Αρχειοθήκη ιστολογίου

Παρασκευή 22 Σεπτεμβρίου 2017

Logical Paradoxes and Paradoxical Constellations in Medicolegal Assessment

Abstract

In medicolegal contexts, the expert is confronted with a number of apparent or seemingly paradox constellations that are mostly not even explicit to the assessor involved, yet when they occur, they may have a profound effect on the shaping of the expert's opinion and, subsequently, on the outcome of litigation. Because the paradoxes in this forensic work have not been made explicit for the most part in the field, it can be assumed that forensic experts themselves are often unaware of paradoxical situations and logical incoherence to be found in many cases. Difficulties to positively diagnose somatoform and dissociative disorders in disability claimants and compensation-seeking litigants are among the most prominent of these paradoxes. For example, in these diagnoses, presumably unconscious core motives and an involuntarily, unconsciously distorted symptom presentation (both being central for the diagnosis) might contrast with conscious symptom magnification and pursuit of monetary interests on the part of the complainant (external incentives in the form of disability or compensation seeking). Other paradoxes discussed in more detail are linked with symptom validity assessment in forensic psychology. Logical dilemmas and paradoxes, if not placed at the forefront in forensic psychological evaluations, potentially undermine the quality of forensic determinations.



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mcr-1 and mcr-2 variant genes identified in Moraxella species isolated from pigs in Great Britain from 2014 to 2015

Abstract
Objectives
To determine the occurrence of mcr-1 and mcr-2 genes in Gram-negative bacteria isolated from healthy pigs in Great Britain.
Methods
Gram-negative bacteria (n =657) isolated from pigs between 2014 and 2015 were examined by WGS.
Results
Variants of mcr-1 and mcr-2 were identified in Moraxella spp. isolated from pooled caecal contents of healthy pigs at slaughter collected from six farms in Great Britain. Other bacteria, including Escherichia coli from the same farms, were not detected harbouring mcr-1 or mcr-2. A Moraxella porci-like isolate, MSG13-C03, harboured MCR-1.10 with 98.7% identity to MCR-1, and a Moraxella pluranimalium-like isolate, MSG47-C17, harboured an MCR-2.2 variant with 87.9% identity to MCR-2, from E. coli; the isolates had colistin MICs of 1–2 mg/L. No intact insertion elements were identified in either MSG13-C03 or MSG47-C17, although MSG13-C03 harboured the conserved nucleotides abutting the ISApl1 composite transposon found in E. coli plasmids and the intervening ∼2.6 kb fragment showed 97% identity. Six Moraxella osloensis isolates were positive for phosphoethanolamine transferase (EptA). They shared 62%–64.5% identity to MCR-1 and MCR-2, with colistin MICs from 2 to 4 mg/L. Phylogenetic analysis indicated that MCR and EptA have evolved from a common ancestor. In addition to mcr, the β-lactamase gene, blaBRO-1, was found in both isolates, whilst the tetracycline resistance gene, tetL, was found in MSG47-C17.
Conclusions
Our results add further evidence for the mobilization of the mcr-pap2 unit from Moraxella via composite transposons leading to its global dissemination. The presence of mcr-pap2 from recent Moraxella isolates indicates they may comprise a reservoir for mcr.

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Plazomicin activity against polymyxin-resistant Enterobacteriaceae, including MCR-1-producing isolates

Abstract
Objectives
Plazomicin, a novel aminoglycoside with in vitro activity against MDR Gram-negative organisms, is under development to treat patients with serious enterobacterial infections. We evaluated the activity of plazomicin and comparators against colistin-resistant enterobacterial isolates.
Methods
Susceptibility to plazomicin and comparators was tested by broth microdilution for a collection of 95 colistin-resistant enterobacterial isolates collected from 29 hospitals in eight countries. Forty-two isolates (Klebsiella pneumoniae and Klebsiella oxytoca) possessed chromosomally encoded resistance mechanisms to colistin, 21 isolates (Escherichia coli and Salmonella enterica) expressed the mcr-1 gene, 8 isolates (Serratia, Proteus, Morganella and Hafnia) were intrinsically resistant to colistin and 24 isolates (K. pneumoniae, E. coli and Enterobacter spp.) had undefined, non-mcr-1 mechanisms. Susceptibility profiles were defined according to CLSI for aminoglycosides and to EUCAST for colistin and tigecycline.
Results
Plazomicin inhibited 89.5% and 93.7% of the colistin-resistant enterobacterial isolates at ≤ 2 and ≤4 mg/L, respectively. MICs of plazomicin were ≤2 mg/L for all of the mcr-1 positive isolates and ≤4 mg/L for all the intrinsic colistin-resistant Enterobacteriaceae. Non-susceptibility to currently marketed aminoglycosides was common: amikacin, 16.8%; gentamicin, 47.4%; and tobramycin, 63.2%. Plazomicin was the most potent aminoglycoside tested with an MIC90 of 4 mg/L, compared with 32, >64 and 64 mg/L for amikacin, gentamicin and tobramycin, respectively.
Conclusions
Plazomicin displayed potent activity against colistin-resistant clinical enterobacterial isolates, including those expressing the mcr-1 gene. Plazomicin was more active than other aminoglycosides against this collection of isolates. The further development of plazomicin for the treatment of infections due to MDR Enterobacteriaceae is warranted.

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Dental staining after doxycycline use in children

Abstract
Background
The use of doxycycline has been avoided before 8 years of age due to known dental staining caused by tetracyclines, although doxycycline differs from classical tetracyclines in many ways. Doxycycline is still an important antimicrobial agent, but its dental safety is not well studied.
Objectives
To examine the state of permanent teeth after doxycycline exposure in children <8 years of age.
Methods
Details of doxycycline treatment were collected from medical records. After the eruption of permanent teeth the dental status was examined by an experienced paediatric dentist for detection of dental staining and enamel hypoplasia. The resulting dental photographs were evaluated by a second independent experienced paediatric dentist.
Results
The mean age of 38 study subjects at the time of doxycycline treatment was 4.7 years (range 0.6–7.9 years, SD 2.3). The doxycycline dose was 10 mg/kg/day (varying from 8 to 10 mg/kg/day) for the first 2–3 days and 5 mg/kg/day (varying from 2.5 to 10 mg/kg/day) thereafter. The mean length of the treatment was 12.5 days (SD 6.0) and ranged from 2 to 28 days. Tetracycline-like staining or enamel hypoplasia of developing teeth was detected in none of the subjects.
Conclusions
Doxycycline treatment of small children does not seem to induce permanent tooth staining.

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Identification of a novel qnrA allele, qnrA8 , in environmental Shewanella algae

Sir,

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Population pharmacokinetics of teicoplanin administered by subcutaneous or intravenous route and simulation of optimal loading dose regimen

Abstract
Objectives
To investigate the population pharmacokinetics of teicoplanin in patients treated by the subcutaneous (sc) and/or intravenous (iv) route.
Patients and methods
Non-linear mixed-effects modelling described teicoplanin concentrations from 98 patients with infection caused by Gram-positive cocci. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA) of various dosage regimens.
Results
Teicoplanin concentrations were best described by a two-compartment model with clearance predicted by estimated glomerular filtration rate. Estimated absorption rate constant (between-subject variability) was 0.039 h−1 (77%), clearance was 0.305 L/h (28%), central volume was 10.3 L (49%), inter-compartmental clearance was 4.42 L/h (66%) and peripheral volume was 97.4 L (51%). The sc route was associated with lower initial Cmin and AUC (day 3: loading phase) compared with the iv route. This difference appeared to vanish after 14 days, with comparable simulated PTAs based on the Cmin and AUC for all tested dosages (400, 600, 800 and 1000 mg every 12 h). However, a loading dose regimen with five administrations of either 400 or 600 mg was not sufficient to achieve the target Cmin (≥15 mg/L) for both routes. Also, PTAs for higher MIC (≥1.0 mg/L) were poor with all regimens for both routes.
Conclusions
This is the first study examining the pharmacokinetic/pharmacodynamic implications of using the sc route for teicoplanin. Subcutaneous administration is associated with lower Cmin and AUC values after the loading phase compared with iv administration. Therefore, iv administration should be preferred in the first few days of therapy. This study also shows that loading doses of teicoplanin higher than currently recommended should be used to improve PTA.

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Screening for synergistic activity of antimicrobial combinations against carbapenem-resistant Enterobacteriaceae using inkjet printer-based technology

Abstract
Background
Synergistic combination antimicrobial therapy may provide new options for treatment of MDR infections. However, comprehensive in vitro synergy data are limited and facile methods to perform synergy testing in a clinically actionable time frame are unavailable.
Objectives
To systematically investigate a broad range of antibiotic combinations for evidence of synergistic activity against a collection of carbapenem-resistant Enterobacteriaceae (CRE) isolates.
Methods
We made use of an automated method for chequerboard array synergy testing based on inkjet printer technology in the HP D300 digital dispenser to test 56 pairwise antimicrobial combinations of meropenem, aztreonam, cefepime, colistin, gentamicin, levofloxacin, chloramphenicol, fosfomycin, trimethoprim/sulfamethoxazole, minocycline and rifampicin, as well as the double carbapenem combination of meropenem and ertapenem.
Results
In a screening procedure, we tested these combinations against four CRE strains and identified nine antibiotic combinations that showed potential clinically relevant synergy. In confirmatory testing using 10 CRE strains, six combinations demonstrated clinically relevant synergy with both antimicrobials at the minimum fractional inhibitory concentration (FICI-MIN) in the susceptible or intermediate range in at least one trial. These included two novel combinations: minocycline plus colistin and minocycline plus meropenem. In 80% of strains at least one combination demonstrated clinically relevant synergy, but the combinations that demonstrated synergy varied from strain to strain.
Conclusions
This work establishes the foundation for future systematic, broad-range investigations into antibiotic synergy for CRE, emphasizes the need for individualized synergy testing and demonstrates the utility of inkjet printer-based technology for the performance of automated antimicrobial synergy assays.

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Antiretroviral therapy in geriatric HIV patients: the GEPPO cohort study

J Antimicrob Chemother 2017; 72: 2879–2886

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HIV-1 DNA ultra-deep sequencing analysis at initiation of the dual therapy dolutegravir + lamivudine in the maintenance DOLULAM pilot study

Abstract
Background
The DOLULAM study assessed the efficacy of dolutegravir + lamivudine dual therapy to maintain virological suppression in heavily treatment-experienced HIV-1-infected adults. No virological failure occurred during the first year of the dual therapy.
Objectives
A virological substudy was conducted to assess the prevalence of M184I/V mutations at dual therapy initiation using historical DNA/RNA genotypes and baseline DNA genotype obtained by next-generation sequencing (NGS).
Methods
HIV-1 RT sequences were obtained from DNA and/or historical RNA using Sanger technology. HIV-1 DNA RT and integrase NGS was performed using Illumina® technology.
Results
Among the 27 patients enrolled in the DOLULAM study, historical HIV DNA and RNA Sanger sequences were available in 14 and 18 patients, respectively. At the initiation of DOLULAM, DNA NGS genotypes showed that 45% and 21% of the patients harboured minority resistant variants (MRV) in RT and integrase, respectively. Combining all available genotype data, an M184I/V was observed in 17 of 27 (63%) of the patients. Most M184V were detected in historical RNA genotypes (n = 8 of 11), whereas M184I were exclusively detected in DNA genotypes (n =10, including 7 as MRV). Ten patients displayed defective viral genomes in cellular reservoirs, all including M184I and stop codons. At the time of DOLULAM initiation, M184V was observed in DNA NGS in five patients, including one as MRV.
Conclusions
These first NGS data on HIV DNA at initiation of a switch study showed (i) a high proportion of patients harbouring defective viral genomes, whose mutation M184I is a marker, and (ii) a low number of patients in whom M184V remained as a major viral variant in PBMCs.

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Dolutegravir plus abacavir/lamivudine works in adolescents, but size matters

Sir,

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soxRS induces colistin hetero-resistance in Enterobacter asburiae and Enterobacter cloacae by regulating the acrAB-tolC efflux pump

Abstract
Background
Colistin is the last drug option for the treatment of MDR Gram-negative bacterial infections. Several types of resistance to colistin have been identified, including hetero-resistance, which has been observed in several Gram-negative pathogens. During a routine surveillance project on antimicrobial resistance, we found abnormal colistin-resistant Enterobacter asburiae and Enterobacter cloacae isolates. E. cloacae is an intestinal commensal bacterium and a well-known opportunistic nosocomial pathogen.
Objectives
To characterize the molecular mechanism of colistin hetero-resistance in Enterobacter spp.
Methods
Several approaches (WGS, transposome mutagenesis and RT–PCR analysis) were used to discover the molecular mechanism of colistin hetero-resistance.
Results
Genomic analysis of mutant clones generated by transposome mutagenesis suggests that hetero-resistance is linked with overexpression of the acrAB-tolC efflux pump. Transcriptional analysis further found that naturally elevated soxRS triggers the induction of the acrAB-tolC efflux pump proteins followed by the development of colistin hetero-resistance in E. asburiae and E. cloacae. Transcriptional analysis results were further verified as demonstrating the development of hetero-resistance in colistin-susceptible strains by plasmid-based overexpression of soxRS.
Conclusions
Our observations highlight the importance of such findings, which previously were only superficially described because of the challenges associated with their detection, in the context of common modes of colistin resistance in Gram-negative bacteria. This study constitutes a unique demonstration of efflux-based high-level colistin hetero-resistance, controlled by a soxRS regulator in Gram-negative bacteria.

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Resolution of porphyria cutanea tarda in HIV and mixed HCV coinfection after direct-acting antiviral (DAA) therapy

Sir,

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Lord Soulsby of Swaffham Prior, 23 June 1926–8 May 2017

Ernest Jackson Lawson Soulsby, better known as Baron Soulsby of Swaffham Prior, led an extraordinarily varied life. He was brought up on a farm in Westmoreland (which is still farmed by the family) and then trained as a veterinarian at Royal (Dick) Veterinary College, Edinburgh, Scotland. From the beginning his interest focused on parasitology with his first publication appearing in 1954.1 His first research base was Bristol, then Cambridge followed by Pennsylvania, from where he travelled widely earning the irreverent title of 'the Pan Am Professor of Parasitology'!

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Validation of adapted daily dose definitions for hospital antibacterial drug use evaluation: a multicentre study

Abstract
Background
The WHO/ATC (Anatomical Therapeutic Chemical) index DDD (WHO-DDD) is commonly used for drug consumption measurement. Discrepancies between WHO-DDD and actual prescribed daily doses (PDD) in hospitals have prompted alternative dose definitions adapted to doses recommended in hospital practice guidelines [recommended daily doses (RDD)].
Methods
In order to validate RDD we performed modified point prevalence surveys in 24 acute care hospitals and recorded 20620 PDD of antibiotics given to 4226 adult patients on the day of the survey and the 6 preceding days. We calculated RDD and WHO-DDD and compared them with PDD.
Results
The rate of RDD corresponding to PDD was higher than the corresponding rate for WHO-DDD (pooled data, 55% versus 30%) and the differences were similar across the hospital sample, but varied according to drug/drug class, route of administration, indication and renal function. RDD underestimated actual consumption by 14% overall, while WHO-DDD overestimated total antibacterial consumption by 28% (pooled data; median values RDD −10% versus WHO-DDD +32%). The deviations of estimated from actual drug use volumes were largest for β-lactams (RDD −11% versus WHO-DDD +49%), in particular for penicillins (−11% versus +64%), if WHO-DDD were used.
Conclusions
Hospital antibiotic consumption surveillance systems using current WHO-DDD should address the uneven discrepancies between actual prescribing and consumption estimates according to drug class that may lead to misclassification in benchmark analyses. We recommend using validated RDD as a supplementary measure to the WHO-DDD for detailed analyses.

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Determination of alternative ceftolozane/tazobactam dosing regimens for patients with infections due to Pseudomonas aeruginosa with MIC values between 4 and 32 mg/L

Abstract
Background
Optimization of the antibiotics for patients with infections due to MDR Pseudomonas aeruginosa (MDR-PA) often requires consideration of alternate dose and infusion times that can be influenced by renal function.
Objectives
We sought to identify ceftolozane/tazobactam dosing schemes that optimized the probability of target attainment (PTA) against infections due to MDR-PA with ceftolozane/tazobactam MICs between 4 and 32 mg/L across different categories of renal function.
Methods
A prior validated ceftolozane/tazobactam population pharmacokinetic model was used for Monte Carlo simulation of 128 alternate permutations of dose, infusion time and renal function in 5000 cases/permutation. Four ceftolozane/tazobactam doses (250/125 mg to 2/1 g) every 8 h with infusion durations of 1–7 h and as continuous infusions were simulated. The model simulated ceftolozane/tazobactam clearance as a function of creatinine clearance (CLCR) within four categories of estimated renal function: 15–29, 30–50, 51–120 and 121–180 mL/min. The PTA was benchmarked on 40% free ceftolozane/tazobactam concentration time above the MIC.
Results
The 512 alternate scenarios identified the current ceftolozane/tazobactam dose of 1/0.5 g to be optimal for MICs ≤32 mg/L (CLCR 15–50 mL/min), ≤16 mg/L (CLCR 51–120 mL/min) and ≤8 mg/L (CLCR 121–180 mL/min). Extended infusion of 4–5 h had a higher PTA than shorter and continuous infusions in simulations of augmented renal clearance across infections with MICs of 4–32 mg/L.
Conclusions
Extended infusion ceftolozane/tazobactam regimens should be investigated as a potential dosing solution to improve the PTA against infections due to MDR-PA with higher ceftolozane/tazobactam MICs.

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Influence of ABCB11 and HNF4 α genes on daclatasvir plasma concentration: preliminary pharmacogenetic data from the Kineti-C study

Abstract
Background
Daclatasvir is an inhibitor of HCV non-structural 5A protein and is a P-glycoprotein substrate. Pharmacogenetics has had a great impact on previous anti-HCV therapies, particularly considering the association of IL-28B polymorphisms with dual therapy outcome.
Objectives
We investigated the association between daclatasvir plasma concentrations at 2 weeks and 1 month of therapy and genetic variants (SNPs) in genes encoding transporters and nuclear factors (ABCB1, ABCB11 and HNF4α).
Patients and methods
Allelic discrimination was achieved through real-time PCR, whereas plasma concentrations were evaluated through LC–MS/MS.
Results
Fifty-two patients were analysed, all enrolled in the Kineti-C study. HNF4α 975 C > G polymorphism was found to be associated with the daclatasvir plasma concentrations at 2 weeks (P =0.009) and 1 month of therapy (P =0.006). Linear regression analysis suggested that, at 2 weeks of therapy, age, baseline BMI and haematocrit were significant predictors of daclatasvir concentrations, whereas at 1 month of therapy ABCB111131 CC and HNF4α CG/GG genotypes were significant predictors of daclatasvir concentrations.
Conclusions
These are the first and preliminary results from our clinical study focusing on daclatasvir pharmacogenetics, showing that this approach could have a role in the era of new anti-HCV therapies.

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Is there any difference in quality of prescribing between antibacterials and antifungals? Results from the first global point prevalence study (Global PPS) of antimicrobial consumption and resistance from 53 countries

Abstract
Objectives
To compare the quality of antibacterial with antifungal prescribing in the world.
Methods
Data from the global point prevalence study (Global PPS) were used. The Global PPS took place on any one day between February and June 2015 in 335 participating hospitals from 53 countries. It collected demographic data on patients treated with antimicrobials and data on prescription characteristics of the antimicrobials. For the present study, the quality of antibiotic prescription was compared with antifungal prescription using logistic regression analysis. The following indicators were compared: the presence of the reason for prescription and stop/review date in notes, and compliance with a local guideline.
Results
There were 48565 antimicrobial prescriptions for 34731 patients [median age 63 years (range 0–106); 52.6% male] in the Global PPS. Among these antimicrobials, 43513 (89.6%) were antibacterials and 2062 were antifungals for systematic use, and these data were used in this study. Reasons for prescriptions [77.7% versus 71.8%, OR 1.4 (95% CI 1.2–1.5)] and stop/review dates [38.3% versus 31.9%, OR 1.3 (1.2–1.5)] were found more often in notes for antibacterials than for antifungals. Antibacterials were prescribed less often according to local guidelines than antifungals [57.0% versus 71.0%, OR 0.6 (0.5–0.6)].
Conclusions
There are differences in the quality of antibacterial and antifungal prescribing and we identified opportunities that can be used to improve the quality of antimicrobial prescribing.

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PointFinder: a novel web tool for WGS-based detection of antimicrobial resistance associated with chromosomal point mutations in bacterial pathogens

Abstract
Background
Antibiotic resistance is a major health problem, as drugs that were once highly effective no longer cure bacterial infections. WGS has previously been shown to be an alternative method for detecting horizontally acquired antimicrobial resistance genes. However, suitable bioinformatics methods that can provide easily interpretable, accurate and fast results for antimicrobial resistance associated with chromosomal point mutations are still lacking.
Methods
Phenotypic antimicrobial susceptibility tests were performed on 150 isolates covering three different bacterial species: Salmonella enterica, Escherichia coli and Campylobacter jejuni. The web-server ResFinder-2.1 was used to identify acquired antimicrobial resistance genes and two methods, the novel PointFinder (using BLAST) and an in-house method (mapping of raw WGS reads), were used to identify chromosomal point mutations. Results were compared with phenotypic antimicrobial susceptibility testing results.
Results
A total of 685 different phenotypic tests associated with chromosomal resistance to quinolones, polymyxin, rifampicin, macrolides and tetracyclines resulted in 98.4% concordance. Eleven cases of disagreement between tested and predicted susceptibility were observed: two C. jejuni isolates with phenotypic fluoroquinolone resistance and two with phenotypic erythromycin resistance and five colistin-susceptible E. coli isolates with a detected pmrB V161G mutation when assembled with Velvet, but not when using SPAdes or when mapping the reads.
Conclusions
PointFinder proved, with high concordance between phenotypic and predicted antimicrobial susceptibility, to be a user-friendly web tool for detection of chromosomal point mutations associated with antimicrobial resistance.

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Plasma treatment as an efficient tool for controlled drug release from polymeric materials: A review

Publication date: 28 November 2017
Source:Journal of Controlled Release, Volume 266
Author(s): D.G. Petlin, S.I. Tverdokhlebov, Y.G. Anissimov
One of the most actively developing fields in modern medicine is controlled drug delivery, an ability to keep optimal concentration of a drug at the desired body location. In particular, the most attention for potential use as drug delivery vehicles is drawn towards biodegradable polymeric materials. This is due to the versatility of tools for their fabrication, as well as due to the need to extract them after implantation being eliminated. In order to enhance polymer characteristics in terms of biocompatibility their surface can be functionalized. Plasma treatment is a method for the modification of material surface properties, which spans a wide range of applications in tissue engineering and regenerative medicine. The main advantage of this method is its ability to modify a polymeric surface without altering the bulk properties of materials, thus preserving original mechanical characteristics. Moreover, plasma modification is well-known for its speed, excluded need for solvents, and scalability. Recently, this approach has been gaining popularity for drug delivery applications. The applications of plasma treatment during the fabrication of drug delivery vehicles include surface activation, enhanced wettability, the fabrication of hydrophobic barrier layer, induced cross-linking and improved drug loading. This review covers the variety of approaches, applied to different polymeric biomaterials, including non-woven meshes, films, microparticles, microneedles and tablets, in order to achieve a controlled drug release. The applications of drug delivery devices with an implemented plasma treatment modification are also described.

Graphical abstract

image


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Advances in the design of solid lipid nanoparticles and nanostructured lipid carriers for targeting brain diseases

Publication date: 28 October 2017
Source:Journal of Controlled Release, Volume 264
Author(s): Christos Tapeinos, Matteo Battaglini, Gianni Ciofani
Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) comprise a category of versatile drug delivery systems that have been used in the biomedical field for >25years. SLNs and NLCs have been used for the treatment of various diseases including cardiovascular and cerebrovascular, and are considered a standard treatment for the latter, due to their inherent ability to cross the blood brain barrier (BBB). In this review, a presentation of the most important brain diseases (brain cancer, ischemic stroke, Alzheimer's disease, Parkinson's disease and multiple sclerosis) is approached, followed by the basic fabrication techniques of SLNs and NLCs. A detailed description of the reported studies of the last seven years, of active and passive targeting SLNs and NLCs for the treatment of glioblastoma multiforme and of other brain cancers, as well as for the treatment of neurodegenerative diseases is also carried out. Finally, a brief description of the advantages, the disadvantages, and the future perspectives in the use of these nanocarriers is reported, aiming at giving an insight of the limitations that have to be overcome in order to result in a delivery system with high therapeutic efficacy and without the limitations of the existing nano-systems.

Graphical abstract

image


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Comprehensive survey of vitiligo patients in the northeast of China using a predesigned questionnaire

Abstract

To assess the sociodemographic data and clinical information of outpatients affected by vitiligo in the northeast of China, vitiligo patients or guardians who presented to the clinic were invited to participate in an exploratory questionnaire. The questionnaire consisted of two sections related to vitiligo, including sociodemographic data and clinical information. A total of 983 vitiligo patients answered the questionnaire. The rates of female and male patients were comparable. The investigated patients were mostly young and middle-aged. Most patients suffered from vitiligo in childhood or young adulthood. Vitiligo vulgaris was the most common type of vitiligo in clinic and 53.0% of patients were categorized as body surface area (BSA) of 10% or less. In response to the latest treatment, 43.6% of patients achieved good response (completely stopped or almost disappeared). More patients at active stage showed good response than the patients at stable stage (χ2 = 7.866, P < 0.05). Chronic comorbid condition(s) were observed in 12.6% of patients with BSA of more than 10%, whereas those were seen in 6.0% of patients with BSA of 10% or less (χ2 = 12.969, P < 0.05). In conclusion, active vitiligo seems to respond better than stable vitiligo and complications with other autoimmune diseases more frequently observed in severe patients than mild patients. The current study presented a comprehensive understanding of vitiligo in the northeast of China.



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Soil N mineralization profiles of co-existing woody vegetation islands at the alpine tree line

Abstract

Tree lines form a transition ecotone from forest to tundra both at high elevation and high latitude and occur in a number of different forms. Nitrogen (N) deficiency is considered to be a factor involved in tree line formation, and also N dynamics are considered to differ between the trees and the ericaceous vegetation of the tundra. In the Austrian Alps at the tree line, N availability and N mineralization in soils of different vegetation types (Picea abies, Pinus mugo and Rhododendron ferrugineum) as well as total phenols were determined. Soil from under P. abies was taken from two different tree line forms, an island type and a diffuse type, as well as from P. abies growing at a lower elevation. N mineralization was measured in situ using a covered PVC tube incubation method and in a laboratory incubation under controlled conditions. Ion exchange resin capsules were installed at the interface of humus and mineral soil for estimating N in the soil solution. Net N mineralization showed a similar pattern for the vegetation types for both the in situ and laboratory incubation. The soil humus layer had the highest levels of N mineralization compared to the other soil layers. N mineralization rates were similar in P. abies and P. mugo at the tree line regardless of tree line form. Rates of N mineralization were lower under R. ferrugineum than the tree species, but this lower rate was not related to the occurrence of high levels of total phenols in the soil. Nitrogen deficiency was not evident in the island-type tree line, but was evident in the diffuse tree line type.



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How to deal with your antidepressants giving you major dry mouth

They've played a massive part in bringing me out of a depressive period that made me come home from work, lie down, and refuse to move from bed or actually go to sleep for the next five hours. They've significantly reduced the frequency of my thoughts of topping myself.



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Cytochrome P450 Genes (CYP2E1 and CYP1A1) Variants and Susceptibility to Chronic Hepatitis B Virus Infection

Abstract

Hepatitis B virus (HBV) infection is a worldwide health concern which is associated with significant morbidity and mortality. Both viral and host factors have a significant effect on infection, replication and pathogenesis of HBV. The aim of this study was to investigate the effect of CYP2E1 and CYP1A1 genetic variants on susceptibility to HBV. 143 individuals including 54 chronic HBV patients and 89 healthy controls were enrolled in the genotyping procedure. rs2031920 and rs3813867 at CYP2E1 as well as rs4646421 and rs2198843 at CYP1A1 loci were studied in all subjects using PCR–RFLP (restriction fragment length polymorphism) analysis. Both variants at CYP2E1 locus were monomorphic in all studied subjects. Genotype frequency of rs4646421 was significantly different between chronic HBV patients and healthy blood donors (P = 0.04, OR 4.31; 95% CI 1.04–17.7). Furthermore, individuals carrying at least one C allele (CC or CT genotypes) for rs4646421 seemed to have a decrease risk of hepatitis in comparison with TT genotype (P = 0.039). Our results showed a relationship between rs4646421 TT genotype (rare genotype) and the risk for developing chronic HBV infection (four times higher). Further studies are needed to examine the role of CYP1A1 polymorphism in susceptibility to chronic HBV infection.



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Validation of the Vascular quality of life questionnaire – 6 for clinical use in patients with lower limb peripheral arterial disease

The VascuQoL-6 (VQ-6) health-related quality of life questionnaire, a short version of the disease-specific VascuQoL-25, was developed for clinical practice and use in vascular registries. The study purpose wa...

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Bayesian clinical trial designs: Another option for trauma trials?

imageABSTRACT: Conducting clinical trials in trauma care is challenging. As new treatments become available, we are faced with the dilemma of how to confirm their effectiveness and strengthen the evidence base. Randomized controlled trials are the criterion standard, but target groups in trauma care are often small and specialized, making the classic approach to trial design difficult. Bayesian designs represent an innovative means of increasing trial efficiency and conducting trials with more realistic sample sizes. This article examines the design of such trials, using the UK-REBOA Trial as an example.

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An interpretation of the new international MAP guideline for the management of Milk Allergy in Primary Care

General Practitioners suffer from guideline fatigue. They come fast and furious in many complicated forms. Cow's milk allergy (CMA) is one of the most common presentations of food allergy seen in early childho...

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Crystal structure of l-glutamate N-acetyltransferase ArgA from Mycobacterium tuberculosis

Publication date: Available online 22 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Xiuna Yang, Lijie Wu, Yajun Ran, Ao Xu, Bing Zhang, Xiaolin Yang, Rongguang Zhang, Zihe Rao, Jun Li
l-arginine is used as a source of both carbon and nitrogen in Mycobacterium tuberculosis (Mtb) and its biosynthesis is essential for the pathogen's survival. MtbArgA (Rv2747) catalyzes the initial step in l-arginine biosynthesis by transferring an acetyl group from acetyl coenzyme A (AcCoA) to l-glutamate. MtbArgA is a class III N-acetylglutamate synthase (NAGS) with no structural information. Here, we solved the crystal structure of MtbArgA complexed with AcCoA and l-glutamate. The overall structure adopts a classic fold of the GCN5-related N-acetyltransferase (GNAT) family, characterized by a "V"-shaped cleft and β-bulge, but uses distinct residues for the binding and reaction of AcCoA. In particular, its activity depends on dimerization to form a deep, vast pocket for l-glutamate binding. Interestingly, in the structure, l-glutamate binds at a site far away from AcCoA, implying a mechanism of separate capture and catalysis. Additionally, based on a docking model of l-glutamate at the catalytic site, a one-step sequential mechanism was proposed for enzymatic catalysis. Important sites for substrate binding and catalysis were also evaluated by site-directed mutagenesis study and activity analysis. The unique features of the MtbArgA structure will provide useful insights for inhibitor design and anti-tuberculosis drug discovery.

Graphical abstract

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Reversible association of proteins into sub-visible amorphous aggregates using short solubility controlling peptide tags

Publication date: Available online 22 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Md. Golam Kabir, Mohammad Monirul Islam, Yutaka Kuroda
Careful analysis of sub-visible amorphous aggregates, where proteins associate non- covalently in either native or denatured states without forming a specific quaternary structure, may shed insight into the mechanisms of protein aggregation and solubility. Here we report a biophysical and biochemical analysis of our model protein, a bovine pancreatic trypsin inhibitor variant (BPTI-19A), whose oligomerization were controlled by attaching solubility controlling peptide tags (SCP tags) to its C terminus, which are short peptides composed of a single type of amino acid that modulate protein solubility. The dynamic light scattering and static light scattering at 25°C indicated that 11 out of 15 SCP tags merely affected the hydrodynamic radius and light scattering intensity of our reference variants BPTI-19A and BPTI-C2G. On the other hand, hydrophobic SCP tags composed of 5 Ile (C5I) or 5 Leu (C5L) were associated into sub-visible aggregates. Circular dichroism indicated that all tagged BPTI variants had the same secondary structure contents as the reference BPTI-19A at 25°C, suggesting that BPTI-C5I and C5L kept their native structure upon association. Furthermore, the thermal denaturation of all of the BPTI variants were fully reversible and typical of natively folded small globular proteins, as monitored by CD at 222 nm. However, the thermal stability of BPTI-19A tagged with hydrophobic residues decreased with increasing protein concentration and tag's hydrophobicity, and BPTI-C5I and C5L were partially denatured at 37°C. Biochemical stability assessed by limited proteolysis with pepsin correlated with the extent of the variants' aggregation, and the large sub-visible aggregates formed by BPTI-C5I and C5L significantly increased their resistance to pepsin proteolysis. Altogether, these observations indicated that hydrophobic SCP tags led to the reversible association of native-like proteins into sub-visible soluble amorphous aggregates resistant to pepsin digestion.

Graphical abstract

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Utilizing tagged paramagnetic shift reagents to monitor protein dynamics by NMR

Publication date: Available online 22 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Libin Ye, Ned van Eps, Xiang Li, Oliver P. Ernst, R. Scott Prosser
Calmodulin is a ubiquitous calcium sensor protein, known to serve as a critical interaction hub with a wide range of signaling partners. While the holo form of calmodulin (CaM-4Ca2+) has a well-defined ground state structure, it has been shown to undergo exchange, on a millisecond timescale, to a conformation resembling that of the peptide bound state. Tagged paramagnetic relaxation agents have been previously used to identify long-range dipolar interactions through relaxation effects on nuclear spins of interest. In the case of calmodulin, this lead to the determination of the relative orientation of the N- and C-terminal domains and the presence of a weakly populated peptide bound like state. Here, we make use of pseudocontact shifts from a tagged paramagnetic shift reagent which allows us to define minor states both in 13C and 15N NMR spectra and through 13C- and 15N-edited 1H-CPMG relaxation dispersion measurements. This is validated by pulsed EPR (DEER) spectroscopy which reveals an ensemble consisting of a compact peptide-bound like conformer, an intermediate peptide-bound like conformer, and a (dumbbell-like) extended ground state conformer of CaM-4Ca2+, where addition of the MLCK peptide increases the population of the peptide-bound conformers. This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman.



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An interpretation of the new international MAP guideline for the management of Milk Allergy in Primary Care

General Practitioners suffer from guideline fatigue. They come fast and furious in many complicated forms. Cow's milk allergy (CMA) is one of the most common presentations of food allergy seen in early childho...

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Patterns of care and impact of brachytherapy boost utilization for squamous cell carcinoma of the base of tongue in a large, national cohort

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Publication date: Available online 22 September 2017
Source:Brachytherapy
Author(s): Anna Lee, Babak Givi, S. Peter Wu, Moses M. Tam, Naamit K. Gerber, Kenneth S. Hu, Peter Han, David Schreiber
PurposeThe National Cancer Data Base was analyzed to evaluate the patterns of care and impact of brachytherapy (BT) boost on overall survival (OS) for patients with squamous cell carcinoma of the base of tongue.Methods and MaterialsPatients with nonmetastatic squamous cell carcinoma of the base of tongue between 2004 and 2012 who received concurrent external beam radiation therapy (EBRT) and chemotherapy with or without BT boost in the definitive setting were queried. Overall survival was assessed by the Kaplan-Meier method. Cox regression analysis was used to identify covariates that affected OS.ResultsThere were 15,934 patients included in this study; 137 (0.9%) received EBRT + BT and the remaining received EBRT only. Median followup was 41.2 months. The utilization of BT boost declined from 2.1% in 2004 to 0.2% in 2012 (p < 0.0001), whereas intensity-modulated radiation therapy use increased from 22.8% in 2004 to 69.2% in 2012 (p < 0.0001). The three- and 5-year OS was 83.2% and 78.3% for patients receiving EBRT + BT compared with 77.4% and 69.0% for those receiving EBRT only (p = 0.03). The difference in survival was significantly better among patients with T3-4 tumors with EBRT + BT boost (p = 0.009) however, there was no survival benefit among patients with T1-2 tumors (p = 0.72). The analysis was repeated with patients who received intensity-modulated radiation therapy vs. EBRT with BT boost and the survival difference was sustained only for those with T3-4 tumors (p = 0.02).ConclusionsBrachytherapy boost has decreased in its utilization even though it was associated with favorable survival outcomes particularly among patients with higher T-stage tumors.



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An integrated system for clinical treatment verification of HDR prostate brachytherapy combining source tracking with pretreatment imaging

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Publication date: Available online 22 September 2017
Source:Brachytherapy
Author(s): Ryan L. Smith, Max Hanlon, Vanessa Panettieri, Jeremy L. Millar, Bronwyn Matheson, Annette Haworth, Rick D. Franich
PurposeHigh-dose-rate (HDR) prostate brachytherapy treatment is usually delivered in one or a few large dose fractions. Poor execution of a planned treatment could have significant clinical impact, as high doses are delivered in seconds, and mistakes in an individual fraction cannot be easily rectified. Given that most potential errors in HDR brachytherapy ultimately lead to a geographical miss, a more direct approach to verification of correct treatment delivery is to directly monitor the position of the source throughout the treatment. In this work, we report on the clinical implementation of our treatment verification system that uniquely combines the 2D source-tracking capability with 2D pretreatment imaging, using a single flat panel detector (FPD).Methods and MaterialsThe clinical brachytherapy treatment couch was modified to allow integration of the FPD into the couch. This enabled the patient to be set up in the brachytherapy bunker in a position that closely matched that at treatment planning imaging. An anteroposterior image was acquired of the patient immediately before treatment delivery and was assessed by the Radiation Oncologist online, to reestablish the positions of the catheters relative to the prostate. Assessment of catheter positions was performed in the left-right and superior-inferior directions along the entire catheter length and throughout the treatment volume. Source tracking was then performed during treatment delivery, and the measured position of the source dwells were directly compared to the treatment plan for verification.ResultsThe treatment verification system was integrated into the clinical environment without significant change to workflow. Two patient cases are presented in this work to provide clinical examples of this system, which is now in routine use for all patient treatments in our clinic. The catheter positions were visualized relative to the prostate, immediately before treatment delivery. For one of the patient cases presented in this work, they agreed with the treatment plan on average by 1.5 mm and were identifiable as a predominantly inferior shift. The source tracking was performed during treatment delivery, and for the same case, the mean deviation from the planned dwell positions was 1.9 mm (max = 4.9 mm) for 280 positions across all catheters.ConclusionWe have implemented our noninvasive treatment verification system based on an FPD in the clinical environment. The device is integrated into a patient treatment couch, and the process is now included in the routine clinical treatment procedure with minor impact on workflow. The system which combines both 2D pretreatment imaging and HDR 2D source tracking provides a range of information that can be used for comprehensive treatment verification. The system has the potential to meaningfully improve safety standards by allowing widespread adoption of routine treatment verification in HDR brachytherapy.



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Time-resolved in vivo dosimetry for source tracking in brachytherapy

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Publication date: Available online 22 September 2017
Source:Brachytherapy
Author(s): Jacob Graversen Johansen, Susanne Rylander, Simon Buus, Lise Bentzen, Steffen Bjerre Hokland, Christian Skou Søndergaard, Anders Karl Mikael With, Gustavo Kertzscher, Kari Tanderup
PurposeThe purpose of this article is to demonstrate that brachytherapy source tracking can be realized with in vivo dosimetry. This concept could enable real-time treatment monitoring.MethodsIn vivo dosimetry was incorporated in the clinical routine during high-dose-rate prostate brachytherapy at Aarhus University Hospital. The dosimetry was performed with a radioluminescent crystal positioned in a dedicated brachytherapy needle in the prostate. The dose rate was recorded every 50–100 ms during treatment and analyzed retrospectively. The measured total delivered dose and dose rates for each dwell position with dwell times >0.7 s were compared with expected values. Furthermore, the distance between the source and dosimeter, which was derived from the measured dose rates, was compared with expected values. The measured dose rate pattern in each needle was used to determine the most likely position of the needle relative to the dosimeter.ResultsIn total, 305 needles and 3239 dwell positions were analyzed based on 20 treatments. The measured total doses differed from the expected values by −4.7 ± 8.4% (1SD) with range (−17% to 12%). It was possible to determine needle shifts for 304 out of 305 needles. The mean radial needle shift between imaging and treatment was 0.2 ± 1.1 mm (1SD), and the mean longitudinal shift was 0.3 ± 2.0 mm (1SD).ConclusionTime-resolved in vivo dosimetry can be used to provide geometric information about the treatment progression of afterloading brachytherapy. This information may provide a clear indication of errors and uncertainties during a treatment and, therefore, enables real-time treatment monitoring.



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Image-guided high-dose-rate intracavitary brachytherapy in the treatment of medically inoperable early-stage endometrioid type endometrial adenocarcinoma

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Publication date: Available online 22 September 2017
Source:Brachytherapy
Author(s): Scott E. Jordan, Ida Micaily, Enrique Hernandez, J. Stuart Ferriss, Curtis T. Miyamoto, Shidong Li, Bizhan Micaily
PurposeThe purpose of this case series is to describe the treatment and outcomes of a cohort of patients with inoperable early-stage endometrioid endometrial cancer with 3D image-guided high-dose-rate (HDR) intracavitary brachytherapy.MATERIALS AND METHODSA review was performed of patients with early-stage endometrial cancer who underwent primary radiation treatment between 2010 and 2016. Staging and treatment planning were performed CT, pelvic ultrasound, and pelvic MRI. Gross tumor volume (GTV) was defined as the MRI or ultrasound demonstrated endometrial stripe width, with the entire uterine corpus, cervix, and proximal vagina representing the clinical target volume (CTV). Dosimetry calculations were performed in each fraction of HDR brachytherapy.RESULTSEight patients received external beam radiation therapy followed by intracavitary HDR brachytherapy. Seven patients underwent intracavitary HDR brachytherapy alone. In all patients, mean cumulative dose to 90% (D90) of GTV was 95.99 Gy in equivalent dose in 2 Gy fractions (EQD2, α/β = 10). Mean cumulative D90 EQD2 to CTV was 51.64 Gy. Average follow-up was 29 months. Four patients died from concurrent disease(s) at an average of 2.83 years after completion of treatment. Except for 1 (6.6%) patient who recurred at 9 months following completion of treatment, all patients remained disease-free for the remainder of follow-up.ConclusionsIn patients who are poor surgical candidates and have early-stage endometrioid type endometrial carcinoma, image-guided HDR intracavitary brachytherapy carries minimal side effects and a high response rate.



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Maple syrup urine disease

Maple syrup urine disease: A hereditary disease that is due to deficiency of an enzyme involved in amino acid metabolism, characterized by urine that smells like maple syrup. In maple syrup urine disease, the three branched-chain amino acids (leucine, isoleucine, and valine) cannot be metabolized (processed), and they build up in the blood, causing problems with brain function and leading to mental retardation, physical disability, and death, if not treated. Treatment involves use of a special diet and monitoring of protein intake.



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Factors influencing the absorption of vitamin D in GIT: an overview

Abstract

Vitamin D refers to a group of secosteroid compounds and recognized as the antirachitic vitamin, as it counters rickets, mineral desorption from fully-grown bones (Osteodistrophy), bone, joint disorders, and fragility of bones. On one hand, there is scarcity of vitamin D rich food while on other hand a number of factors negotiate its absorption efficiency in human gastrointestinal tract (GIT). These factors include variations in the physiochemical state of the vitamin D (molecular forms, potency and their physiological linkages), the complexity of food matrix (the amount and type of fatty acids, dietary fibers and presence/absence of vitamin D enhancer and inhibitor), and its interaction of other fat soluble compounds with vitamin D as well as the host-associated factors (age, disease, surgery, obesity, genetic variation etc.). It is hypothesized that the bioavailability of vitamin D in GIT is compromised if there changes within these factors. Present article is intended to review the contribution of these factors anticipated to be influencing vitamin D absorption in GIT.



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Oil shale powders and their interactions with ciprofloxacin, ofloxacin, and oxytetracycline antibiotics

Abstract

The interaction of oil shale, as a widespread sedimentary rock, with common antibiotics ofloxacine, oxytetracycline, and ciprofloxacine was studied. The selected Moroccan deposit and its thermally treated forms were fully characterized from a chemical and structural point of view, indicating the prevalence of quartz as a mineral component together with aluminum- and iron-rich phase that are converted into Al-doped iron oxide phases upon heating. The presence of 4 wt% organics was also detected, which was removed at 550 °C without significant loss of specific surface area. The pseudo-second-order kinetic model and Langmuir equation were found the most adequate to reproduce the kinetics and isothermal sorption experiments. These analyses enlighten the contribution of the organic matter on antibiotic retention as well as the key role of hydrophobic interactions on the molecule-mineral surface interactions. Our results emphasize the possible contribution of raw oil shale in the accumulation of antibiotics in soils and suggest that thermally treated oil shell powders can constitute cheap mineral sorbents for environmental cleaning.



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Gallic acid induces G1 phase arrest and apoptosis of triple-negative breast cancer cell MDA-MB-231 via p38 mitogen-activated protein kinase/p21/p27 axis.

Gallic acid (GA) possesses potential antitumoral activity on different types of malignancies. In this study, we aimed to explore the antitumoral effects of GA on triple-negative breast cancer (TNBC) cells, the breast cancer cells showing resistance to hormonal therapy or HER2 receptor targeting therapy. We observed that GA treatment significantly decreased the cell viability of human TNBC cell line MDA-MB-231 and HS578T in a dose-dependent manner. In addition, GA exerted a relative lower cytotoxicity on noncancer breast fibroblast MCF-10F. Next, we analyzed the changes of cell-cycle distribution in response to GA treatment and found that GA led to an increase of G0/G1 and sub-G1 phase ratio in MDA-MB-231 cells. We further explored the crucial mediators controlling cell cycle and inducing apoptotic signaling, and the findings showed that GA downregulated cyclin D1/CDK4 and cyclin E/CDK2, upregulated p21Cip1and p27Kip1, and induced activation of caspase-9 and caspase-3. In addition, we demonstrated that p38 mitogen-activated protein kinase was involved in the GA-mediated cell-cycle arrest and apoptosis. Collectively, our findings indicate that GA inhibits the cell viability of TNBC cells, which may attribute to the G1 phase arrest and cellular apoptosis via p38 mitogen-activated protein kinase/p21/p27 axis. Thus, we suggest that GA could be beneficial to TNBC treatment. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Human MMAA induces the release of inactive cofactor and restores methylmalonyl-CoA mutase activity through their complex formation

Publication date: Available online 22 September 2017
Source:Biochimie
Author(s): Toshiko Takahashi-Iñiguez, Alfonso González-Noriega, Colette Michalak, María Elena Flores
Human mitochondrial methylmalonyl-CoA mutase (hMCM) is an isomerase that converts methylmalonyl-CoA to succinyl-CoA, a crucial step for the incorporation of some compounds derived from the diet into the central metabolism. hMCM employs highly reactive radicals from its cofactor (adenosylcobalamin, AdoCbl) to perform its reaction. Our previous work demonstrated that hMCM loses activity during catalysis and that the interaction with human MMAA (hMMAA), a GTPase protein, avoided this loss or restored hMCM activity. Even so, the mechanism by which hMMAA exerted these chaperone functions has not been described. In this work report that the formation and accumulation of OH2Cbl, the oxidized form of the AdoCbl cofactor formed during catalysis, is the cause of hMCM inactivation. Additionally, we demonstrate that the complex formation of hMCM/hMMAA decreases the rate of oxidized cofactor formation, protecting the hMCM enzyme. Moreover, an inactive model of hMCM was used to demonstrate that hMMAA is able to remove the damaged cofactor through GTP hydrolysis. Additionally, a modification in the kinetic parameters of hMCM in presence of hMMAA was observed, and for the first time, the in vivo localization of hMMAA and its co-localization with hMCM in human fibroblasts mitochondria were demonstrated.



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Clozapine-induced acute gastrointestinal necrosis: a case report

Clozapine is known to cause fecal impaction and ileus with resultant colonic necrosis due to compression of colonic mucosa. There are rare reports of clozapine causing necrosis of other portions of the gastroi...

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N-of-1 trials for assessing the effects of deprescribing medications on short-term clinical outcomes in older adults: a systematic review

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Publication date: Available online 22 September 2017
Source:Journal of Clinical Epidemiology
Author(s): Alexander J. Clough, Sarah N. Hilmer, Sharon L. Naismith, Luke Kardell, Danijela Gnjidic
ObjectiveTo determine the feasibility of using the N-of-1 method for deprescribing trials in older adults.Study Design and SettingSystematic review identifying any human studies conducted in older adults (≥ 50 years), deprescribing any long-term treatment over less than a year using the N-of-1 trial method. Two authors independently reviewed all articles for eligibility and extracted data. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Quality assessment of trials was carried out using the Physiotherapy Evidence Database (PEDro) scale.ResultsSix studies were identified and extracted. All trials investigated the efficacy of therapies for treating diseases. Four trials resulted in a significant number of patients (44-64%) discontinuing their medication due to non-significant benefits of treatment. In two studies, all participants remained on their respective treatment after trial completion.ConclusionThe use of the N-of-1 method was able to effectively determine the impact of individual treatments on patient-specific outcomes, improving the care of older adults. However, use of the N-of-1 method has rarely been reported in deprescribing research, although it has been utilised in other fields.



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Registry-based randomized controlled trials merged the strength of randomized controlled trails and observational studies and give rise to more pragmatic trials

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Publication date: Available online 22 September 2017
Source:Journal of Clinical Epidemiology
Author(s): Tim Mathes, Stefanie Buehn, Peggy Prengel, Dawid Pieper
ObjectiveTo analyze the features of registry-based randomized trials (rRCT).Study DesignWe systematically searched PubMed for rRCTs. Study selection was performed independently by two reviewers. We extracted all data in standardized tables and prepared descriptive summary statistics.ResultsThe search resulted in 1202 hits. We included 71 rRCTs. Most rRCTs were from Denmark and Sweden. Chronic conditions were considered in 82.2%. A preventive intervention was examined in 45.1%. The median of included patients was 2000 (range: 69-246,079). Definition of the study population was mostly broad. Study procedures were regularly little standardized. The number of included and analyzed patients was the same in 82.1%. In half of the rRCTs more than one registry was utilized. Various linkage techniques were used. In median two outcomes were collected from the registry/ies. The median follow-up of the rRCTs was 5.3 years (range: 6 weeks-27 years). Information on quality of registry data was reported in 11.3%.ConclusionrRCTs can provide valid (randomization, low lost-to-follow-up rates, generalizable) patient important long-term comparative-effectiveness data for relative little effort. Researchers planning a RCT should always check whether existing registries can be used for data collection. Reporting on data quality must be improved for use in evidence synthesis.



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Study design classification of registry-based studies in systematic reviews

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Publication date: Available online 22 September 2017
Source:Journal of Clinical Epidemiology
Author(s): Tim Mathes, Dawid Pieper




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Validation of a questionnaire measuring transitional patient safety climate indicated differences in transitional patient safety climate between primary and secondary care

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Publication date: Available online 22 September 2017
Source:Journal of Clinical Epidemiology
Author(s): Marije A. van Melle, Henk F. van Stel, Judith M. Poldervaart, Niek J. de Wit, Dorien LM. Zwart
BackgroundThis study describes the development and validation of the TRAnsitional patient safety Climate Evaluation (TRACE) questionnaire, measuring transitional patient safety climate from the perspective of general practitioners and hospital physicians. Patient safety climate reflects the professionals' perception of the organizational patient safety culture.Study Design and SettingsIn the development of the TRACE we adjusted existing questionnaires on patient safety culture. Exploratory factor analysis (EFA) was performed. Internal consistency and correlations between factors and a global transitional patient safety rating were calculated.ResultsIn total, 162 questionnaires were completed (response 23%; general practice: N=97, hospital physicians: N=65). Analysis of all respondents did not provide an interpretable factor solution. However, the EFA on the results of hospital physicians revealed 4 relevant factors: (1) Collaboration, (2) Speaking up, (3) Communication on transitional incidents and improvement measures, and (4) Transitional patient safety management. The internal consistency of these factors was good for hospital respondents (0.71 to 0.87) and fair to acceptable for general practices' respondents (0.63 to 0.72).ConclusionsAlthough the TRACE questionnaire did not provide a solid factor structure in a combined sample of general practice and hospital respondents, the factors found reliable in hospital setting had acceptable reliability in general practice setting.



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The effects on the student-teacher relationship in a one-to-one technology classroom

Abstract

This embedded case study explores the student-teacher relationship in a one-to-one technology environment. The actual change in relationship in a one-to-one classroom was examined. The study was guided by the self-system theory of motivation and its three characteristics of autonomy, relatedness, and competency as a theoretical framework. To explore this topic, the researchers considered the perspectives of four classroom teachers and 207 high school students at a suburban public high school in New Jersey. The case study research utilized teacher interviews, classroom observations, student surveys, and a student focus group. The findings revealed a notable change in the relationship between teachers and students within the one-to-one environment. The change existed in the connectivity between the teachers and their students beyond the classroom and school. The researchers concluded that the teachers and their students did have a positive relationship in a one-to-one environment and that relationship depended on the teacher's ability to engage students using the one-to-one device. The researchers concluded that the one-to-one environment creates an autonomous learning environment for students; teachers and students have a relatedness that extends beyond the traditional boundaries of a school; and a higher level of competency in both teachers and students creates a more engaging classroom. As one-to-one technology environments are becoming more popular across the country, this study contributes to a better understanding of the expected changes in teacher-student relationships before issues of conflict occur.



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Towards automated e-counselling system based on counsellors emotion perception

Abstract

Emotions are a core semantic component of human communication. Since counsellors are humans we assume that their own state of emotions could affect their intuitional effort when taking decisions concerning their clients. Therefore, the accuracy of detected emotions by counsellors could be doubtful. And this highlights the need for complementing the intuitional effort of counsellors by computational approach. Therefore, ascertaining the efficacy of computational algorithm, there is the need to benchmark with humans. In this paper, we explore empirically, the extent to which counsellors own emotional states influence their perception of emotions expressed in text. This influence is investigated through the level of agreement among counsellors when annotating emotions expressed in students' personal life's stories. The result shows strong intra-counsellor annotation agreement of emotions while inter-counsellors annotation agreement was low. Furthermore, the intra-annotation agreement of emotions was found to be strongly correlated to the counsellors' self-reported emotions. We speculate, based on the findings, that the emotional state of counsellors influences their emotion perception while tracking emotions in text. Based on the results, we discuss the advantages of using an automated e-counselling system for emotion analysis.



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Physical Activity in Preventing Alzheimer’s Disease and Cognitive Decline: A Narrative Review

Abstract

A large body of epidemiological and experimental data exploring the relationship between physical activity (PA) and Alzheimer's disease (AD) are now available. Despite observational evidence supporting a role for PA in delaying the onset of AD, randomised controlled trials have reported mixed findings, likely due to the heterogeneity in study cohorts, outcome measures, and the adopted PA intervention. The primary objective of this narrative review is to evaluate the extant evidence on the relationship between PA, cognitive decline and AD in older populations. The interaction between PA and the putative mechanisms underlying AD progression, including genetic factors and amyloid-β levels will be explored. In this context, particular attention will be given to studies assessing PA in the early clinical and preclinical, asymptomatic stages of AD. Based on current evidence, clinical considerations for implementation of exercise-based interventions are discussed, along with limitations of previous research and directions for future studies.



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Recruiting primary care physicians to qualitative research: Experiences and recommendations from a childhood cancer survivorship study

Abstract

Background

Primary care physicians (PCPs) are essential for healthcare delivery but can be difficult to recruit to health research. Low response rates may impact the quality and value of data collected. This paper outlines participant and study design factors associated with increased response rates among PCPs invited to participate in a qualitative study at Sydney Children's Hospital, Australia.

Procedure

We invited 160 PCPs by post, who were nominated by their childhood cancer patients in a survey study. We followed-up by telephone, email, or fax 2 weeks later.

Results

Without any follow-up, 32 PCPs opted in to the study. With follow-up, a further 42 PCPs opted in, with email appearing to be the most effective method, yielding a total of 74 PCPs opting in (46.3%). We reached data saturation after 51 interviews. On average, it took 34.6 days from mail-out to interview completion. Nonrespondents were more likely to be male (= 0.013). No survivor-related factors significantly influenced PCPs' likelihood of participating. Almost double the number of interviews were successfully completed if scheduled via email versus phone. Those requiring no follow-up did not differ significantly to late respondents in demographic/survivor-related characteristics.

Conclusion

PCP factors associated with higher opt in rates, and early responses, may be of interest to others considering engaging PCPs and/or their patients in cancer-related research, particularly qualitative or mixed-methods studies. Study resources may be best allocated to email follow-up, incentives, and personalization of study documents linking PCPs to patients. These efforts may improve PCP participation and the representativeness of study findings.



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Recurrent desmoplastic small round cell tumor responding to an mTOR inhibitor containing regimen

Abstract

Desmoplastic small round cell tumor (DSRCT) is a rare mesenchymal tumor that typically presents with multiple abdominal masses. Initial treatment is multimodal in nature. Patients with relapsed DSRCT have a poor prognosis, and there are no standard therapies. We report our experience with five patients treated with vinorelbine, cyclophosphamide, and temsirolimus (VCT). Median number of VCT courses delivered was 7 (range 4–14 courses), and partial response was observed in all patients. Median time to progression or relapse was 8.5 months (range 7–16 months). Neutropenia and mucositis were most common toxicities (n = 4 each).



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Palonosetron is nonsuperior to ondansetron in acute phase but provides superior antiemetic control in delayed phase for pediatric patients administered highly emetogenic chemotherapy

Abstract

Purpose

Chemotherapy-induced nausea and vomiting (CINV) in children remains to be a major side effect despite antiemetic treatment. Palonosetron is a new generation 5-HT3 receptor antagonists effective against acute and delayed nausea and vomiting. This study aimed to compare the therapeutic values of palonosetron and ondansetron in preventing pediatric CINV.

Methods

A prospective, randomized, double-blind, parallel controlled study was conducted in 0–18 years old cancer patients administered highly emetogenic chemotherapy, with different dosage of palonosetron or ondansetron, both followed by dexamethasone. The patients were observed for vomiting and nausea from 0 to 120 hr after chemotherapy initiation. All adverse events (AEs) during the study period were recorded. This study was registered with the Chinese Clinical Trial Registry, number ChiCTR-TRC-14004891.

Results

Between August 2014 and July 2016, 565 patients were randomly assigned to receive 5 μg/kg palonosetron (n = 185), 10 μg/kg palonosetron (n = 186), and 3 × 150 μg/kg ondansetron (n = 194), of whom 181, 185, and 189, respectively, were included in the efficacy analysis. Complete response (CR) rates during the acute phase were 69.1, 69.7, and 64.6%, respectively, in the 5 μg/kg palonosetron, 10 μg/kg palonosetron, and ondansetron groups. In the delayed phase, 10 μg/kg palonosetron (CR, 53.5%) showed superiority to 5 μg/kg palonosetron (CR, 39.8%) and ondansetron (CR, 32.8%) groups (P < 0.05). The most frequently observed drug-related AEs were nervous system disorders, mainly headache, with an incidence of 2.8, 2.2, and 2.6% in each group, respectively.

Conclusion

Combination of palonosetron plus dexamethasone is highly effective in controlling acute and delayed CINV, with palonosetron superior to ondansetron.



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A phase II study of radioimmunotherapy with intraventricular 131I-3F8 for medulloblastoma

Abstract

Background

High-risk and recurrent medulloblastoma (MB) is associated with significant mortality. The murine monoclonal antibody 3F8 targets the cell-surface disialoganglioside GD2 on MB. We tested the efficacy, toxicity, and dosimetry of compartmental radioimmunotherapy (cRIT) with intraventricular 131I-labeled 3F8 in patients with MB on a phase II clinical trial.

Methods

Patients with histopathologically confirmed high-risk or recurrent MB were eligible for cRIT. After determining adequate cerebrospinal fluid (CSF) flow, patients received 2 mCi (where Ci is Curie) 124I-3F8 or 131I-3F8 with nuclear imaging for dosimetry, followed by up to four therapeutic (10 mCi/dose) 131I-3F8 injections. Dosimetry estimates were based on serial CSF and blood samplings over 48 hr plus region-of-interest analyses on serial imaging scans. Disease evaluation included pre- and posttherapy brain/spine magnetic resonance imaging approximately every 3 months for the first year after treatment, and every 6–12 months thereafter.

Results

Forty-three patients received a total of 167 injections; 42 patients were evaluable for outcome. No treatment-related deaths occurred. Toxicities related to drug administration included acute bradycardia with somnolence, headache, fatigue, and CSF pleocytosis consistent with chemical meningitis and dystonic reaction. Total CSF absorbed dose was 1,453 cGy (where Gy is Gray; 350.0–2,784). Median overall survival from first dose of cRIT was 24.9 months (95% confidence interval [CI]:16.3–55.8). Patients treated in radiographic and cytologic remission were at a lower risk of death compared to patients with radiographically measurable disease (hazard ratio: 0.40, 95% CI: 0.18–0.88, P = 0.024).

Conclusions

cRIT with 131I-3F8 is safe, has favorable dosimetry to CSF, and when added to salvage therapy using conventional modalities, may have clinical utility in maintaining remission in high-risk or recurrent MB.



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BDNF/TrkB axis activation promotes epithelial–mesenchymal transition in idiopathic pulmonary fibrosis

Neurotrophins (NT) belongs to a family of growth factors which promotes neurons survival and differentiation. Increasing evidence show that NT and their receptor are expressed in lung tissues suggesting a poss...

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Treatment of lumbar degenerative disc disease-associated radicular pain with culture-expanded autologous mesenchymal stem cells: a pilot study on safety and efficacy

Degenerative disc disease (DDD) is a common cause of lower back pain with radicular symptoms and has a significant socioeconomic impact given the associated disability. Limited effective conservative therapeut...

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Infiltrating Lobular Breast Cancer Presenting as Isolated Gastric Metastasis: a Case Report



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Molecular and clinical spectra of FBXL4 deficiency

Abstract

F-box and leucine-rich repeat protein 4 (FBXL4) is a mitochondrial protein whose exact function is not yet known. However, cellular studies have suggested that it plays significant roles in mitochondrial bioenergetics, mitochondrial DNA (mtDNA) maintenance, and mitochondrial dynamics. Biallelic pathogenic variants in FBXL4 are associated with an encephalopathic mtDNA maintenance defect syndrome that is a multisystem disease characterized by lactic acidemia, developmental delay, and hypotonia. Other features are feeding difficulties, growth failure, microcephaly, hyperammonemia, seizures, hypertrophic cardiomyopathy, elevated liver transaminases, recurrent infections, variable distinctive facial features, white matter abnormalities and cerebral atrophy found in neuroimaging, combined deficiencies of multiple electron transport complexes, and mtDNA depletion. Since its initial description in 2013, 36 different pathogenic variants in FBXL4 were reported in 50 affected individuals. In this report, we present 37 additional affected individuals and 11 previously unreported pathogenic variants. We summarize the clinical features of all 87 individuals with FBXL4-related mtDNA maintenance defect, review FBXL4 structure and function, map the 47 pathogenic variants onto the gene structure to assess the variants distribution, and investigate the genotype-phenotype correlation. Finally, we provide future directions to understand the disease mechanism and identify treatment strategies.

This article is protected by copyright. All rights reserved



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Endonucleolytic cleavage in the expansion segment 7 of 25S rRNA is an early marker of low-level oxidative stress in yeast. [Cell Biology]

The ability to detect and respond to oxidative stress is crucial to the survival of living organisms. In cells, sensing of increased levels of reactive oxygen species (ROS) activates many defensive mechanisms that limit or repair damage to cell components. The ROS-signaling responses necessary for cell survival under oxidative stress conditions remain incompletely understood, especially for the translational machinery. Here, we found that drug treatments or a genetic deficiency in the thioredoxin system that increase levels of endogenous hydrogen peroxide in the yeast Saccharomyces cerevisiae promote site-specific endonucleolytic cleavage in 25S ribosomal RNA (rRNA) adjacent to the c-loop of the expansion segment 7 (ES7), a putative regulatory region located on the surface of the 60S ribosomal subunit. Our data also show that ES7c is cleaved at early stages of the gene expression program that enables cells to successfully counteract oxidative stress, and is not a prerequisite or consequence of apoptosis. Moreover, the 60S subunits containing ES7c-cleaved rRNA cofractionate with intact subunits in sucrose gradients and repopulate polysomes after a short starvation-induced translational block, indicating their active role in translation. These results demonstrate that ES7c cleavage in rRNA is an early and sensitive marker of increased ROS levels in yeast cells and suggest that changes in ribosomes may be involved in the adaptive response to oxidative stress.

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Myristoylation of Src kinase mediates Src induced and high fat diet accelerated prostate tumor progression in mice [Molecular Bases of Disease]

Exogenous fatty acids provide substrates for energy production and the biogenesis of the cytoplasmic membrane, but they also enhance cellular signaling during cancer cell proliferation. However, it remains controversial whether dietary fatty acids are correlated with tumor progression. In this study, we demonstrate that increased Src kinase activity is associated with high fat diet accelerated progression of prostate tumors and that Src kinases mediate this pathological process. Moreover, in the in vivo prostate regeneration assay, host SCID mice carrying Src(Y529F) transduced regeneration tissues were fed with a low fat diet or a high fat diet and treated with vehicle or dasatinib. The high fat diet not only accelerated Src induced prostate tumorigenesis in mice, but also compromised the inhibitory effect of the anticancer drug dasatinib on Src kinase oncogenic potential in vivo. We further show that myristoylation of Src kinase is essential to facilitate Src induced and high fat diet accelerated tumor progression. Mechanistically, metabolism of exogenous myristic acid increased the biosynthesis of myristoyl CoA and myristoylated Src, and promoted Src kinase mediated oncogenic signaling in human cells. Of the fatty acids tested, only exogenous myristic acid contributed to increased intracellular myristoyl CoA levels. Our results suggest that targeting Src kinase myristoylation, which is required for Src kinase association at the cellular membrane, blocks dietary fat accelerated tumorigenesis in vivo. Our findings uncover a molecular basis of how the metabolism of myristic acid stimulates high fat diet mediated prostate tumor progression.

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Human Rab small GTPase- and class V myosin-mediated membrane tethering in a chemically defined reconstitution system [Cell Biology]

Membrane tethering is a fundamental process essential for compartmental specificity of intracellular membrane trafficking in eukaryotic cells. Rab-family small GTPases and specific sets of Rab-interacting effector proteins, including coiled-coil tethering proteins and multisubunit tethering complexes, have been reported to be responsible for membrane tethering. However, whether and how these key components directly and specifically tether subcellular membranes still remains enigmatic. Using chemically defined proteoliposomal systems reconstituted with purified human Rab proteins and synthetic liposomal membranes to study the molecular basis of membrane tethering, we established here that Rab-family GTPases have a highly conserved function to directly mediate membrane tethering, even in the absence of any types of Rab effectors such as the so-called tethering proteins. Moreover, we demonstrate that membrane tethering mediated by endosomal Rab11a is drastically and selectively stimulated by its cognate Rab effectors, class V myosins (Myo5A and Myo5B), in a GTP-dependent manner. Of note, Myo5A and Myo5B exclusively recognized and cooperated with the membrane-anchored form of their cognate Rab11a to support membrane tethering mediated by trans-Rab assemblies on apposing membranes. Our findings support the novel concept that Rab-family proteins provide a bona fide membrane tether to physically and specifically link two distinct lipid bilayers of subcellular membranes. They further indicate that Rab-interacting effector proteins, including class V myosins, can regulate these Rab-mediated membrane tethering reactions.

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Plasma membrane phosphatidylinositol 4-phosphate and 4,5-bisphosphate determine the distribution and function of K-Ras4B but not H-Ras proteins [Signal Transduction]

Plasma membrane (PM) localization of Ras proteins is crucial for transmitting signals upon mitogen stimulation. Posttranslational lipid modification of Ras proteins plays an important role in their recruitment to the PM. Electrostatic interactions between negatively charged PM phospholipids and basic amino acids found in K-Ras4B (K-Ras) but not in H-Ras are important for permanent K-Ras localization to the PM. Here, we investigated how acute depletion of negatively charged PM polyphosphoinositides (PPIns) from the PM alters the intracellular distribution and activity of K- and H-Ras proteins. PPIns depletion from the PM was achieved either by agonist-induced activation of phospholipase C β or with a rapamycin-inducible system in which various PI phosphatases were recruited to the PM. Redistribution of the two Ras proteins was monitored with confocal microscopy or with a recently developed bioluminescent energy transfer (BRET)-based approach involving fusion of the Ras C-terminal targeting sequences or the entire Ras proteins to Venus fluorescent protein. We found that PM PPIns depletion caused rapid translocation of K-Ras but not H-Ras from the PM to the Golgi. PM depletion of either phosphatidylinositol 4-phosphate (PtdIns4P) or PtdIns(4,5)P2, but not PtdIns(3,4,5)P3, was sufficient to evoke K-Ras translocation. This effect was diminished by deltarasine, an inhibitor of the Ras-phosphodiesterase interaction, or by simultaneous depletion of the Golgi PtdIns4P. The PPIns depletion decreased incorporation of [3H]-Leucine in K-Ras-expressing cells, suggesting that Golgi-localized K-Ras is not as signaling competent as its PM-bound form. We conclude that PPIns in the PM are important regulators of K-Ras mediated signals.

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Phosphomimetic S3D-Cofilin Binds But Only Weakly Severs Actin Filaments [Enzymology]

Many biological processes, including cell division, growth, and motility, rely on rapid remodeling of the actin cytoskeleton and on actin-filament severing by the regulatory protein cofilin. Phosphorylation of vertebrate cofilin at serine 3 (Ser-3) regulates both actin binding and severing. Substitution of serine with aspartate at position 3 (S3D) is widely used to mimic cofilin phosphorylation in cells and in vitro. The S3D substitution weakens cofilin binding to filaments, and it is presumed that subsequent reduction in cofilin occupancy inhibits filament severing, but this hypothesis has remained untested. Here, using time-resolved phosphorescence anisotropy, electron cryomicroscopy, and all-atom molecular dynamics simulations, we show that S3D-cofilin indeed binds filaments with lower affinity, but also with a higher cooperativity than wild-type cofilin, and severs actin weakly across a broad range of occupancies. We found that three factors contribute to the severing deficiency of S3D-cofilin. First, the high cooperativity of S3D-cofilin generates fewer boundaries between bare and decorated actin segments where severing occurs preferentially. Second, S3D-cofilin only weakly alters filament bending and twisting dynamics and therefore does not introduce the mechanical discontinuities required for efficient filament severing at boundaries. Third, Ser-3 modification (i.e. substitution with Asp or phosphorylation) undocks and repositions the cofilin N-terminus away from the filament axis, which compromises S3D-cofilins ability to weaken longitudinal filament subunit interactions. Collectively, our results demonstrate that, in addition to inhibiting actin binding, Ser-3 modification favors formation of a cofilin binding mode that is unable to sufficiently alter filament mechanical properties and promote severing.

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Translesion synthesis DNA polymerases promote error-free replication through the minor-groove DNA adduct 3-deaza-3-methyl adenine [DNA and Chromosomes]

N3-methyladenine (3-MeA) is formed in DNA by reaction with S-adenosyl methionine, the reactive methyl donor, and by reaction with alkylating agents. 3-MeA protrudes into the DNA minor groove and strongly blocks synthesis by replicative DNA polymerases (Pols). However, the mechanisms for replicating through this lesion in human cells remain unidentified. Here we analyzed the roles of translesion synthesis (TLS) Pols in the replication of 3-MeA-damaged DNA in human cells. Because 3-MeA has a short half-life in vitro, we used the stable 3-deaza analog, 3-deaza-3-methyl adenine (3-dMeA), which blocks the DNA minor groove similarly to 3-MeA. We found that replication through the 3-dMeA adduct is mediated via three different pathways, dependent upon Polι/Polκ, Polθ, and Polζ. As inferred from biochemical studies, in the Polι/Polκ pathway, Polι inserts a nucleotide (nt) opposite 3-dMeA and Polκ extends synthesis from the inserted nt. In the Polθ pathway, Polθ carries out both the insertion and extension steps of TLS opposite 3-dMeA, and in the Polζ pathway, Polζ extends synthesis following nt insertion by an as yet unidentified Pol. Steady-state kinetic analyses indicated that Polι and Polθ insert the correct nt T opposite 3-dMeA with a much reduced catalytic efficiency and that both Pols exhibit a high propensity for inserting a wrong nt opposite this adduct. However, in spite of their low fidelity of synthesis opposite 3-dMeA, TLS opposite this lesion replicates DNA in a highly error-free manner in human cells. We discuss the implications of these observations for TLS mechanisms in human cells..

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Bacterial DnaB helicase interacts with the excluded strand to regulate unwinding [Molecular Biophysics]

Replicative hexameric helicases are thought to unwind duplex DNA by steric exclusion (SE), where one DNA strand is encircled by the hexamer and the other is excluded from the central channel. However, interactions with the excluded strand on the exterior surface of hexameric helicases have also been shown to be important for DNA unwinding, giving rise to the steric exclusion and wrapping (SEW) model. For example, the archaeal SsoMCM helicase has been shown to unwind DNA via a SEW mode to enhance unwinding efficiency. Using single molecule FRET (smFRET), we now show that the analogous E. coli DnaB helicase also interacts specifically with the excluded DNA strand during unwinding. Mutation of several conserved and positively-charged residues on the exterior surface of EcDnaB resulted in increased interaction dynamics and states compared to wild-type. Surprisingly, these mutations also increased the DNA unwinding rate, suggesting that electrostatic contacts with the excluded strand act as a regulator for unwinding activity. In support, experiments neutralizing charge of the excluded strand with a morpholino substrate instead of DNA also dramatically increased the unwinding rate. Of note, although the stability of the excluded strand was nearly identical for EcDnaB and SsoMCM, these enzymes are from different superfamilies and unwind DNA with opposite polarities. These results support the SEW model of unwinding for EcDnaB that expands on the existing SE model of hexameric helicase unwinding to include contributions from the excluded strand to regulate the DNA unwinding rate.

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Interaction between the AAA+ ATPase p97 and its cofactor ataxin3 in health and disease: Nucleotide-induced conformational changes regulate cofactor binding [Protein Structure and Folding]

p97 is an essential ATPase associated with various cellular activities (AAA+) that functions as a segregase in diverse cellular processes, including the maintenance of proteostasis. p97 interacts with different cofactors that target it to distinct pathways; an important example is the deubiquitinase ataxin3, which collaborates with p97 in endoplasmic reticulum associated degradation (ERAD). However, the molecular details of this interaction have been unclear. Here, we characterized the binding of ataxin3 to p97, showing that ataxin3 binds with low-micromolar affinity to both wild-type p97 and mutants linked to degenerative disorders known as multisystem proteinopathy 1 (MSP1); we further showed that the stoichiometry of binding is one ataxin3 molecule per p97 hexamer. We mapped the binding determinants on each protein, demonstrating that ataxin3's p97/VCP-binding motif (VBM) interacts with the inter-lobe cleft in the N-domain of p97. We also probed the nucleotide dependence of this interaction, confirming that ataxin3 and p97 associate in the presence of ATP and in the absence of nucleotide, but not in the presence of ADP. Our experiments suggest that an ADP-driven downward movement of the p97 N-terminal domain dislodges ataxin3 by inducing a steric clash between the D1-domain and ataxin3's C-terminus. In contrast, MSP1 mutants of p97 bind ataxin3 irrespective of their nucleotide state, indicating a failure by these mutants to translate ADP binding into a movement of the N-terminal domain. Our model provides a mechanistic explanation for how nucleotides regulate the p97-ataxin3 interaction and why atypical cofactor binding is observed with MSP1 mutants.

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Αναζήτηση αυτού του ιστολογίου

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