system, is involved in colistin resistance in ECC of cluster C-VIII, formerly referred to as Enterobacter hormaechei subsp. steigerwaltii. An in vitro mutant (Eh22-Mut) was selected from a clinical isolate of Eh22. The sequencing analysis of its mgrB gene showed the presence of one nucleotide deletion leading to the formation of a truncated protein of six instead of 47 amino acids. Wild-type mgrB gene from Eh22, as well as that of a clinical strain of Klebsiella pneumoniae used as controls, were cloned and the corresponding recombinant plasmids were used for complementation assays. Results showed a fully restored susceptibility to colistin, and confirmed for the first time that mgrB gene expression plays a key role in acquired resistance to colistin in ECC strains. Full Article
ero Transferable Resistance Gene optrA in Enterococcus faecalis from Swine in Brazil [Mechanisms of Resistance] By aac.asm.org Published On :: 2020-04-06T08:49:25-07:00 OptrA is an ATP-binding cassette (ABC)-F protein that confers resistance to oxazolidinones and phenicols, and can be either plasmid or chromosomally encoded. We isolated 13 Enterococcus faecalis strains possessing linezolid MIC ≥ 4 mg/L from nursery pigs in swine herds located across Brazil. Genome sequence comparison showed that these strains possess optrA in different genetic contexts occurring in 5 different E. faecalis sequence type backgrounds. The optrA gene invariably occurred in association with an araC regulator and a gene encoding a hypothetical protein. In some contexts, this genetic island was able to excise and form a covalently closed circle within the cell which appeared to occur in high abundance, and to be transmissible by co-resident plasmids. Full Article
ero Oral Fosfomycin Treatment for Enterococcal Urinary Tract Infections in a Dynamic In Vitro Model [Pharmacology] By aac.asm.org Published On :: 2020-04-06T08:49:25-07:00 There are limited treatment options for enterococcal urinary tract infections, especially vancomycin-resistant Enterococcus (VRE). Oral fosfomycin is a potential option, although limited data are available guiding dosing and susceptibility. We undertook pharmacodynamic profiling of fosfomycin against E. faecalis and E. faecium isolates using a dynamic in vitro bladder infection model. Eighty-four isolates underwent fosfomycin agar dilution susceptibility testing (E. faecalis MIC50/90 32/64 μg/mL; E. faecium MIC50/90 64/128 μg/mL). Sixteen isolates (including E. faecalis ATCC 29212 and E. faecium ATCC 35667) were chosen to reflect the MIC range and tested in the bladder infection model with synthetic human urine (SHU). Under drug-free conditions, E. faecium demonstrated greater growth restriction in SHU compared to E. faecalis (E. faecium maximal growth 5.8 ± 0.6 log10 CFU/mL; E. faecalis 8.0 ± 1.0 log10 CFU/mL). Isolates were exposed to high and low fosfomycin urinary concentrations after a single dose, and two-doses given daily with low urinary exposure. Simulated concentrations closely matched the target (bias 2.3%). E. faecalis isolates required greater fosfomycin exposure for 3 log10 kill from the starting inoculum compared with E. faecium. The fAUC0-72/MIC and f%T > MIC0-72 for E. faecalis was 672 and 70%, compared to 216 and 51% for E. faecium, respectively. There was no rise in fosfomycin MIC post-exposure. Two doses of fosfomycin with low urinary concentrations resulted in equivalent growth inhibition to a single dose with high urinary concentrations. With this urinary exposure, fosfomycin was effective in promoting suppression of regrowth (>3 log10 kill) in the majority of isolates. Full Article
ero Structural recognition of spectinomycin by resistance enzyme ANT(9) from Enterococcus faecalis [Mechanisms of Resistance] By aac.asm.org Published On :: 2020-04-06T08:49:25-07:00 Spectinomycin is a ribosome-binding antibiotic that blocks the translocation step of translation. A prevalent resistance mechanism is the modification of the drug by aminoglycoside nucleotidyl transferase (ANT) enzymes of the spectinomycin-specific ANT (9) family or by the dual-specificity ANT(3") (9) family that also acts on streptomycin. We previously reported the structural mechanism of streptomycin modification by the ANT(3") (9) AadA from Salmonella enterica. ANT (9) from Enterococcus faecalis adenylates the 9-hydroxyl of spectinomycin. We here present the first structures of spectinomycin bound to an ANT enzyme. Structures were solved for ANT (9) in apo form, in complex with ATP, spectinomycin and magnesium or in complex with only spectinomycin. ANT (9) shows similar overall structure as AadA with an N-terminal nucleotidyltransferase domain and a C-terminal α-helical domain. Spectinomycin binds close to the entrance of the interdomain cleft, while ATP is buried at the bottom. Upon drug binding, the C-terminal domain rotates by 14 degrees to close the cleft, allowing contacts of both domains with the drug. Comparison with AadA shows that spectinomycin specificity is explained by a straight α5 helix and a shorter α5-α6 loop that would clash with the larger streptomycin substrate. In the active site, we observe two magnesium ions, one of them in a previously un-observed position that may activate the 9-hydroxyl for deprotonation by the catalytic base Glu-86. The observed binding mode for spectinomycin suggests that also spectinamides and aminomethyl spectinomycins, recent spectinomycin analogues with expansions in position 4 of the C ring, will be subjected to modification by ANT (9) and ANT(3") (9) enzymes. Full Article
ero Structural basis of reduced susceptibility to ceftazidime-avibactam and cefiderocol in Enterobacter cloacae due to AmpC R2 loop deletion [Mechanisms of Resistance] By aac.asm.org Published On :: 2020-04-13T08:15:30-07:00 Ceftazidime–avibactam and cefiderocol are two of the latest generation β-lactam agents that possess expanded activity against highly drug-resistant bacteria, including carbapenem-resistant Enterobacterales. Here we show that structural changes in AmpC β-lactamases can confer reduced susceptibility to both agents. A multidrug-resistant Enterobacter cloacae clinical strain (Ent385) was found to be resistant to ceftazidime–avibactam and cefiderocol without prior exposure to either agent. The AmpC β-lactamase of Ent385 (AmpCEnt385) contained an alanine–proline deletion at positions 294–295 (A294_P295del) in the R2 loop. AmpCEnt385 conferred reduced susceptibility to ceftazidime–avibactam and cefiderocol when cloned into Escherichia coli TOP10. Purified AmpCEnt385 showed increased hydrolysis of ceftazidime and cefiderocol compared with AmpCEnt385Rev, in which the deletion was reverted. Comparisons of crystal structures of AmpCEnt385 and AmpCP99, the canonical AmpC of E. cloacae, revealed that the two-residue deletion in AmpCEnt385 induced drastic structural changes of the H-9 and H-10 helices and the R2 loop, which accounted for the increased hydrolysis of ceftazidime and cefiderocol. The potential for a single mutation in ampC to confer reduced susceptibility to both ceftazidime–avibactam and cefiderocol requires close monitoring.Importance Ceftazidime–avibactam and cefiderocol are newly approved β-lactam agents that possess broad spectrum activity against multidrug-resistant (MDR) Gram-negative bacteria. We show here that a two amino-acid deletion in the chromosomal AmpC β-lactamase, identified in a clinical strain of Enterobacter cloacae, confers reduced susceptibility to both agents. By crystallographic studies of free and drug-bound forms of enzyme, we demonstrate that this deletion in AmpC induces slanting of the H-9 helix that is directly connected with the R2 loop, and disappearance of the H-10 helix, is directly responsible for increased hydrolysis of ceftazidime and cefiderocol. These findings provide novel insights into how MDR Gram-negative bacteria may evolve their β-lactamases to survive selective pressure from these newly developed β-lactam agents. Full Article
ero Epidemiological study on prevalence, serovar diversity, multi-drug resistance and CTX-M-type extended-spectrum {beta}-lactamases of Salmonella spp. from patients with diarrhea, food of animal origin, and pets in several provinces of China [Epidemiology an By aac.asm.org Published On :: 2020-04-20T08:36:46-07:00 A total of 2,283 Salmonella spp. isolates were recovered from 18,334 samples including patients with diarrhea, food of animal origin and pets across 5 provinces of China. The highest prevalence of Salmonella spp. was detected in chicken meats (39.3%, 486/1,237). Fifteen serogroups and 66 serovars were identified, with Typhimurium and Enteritidis being the most dominant. Most (85.5%, 1,952/2,283) isolates exhibited resistant to ≥ 1 antimicrobial and 56.4% were multi-drug resistant (MDR). A total of 222 isolates harbored extended-spectrum β-lactamases (ESBLs), 200 of which were CTX-M-type that were mostly detected from chicken meat and turtle fecal. Overall, eight blaCTX-M genes were identified, with blaCTX-M-65, blaCTX-M-123, blaCTX-M-14, blaCTX-M-79, and blaCTX-M-130 being the most prevalent. Totally, 166 of the 222 ESBL-producing isolates had amino acid substitutions in GyrA (S83Y, S83F, D87G, D87N, and D87Y) and ParC (and S80I), whilst the PMQR-encoding genes oqxA/B, qepA, and qnrB/S were detected in almost all isolates. Of the fifteen sequence types (STs) identified in the 222 ESBLs, ST17, ST11, ST34, and ST26 ranked among the top 5 in the number of isolates. Our study revealed considerable serovars diversity, high prevalence of co-occurrence of MDR determinants, including CTX-M-type ESBLs, QRDRs mutations and PMQR genes. This is the first report of CTX-M-130 Salmonella spp. from patients with diarrhea and QRDRs mutations from turtle fecal samples. Our study emphasizes the importance of actions, both in the health care settings and in the veterinary medicine sector, to control the dissemination of MDR, especially the CTX-M Salmonella spp. isolates. Full Article
ero Mutation of kvrA causes OmpK35/36 porin downregulation and reduced meropenem/vaborbactam susceptibility in KPC-producing Klebsiella pneumoniae. [Mechanisms of Resistance] By aac.asm.org Published On :: 2020-04-20T08:36:46-07:00 Meropenem/vaborbactam resistance in Klebsiella pneumoniae is associated with loss of function mutations in the OmpK35 and OmpK36 porins. Here we identify two previously unknown loss of function mutations that confer cefuroxime resistance in K. pneumoniae. The proteins lost were NlpD and KvrA; the latter is a transcriptional repressor controlling capsule production. We demonstrate that KvrA loss reduces OmpK35 and OmpK36 porin production, which confers reduced susceptibility to meropenem/vaborbactam in a KPC-3 producing K. pneumoniae isolate. Full Article
ero Impact of vanA-positive Enterococcus faecium exhibiting diverse susceptibility phenotypes to glycopeptides on 30-day mortality of patients with a bloodstream infection [Epidemiology and Surveillance] By aac.asm.org Published On :: 2020-04-27T08:14:57-07:00 Introduction: This study was performed to evaluate the impacts of vanA-positivity of Enterococcus faecium (EFM) exhibiting diverse susceptibility phenotypes to glycopeptides on clinical outcomes in patients with a bloodstream infection (BSI) through a prospective, multicenter, observational study.Methods: A total of 509 patients with an EFM BSI from eight sentinel hospitals in South Korea during a two-year period were enrolled in this study. Risk factors of the hosts and causative EFM isolates were assessed to determine associations with the 30-day mortality of EFM BSI patients via multivariable logistic regression analyses.Results: The vanA gene was detected in 35.2% (179/509) of EFM isolates; 131 EFM isolates exhibited typical VanA phenotypes (group vanA-VanA), while the remaining 48 EFM isolates exhibited atypical phenotypes (group vanA-Atypical), including VanD (n = 43) and vancomycin-variable phenotypes (n = 5). A multivariable logistic regression indicated that vanA-positivity of causative pathogens was independently associated with the increased 30-day mortality rate in the patients with an EFM BSI; however, there was no significant difference in the survival rates between the patients of the vanA-VanA and vanA-Atypical groups (log-rank test, P = 0.904).Conclusions: A high 30-day mortality rate was observed in patients with vanA-positive EFM BSIs, and vanA-positivity of causative EFM was an independent risk factor for early mortality irrespective of the susceptibility phenotypes to glycopeptides; thus, intensified antimicrobial stewardship is needed to improve clinical outcome of patients with vanA-positive EFM BSI. Full Article
ero Clinically relevant epithelial lining fluid concentrations of meropenem with ciprofloxacin provide synergistic killing and resistance suppression of hypermutable Pseudomonas aeruginosa in a dynamic biofilm model [Pharmacology] By aac.asm.org Published On :: 2020-05-04T08:49:24-07:00 Treatment of exacerbations of chronic Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF) is highly challenging due to hypermutability, biofilm formation and an increased risk of resistance emergence. We evaluated the impact of ciprofloxacin and meropenem as monotherapy and in combination in the dynamic in vitro CDC biofilm reactor (CBR). Two hypermutable P. aeruginosa strains, PAOmutS (MICciprofloxacin 0.25 mg/L, MICmeropenem 2 mg/L) and CW44 (MICciprofloxacin 0.5 mg/L, MICmeropenem 4 mg/L), were investigated for 120h. Concentration-time profiles achievable in epithelial lining fluid (ELF) following FDA-approved doses were simulated in the CBR. Treatments were ciprofloxacin 0.4g every 8h as 1h-infusions (80% ELF penetration), meropenem 6 g/day as continuous infusion (CI; 30% and 60% ELF penetration) and their combinations. Counts of total and less-susceptible planktonic and biofilm bacteria and MICs were determined. Antibiotic concentrations were quantified by UHPLC-PDA. For both strains, all monotherapies failed with substantial regrowth and resistance of planktonic (≥8log10 CFU/mL) and biofilm (>8log10 CFU/cm2) bacteria at 120h (MICciprofloxacin up to 8 mg/L, MICmeropenem up to 64 mg/L). Both combination treatments demonstrated synergistic bacterial killing of planktonic and biofilm bacteria of both strains from ~48h onwards and suppressed regrowth to ≤4log10 CFU/mL and ≤6log10 CFU/cm2 at 120h. Overall, both combination treatments suppressed amplification of resistance of planktonic bacteria for both strains, and biofilm bacteria for CW44. The combination with meropenem at 60% ELF penetration also suppressed amplification of resistance of biofilm bacteria for PAOmutS. Thus, combination treatment demonstrated synergistic bacterial killing and resistance suppression against difficult-to-treat hypermutable P. aeruginosa strains. Full Article
ero Quercetin blocks Ebola Virus infection by counteracting the VP24 Interferon inhibitory function [Antiviral Agents] By aac.asm.org Published On :: 2020-05-04T08:49:24-07:00 Ebola Virus (EBOV) is among the most devastating pathogens causing fatal hemorrhagic fever in humans. The 2013–2016 epidemics resulted in over 11000 deaths, while another outbreak is currently ongoing. Since there is no FDA-approved drug so far to fight EBOV infection, there is an urgent need to focus on drug discovery. Considering the tight correlation between the high EBOV virulence and its ability to suppress the type-I Interferon (IFN-I) system, identifying molecules targeting viral protein VP24, one of the main virulence determinants blocking IFN response, is a promising novel anti-EBOV therapy approach. Hence, in the effort of finding novel EBOV inhibitors, a screening of a small set of flavonoids was performed, showing that Quercetin and Wogonin can suppress the VP24 effect on IFN-I signaling inhibition. The mechanism of action of the most active compound, Quercetin, showing an IC50 value of 7.4 μM, was characterized to significantly restore the IFN-I signaling cascade, blocked by VP24, by directly interfering with the VP24 binding to karyopherin-α and thus restoring P-STAT1 nuclear transport and IFN genes transcription. Quercetin significantly blocked viral infection, specifically targeting EBOV VP24 anti-IFN-I function. Overall, Quercetin is the first identified inhibitor of the EBOV VP24 anti-IFN function, representing a molecule interacting with a viral binding site that is very promising for further drug development aiming to block EBOV infection at the early steps. Full Article
ero Evaluation of leishmanicidal activity of an in silico screened novel inhibitor against ascorbate peroxidase of Leishmania donovani [Mechanisms of Action] By aac.asm.org Published On :: 2020-05-04T08:49:24-07:00 Peroxidases are a group of heterogeneous family of enzyme that plays diverse biological functions. Ascorbate peroxidase is a redox enzyme that is reduced by trypanothione, which plays a central role in the redox defence system of Leishmania. In view of developing new and novel therapeutics, we have performed in silico studies in order to search for ligand library and identification of new drug candidates and its physiological role against promastigotes and intracellular amastigotes of Leishmania donovani. Our results demonstrated that the selected inhibitor ZINC96021026 has significant anti-leishmanial effect and effectively killed both free and intracellular forms of the parasite. ZINC96021026 was found to be identical to ML-240, a selective inhibitor of Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family which was derived from the scaffold of DBeQ, targeting the D2-ATPase domain of the enzyme. ZINC96021026 (ML-240) thus have broad range of cellular functions, thought to be derived from its ability to unfold proteins or disassemble protein complexes besides inhibiting the ascorbate peroxidase activity. ML-240 may inhibits the parasite's ascorbate peroxidase leading to extensive apoptosis and inducing generation of reactive oxygen species. Taken together, our results demonstrated that ML-240 could be an attractive therapeutic option for treatment against leishmaniasis. Full Article
ero Fin24.com | Gold falls as moves to reopen economies erode appetite for havens By www.fin24.com Published On :: Tue, 28 Apr 2020 11:57:28 +0200 The precious metal eased for a third day after US equities hit the highest in almost seven weeks as states including Florida took steps toward easing restrictions. Full Article
ero Dietary Fats and Atherosclerosis From Childhood to Adulthood By pediatrics.aappublications.org Published On :: 2020-04-01T01:00:57-07:00 BACKGROUND: The association of dietary fat distribution with markers of subclinical atherosclerosis during early life is unknown. We examined whether success in achieving the main target of an infancy-onset dietary intervention based on the distribution of dietary fat was associated with aortic and carotid intima-media thickness (IMT) and distensibility from childhood to young adulthood. METHODS: In the prospective randomized controlled Special Turku Coronary Risk Factor Intervention Project trial, personalized dietary counseling was given biannually to healthy children from infancy to young adulthood. The counseling was based on Nordic Nutrition Recommendations, with the main aim of improving the distribution of dietary fat in children’s diets. IMT and distensibility of the abdominal aorta and common carotid artery were measured repeatedly at ages 11 (n = 439), 13 (n = 499), 15 (n = 506), 17 (n = 477), and 19 years (n = 429). The targeted distribution of dietary fat was defined as a ratio of saturated fatty acids to monounsaturated and polyunsaturated fatty acids of <1:2 and as an intake of saturated fatty acids of <10% of energy intake. Participants who met ≥1 of these 2 criteria were defined to achieve the main intervention target. RESULTS: Individuals who achieved the main intervention target had lower aortic IMT (age- and sex-adjusted mean difference 10.4 µm; 95% confidence interval: 0.3 to 20.5 µm) and better aortic distensibility (0.13% per 10 mm Hg; 95% confidence interval: 0.00% to 0.26% per10 mm Hg) compared with their peers who did not meet the target. CONCLUSIONS: Achieving the main target of an infancy-onset dietary intervention, reflecting dietary guidelines, was favorably associated with aortic IMT and distensibility during the early life course. These data support the recommendation of favoring unsaturated fat to enhance arterial health. Full Article
ero Non-HDL Cholesterol Levels in Childhood and Carotid Intima-Media Thickness in Adulthood By pediatrics.aappublications.org Published On :: 2020-04-01T01:00:57-07:00 BACKGROUND: Elevated non–high-density lipoprotein cholesterol (HDL-C) levels are used to identify children at increased cardiovascular risk, but the use of non–HDL-C in childhood to predict atherosclerosis is unclear. We examined whether the National Heart, Lung, and Blood Institute classification of youth non–HDL-C status predicts high common carotid artery intima-media thickness in adulthood. METHODS: We analyzed data from 4 prospective cohorts among 4582 children aged 3 to 19 years who were remeasured as adults (mean follow-up of 26 years). Non–HDL-C status in youth and adulthood was classified according to cut points of the National Heart, Lung, and Blood Institute and the National Cholesterol Education Program Adult Treatment Panel III. High carotid intima-media thickness (cIMT) in adulthood was defined as at or above the study visit-, age-, sex-, race-, and cohort-specific 90th percentile of intima-media thickness. RESULTS: In a log-binomial regression analysis adjusted with age at baseline, sex, cohort, length of follow-up, baseline BMI, and systolic blood pressure, children with dyslipidemic non–HDL-C were at increased risk of high cIMT in adulthood (relative risk [RR], 1.29; 95% confidence interval [CI], 1.07–1.55). Compared with the persistent normal group, the persistent dyslipidemia group (RR, 1.80; 95% CI, 1.37–2.37) and incident dyslipidemia (normal to dyslipidemia) groups (RR, 1.45; 95% CI, 1.07–1.96) had increased risk of high cIMT in adulthood, but the risk was attenuated for the resolution (dyslipidemia to normal) group (RR, 1.17; 95% CI, 0.97–1.41). CONCLUSIONS: Dyslipidemic non–HDL-C levels predict youth at risk for developing high cIMT in adulthood. Those who resolve their non–HDL-C dyslipidemia by adulthood have normalized risk of developing high cIMT in adulthood. Full Article
ero Continuous Albuterol With Benzalkonium in Children Hospitalized With Severe Asthma By pediatrics.aappublications.org Published On :: 2020-04-01T01:00:57-07:00 BACKGROUND AND OBJECTIVES: The albuterol dropper bottle used to prepare solutions for continuous nebulization contains the preservative benzalkonium chloride (BAC). BAC, by itself, has been shown to cause bronchospasm. We hypothesized that BAC would decrease the therapeutic efficacy of albuterol in patients with acute asthma exacerbations. METHODS: We performed a retrospective cohort study comparing the clinical outcomes of patients <18 years of age receiving continuous nebulized albuterol with and without BAC. For the primary end point (duration of continuous albuterol nebulization), we compared the 2 groups with Kaplan-Meier estimate of survival curves, conducted a log-rank test of difference, and adjusted for baseline characteristics using multivariable Cox regression. A P value <.05 was considered significant. RESULTS: A total of 477 patients were included in the analysis (236 exposed to BAC and 241 controls). The duration of continuous nebulization was significantly longer in the BAC group than in the control group (median of 9 vs 6 hours; 15.7% required continuous nebulization compared to 5.8% of controls at 24 hours). The control group was 79% more likely to stop continuous nebulization at any particular point in time (hazard ratio 1.79; 95% confidence interval: 1.45 to 2.22; P < .001) and 43% more likely to stop additional respiratory support (hazard ratio 1.43; 95% confidence interval: 1.16 to 1.75; P < .001). CONCLUSIONS: BAC is a functional albuterol antagonist associated with a longer duration of continuous albuterol nebulization treatment and additional respiratory support, suggesting that preservative-free albuterol formulations are safer for use in continuous nebulization. Full Article
ero 'A Hero to Many Children': Teachers Reflect on Kobe Bryant's Legacy in Class By feedproxy.google.com Published On :: Mon, 27 Jan 2020 00:00:00 +0000 Many teachers scrapped their lesson plans on Monday and gave their students space to talk about Kobe Bryant. Full Article Sports
ero Prolonged Duration of Initial Empirical Antibiotic Treatment Is Associated With Increased Rates of Necrotizing Enterocolitis and Death for Extremely Low Birth Weight Infants By pediatrics.aappublications.org Published On :: 2009-01-01 C. Michael CottenJan 1, 2009; 123:58-66ARTICLES Full Article
ero Hunger in Venezuela becoming 'a fuel more dangerous than gasoline' By feedproxy.google.com Published On :: Sun, 26 Apr 2020 06:18:00 -0600 Lima, Peru, Apr 26, 2020 / 06:18 am (CNA).- An archbishop in Venezuela warned that desperation is growing in the country, as the national coronavirus quarantine measures have compounded a tenuous political and economic situation. He urged people in the country to resist violence and social unrest. Extreme hunger “does not reason or know rules,” said Archbishop Ulises Gutiérrez of Ciudad Bolívar, adding that this desperate hunger “is becoming a fuel more dangerous than gasoline.” Gutiérrez spoke with ACI Prensa, CNA’s Spanish language news partner, in an April 23 interview, after looting and protests broke out in seven states in Venezuela. Protestors objected to price hikes on food and a gasoline shortage exacerbated by the ongoing quarantine that was imposed last month to halt the spread of the COVID-19 pandemic. According to the latest government report, there have been 298 cases and 10 deaths in the country due to the virus. Even before the coronavirus pandemic, Venezuela has been marred by violence and social upheaval under the socialist administration of Nicolas Maduro, with severe shortages of food and medicine, high unemployment, power outages, and hyperinflation. Some 4.5 million Venezuelans have emigrated since 2015. The current COVID-19 quarantine is “aggravating the situation,” the archbishop said, noting that the quarantine was implemented without accompanying measures to protect the most vulnerable. As a result, families are suffering, and many cannot access clean water, electricity or gasoline. The country is experiencing “a totally destroyed economy in which agricultural producers can’t get their products out because they’re not getting gasoline supplied to them, or they have to buy it on the black market for 2 or 3 dollars a liter,” he said. In some cases, crops are rotting in farmers’ fields due to lack of fuel to transport them to market. Gutiérrez voiced concern over the hunger-fueled looting and protests throughout the country, as well as the government’s violent suppression of the protests. “The common denominator in all these protests is hunger,” he stressed. With equipment in short supply and many of the country’s doctors have already emigrated due to the political and economic crisis, Gutiérrez acknowledged, the pandemic poses a significant threat. “In short, the outlook is very dark,” he said. But despite the desperate situation, the archbishop urged people not to resort to looting and violence. “[S]atisfying hunger short term [by committing robbery] only leads to the destruction of regular commerce,” he said. “The situation we’re going through is very tough, difficult, and fragile,” Gutiérrez said, likening the conditions to a pressure cooker, “which could lead us to unprecedented explosive social unrest, which nobody wants, and which would bring with it more hunger and greater suffering for the people.” Still, the archbishop said he has reason for hope: “Our trust is in God and his providence keeps us going, encouraging and accompanying our people, assisting them with our Caritas social programs.” “We have community soup kitchens, a medicine bank, outpatient medical care, programs for infant nutrition and nursing mothers, etc., which although it’s impossible to reach everyone, is a sign of God’s love through the Church,” he said. Full Article Americas
ero How Dangerous Is Your Foreign VPN? By www.pcmag.com Published On :: The US government thinks VPNs based in other countries are a threat, but the question of trustworthiness is more complicated than mere physical addresses. Senior security analyst Max Eddy tells you what you need to know about the software you use to stay safe online. Full Article
ero Portugal welcomes home its conquering heroes By www.uefa.com Published On :: Mon, 11 Jul 2016 18:45:00 GMT "You won with courage, determination, fighting spirit and humility," said the president of Portugal, as Fernando Santos, Cristiano Ronaldo and the team brought the Henri Delaunay Trophy home. Full Article general
ero James Cameron Unveils Strange Mercedes Avatar Concept Car By www.pcmag.com Published On :: From the creepy scales to the gaping wheel arches, the Vision Avtr is not particularly attractive, but it is environmentally friendly, from its vegan leather interior to its compostable battery. Full Article
ero Liam Payne & Chloe X Halle Hail The Heroes During The Coronavirus Pandemic By www.youtube.com Published On :: Fri, 08 May 2020 23:33:32 GMT Source: www.youtube.com - Friday, May 08, 2020All Related Full Article
ero DSHA’s Loans for Heroes Helps Delaware Veterans Find a Place to Call Home in the First State By news.delaware.gov Published On :: Fri, 09 Nov 2012 16:00:28 +0000 Loans for Heroes, which provides veterans with reduced mortgage rates, has funded $3.3 million in mortgage loans since it launched in May of 2012. Full Article Delaware State Housing Authority Former Governor Jack Markell (2009-2017) Office of the Governor Housing qualityoflife ResponsibleGovernment Veterans
ero One Hero at a Time: Update on Delaware’s Challenge to House Homeless Veterans By news.delaware.gov Published On :: Wed, 23 Dec 2015 14:32:39 +0000 On any given night, 100 Veterans in Delaware are homeless. For seven years, Henry Smith was one of them. An honorably discharged Veteran of the U.S. Army, Mr. Smith lived off and on in rooming houses and in 2015 was referred by the Wilmington VA Medical Center to Connections’ VA-funded Supportive Services for Veteran Families (SSVF) program. SSVF provides a range of supportive services and assistance to help Veterans secure housing stability. He entered the program on November 5, 2015 and was housed on December 3. “After being homeless for seven years, I thought housing was impossible,” said Mr. Smith. “My apartment is quiet, clean, and well-kept. Connections worked hard to establish a rapport with the landlord, and I hope more vets get the opportunity to be housed.” Full Article Delaware State Housing Authority Housing qualityoflife ResponsibleGovernment
ero The Dangerous Narrative That Lurks Under the 'Achievement Gap' By feedproxy.google.com Published On :: Thu, 05 Dec 2019 00:00:00 +0000 Black students are not to blame for their lack of educational opportunities, argues assistant principal Eric Higgins. Full Article Achievement+gap
ero Dover Heroin Dealer Sent to Prison By news.delaware.gov Published On :: Fri, 23 Aug 2019 18:15:06 +0000 DOJ Community Engagement Unit Hosts Back to School Fair A Dover man targeted in a drug investigation after selling heroin to an undercover police officer was sentenced to prison. Deputy Attorney General Gregory Babowal secured the sentence for 26-year-old Javon Young. In January 2019, members of the State Police Kent County Drug Unit and Kent […] Full Article Department of Justice Department of Justice Press Releases Attorney General Kathy Jennings Community Engagement Unit Criminal Division Delaware Department of Justice superior court
ero Netflix, Eros Now, other OTT platforms tie up with airlines to tap large user base By www.financialexpress.com Published On :: 2019-10-07T16:43:36+05:30 OTT platforms are partnering with travel agencies, airlines and cruises to tap on-the-go audiences Full Article Brand Wagon Industry
ero Governor Markell Recognizes Recipients of the Delaware Award for Heroism By news.delaware.gov Published On :: Thu, 08 May 2014 20:08:13 +0000 Twenty-seven state employees were recognized for their acts of bravery. Full Article Former Governor Jack Markell (2009-2017) News Office of Management and Budget Office of the Governor "Governor Markell"
ero Prudential norms on Investment in Zero Coupon Bonds By www.lawyersclubindia.com Published On :: Thu, 30 Sep 2010 12:09:51 GMT Prudential norms on Investment in Zero Coupon Bonds Full Article
ero Erosion and Sediment Control Compliance By bids.delaware.gov Published On :: 4/15/2020 Agency: DOT Closing Date: 5/14/2020 Full Article
ero State of Delaware Employees Honored for Excellence and Commitment in State Service, Team Excellence, and Heroism By news.delaware.gov Published On :: Mon, 14 May 2018 13:30:05 +0000 Event held during the celebration of Public Service Recognition Week, May 6-12, 2018. WILMINGTON, Del. (May 11, 2018) —Governor John Carney and Cabinet members celebrated Public Service Recognition Week by applauding the extraordinary work of Delaware’s public servants. Awards for exemplary efforts in service to the State of Delaware were presented at the Governor’s Awards […] Full Article Delaware Health and Social Services Department of Correction Department of Finance Department of Human Resources Department of Natural Resources and Environmental Control Department of Services for Children Youth and their Families Department of Technology and Information Department of Transportation Governor John Carney News Office of Management and Budget Office of the Governor
ero Delaware Health Officials Issue Warning after 2 Deaths Involve Same Stamp on Packets of Heroin By news.delaware.gov Published On :: Tue, 29 May 2018 13:36:00 +0000 NEW CASTLE (May 28, 2018) – Department of Health and Social Services (DHSS) Secretary Dr. Kara Odom Walker is warning people in active substance use in Delaware that two people have died from suspected overdoses in a 24-hour period that involve heroin packets with the same stamp. DHSS is not identifying the stamp so people […] Full Article Delaware Health and Social Services Department of Safety and Homeland Security Division of Public Health News fatal overdose health and safety Naloxone opioid epidemic public safety
ero DPH Advises Residents to Prepare for Dangerously High Temperatures This Week By news.delaware.gov Published On :: Mon, 02 Jul 2018 20:48:39 +0000 As many Delawareans head outside for Fourth of July festivities, the Division of Public Health (DPH) encourages Delaware residents to prepare for extreme heat early this week and prevent heat-related illness as temperatures rise. Temperatures are expected to reach the mid-90s through Tuesday, with the heat index values as high as 105 degrees. Full Article Delaware Health and Social Services Division of Public Health News heat heat stroke pets public health summer warm weather
ero Code Purple Declared As Bitterly Cold Temperatures, Sub-Zero Wind Chills Arrive By news.delaware.gov Published On :: Wed, 30 Jan 2019 14:25:33 +0000 NEW CASTLE (Jan. 30, 2019) With Delaware facing the coldest temperatures of the winter from Wednesday night through Thursday, Code Purple is being declared across the state by the nonprofit and volunteer organizations that operate the shelters to keep people who are homeless safe during dangerous winter weather. When severe snowstorms or sub-zero temperatures are […] Full Article Delaware Health and Social Services Governor John Carney News Office of the Governor code purple cold homeless weather
ero Seek Treatment, Access to Naloxone: Three Suspected Heroin Overdose Deaths in Sussex Co. Involving Same Packet Stamp By news.delaware.gov Published On :: Wed, 13 Mar 2019 19:24:56 +0000 NEW CASTLE (March 13, 2019) – Health and public safety officials are urging people in active use of heroin or other opioids and their families to seek immediate treatment and acquire the overdose-reversing medication naloxone on hand in the wake of three suspected heroin overdose deaths in five days in Sussex County involving the same […] Full Article Delaware Health and Social Services Division of Public Health News Office of the Governor fatal overdose Fentanyl Heroin Naloxone overdose response
ero 2019 Mahindra TUV300 Facelift Review | The feature-rich urban Bolero By www.financialexpress.com Published On :: 2019-08-08T10:39:00+05:30 The facelift infuses life into the Mahindra TUV300 and makes it a more feature-rich SUV than what it was before. We have listed out the pros and cons of this SUV in the video. Full Article
ero Scientists witness true violence of Jupiter’s FEROCIOUS storms in greater detail than ever before By www.rt.com Published On :: Fri, 08 May 2020 09:40:05 +0000 A years-long observation program of the planet Jupiter has revealed some of the most detailed images ever captured of the gas giant, exposing the truly bizarre nature of its ultraviolent, planet-wide storms. Read Full Article at RT.com Full Article
ero Censors crack down on ‘Plandemic’ conspiracy documentary. What’s so dangerous about it? By www.rt.com Published On :: Sat, 09 May 2020 01:01:49 +0000 Pulled from YouTube, censored in internet searches, and denounced by every single mainstream media outlet, what kind of information could make everyone so mad about ‘Plandemic’? We watched it to find out. Read Full Article at RT.com Full Article
ero EU Commission aerosols approach ‘re-invents physics’ for CLP By chemicalwatch.com Published On :: Wed, 06 May 2020 16:20:00 GMT Trade association says proposal misunderstands complexity of spray formation Full Article
ero Covid-19: Deadline extensions, derogations and supply-chain news By chemicalwatch.com Published On :: Thu, 07 May 2020 15:27:00 GMT The latest news and developments Full Article
ero Nurse is the chosen superhero in new Banksy artwork By www.dailystar.com.lb Published On :: 2020-05-07T11:10:00.0000000 'Thanks for all you’re doing,' the artist said in a note for hospital workers. 'I hope this brightens the place up a bit, even if it’s only black and white.' Full Article Culture
ero Zero-emission electric truck showcased by ABB in Switzerland By www.financialexpress.com Published On :: 2019-06-22T00:34:00+05:30 Electric truck by ABB showcased in Swiss capital, Bern. Full Article Industry