bluuebunny/crossref_metadata_2025 huggingface dataset:
Urinary prostaglandin D2 metabolite excretion during the first six months of life was significantly lower in breast‐fed than formula‐fed infants
Authors: Shoji Hiromichi , Ikeda Naho , Kitamura Tomohiro , Suganuma Hiroki , Ohba Mai , Okuno Toshiaki , Yokomizo Takehiko , Shimizu Toshiaki
Published: September 2017

Aim

The metabolic changes that occur during the postnatal weaning period appear to be particularly important for future health, and breast milk is considered to provide the optimal source of infant nutrition. This pilot study from September 2013 to May 2015 examined the effect of breastfeeding on prostaglandin metabolism in healthy term infants.

Methods

Urine samples were collected from 19 infants at one month of age in the Juntendo University Hospital, Tokyo, Japan. The 13 infants in the breast‐fed group received less than 540 mL/week of their intake from formula, and the other six were exclusively fed on formula. At six months, we sampled 14 infants: nine breast‐fed and five receiving formula. The infants were from normal single pregnancies and free from perinatal complications. We analysed urinary prostaglandin metabolites—tetranor prostaglandin E2 metabolite (t‐PGEM) and tetranor prostaglandin D2 metabolite (t‐PGDM)—using liquid chromatography tandem–mass spectrometry.

Results

Urinary t‐PGDM excretion at one and six months was significantly lower in breast‐fed infants than formula‐fed infants. However, urinary t‐PGEM excretion at one and six months was not significantly different between the groups.

Conclusion

Our study showed that the type of feeding in early infancy affected prostaglandin metabolism in healthy term infants.
Importance of the second extracellular loop for melatonin MT1 receptor function and absence of melatonin binding in GPR50
Authors: Clement Nathalie , Renault Nicolas , Guillaume Jean‐Luc , Cecon Erika , Journé Anne‐Sophie , Laurent Xavier , Tadagaki Kenjiro , Cogé Francis , Gohier Arnaud , Delagrange Philippe , Chavatte Philippe , Jockers Ralf
Published: September 2017

Background and Purpose

Recent crystal structures of GPCRs have emphasized the previously unappreciated role of the second extracellular (E2) loop in ligand binding and gating and receptor activation. Here, we have assessed the role of the E2 loop in the activation of the melatonin MT1 receptor and in the inactivation of the closely related orphan receptor GPR50.

Experimental Approach

Chimeric MT1‐GPR50 receptors were generated and functionally analysed in terms of 2‐[125I]iodomelatonin binding, Gi/cAMP signalling and β‐arrestin2 recruitment. We also used computational molecular dynamics (MD) simulations.

Key Results

MD simulations of 300 ns revealed (i) the tight hairpin structure of the E2 loop of the MT1 receptor (ii) the most suitable features for melatonin binding in MT1 receptors and (iii) major predicted rearrangements upon MT1 receptor activation, stabilizing interaction networks between Phe179 or Gln181 in the E2 loop and transmembrane helixes 5 and 6. Functional assays confirmed these predictions, because reciprocal replacement of MT1 and GPR50 residues/domains led to the predicted loss‐ and gain‐of‐melatonin action of MT1 receptors and GPR50 respectively.

Conclusions and Implications

Our work demonstrated the crucial role of the E2 loop for MT1 receptor and GPR50 function by proposing a model in which the E2 loop is important in stabilizing active MT1 receptor conformations and by showing how evolutionary processes appear to have selected for modifications in the E2 loop in order to make GPR50 unresponsive to melatonin.

Linked Articles

This article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc
Echocardiographic guidance and monitoring of left atrial appendage closure with AtriClip during open‐chest cardiac surgery
Authors: Contri Rachele , Clivio Sara , Torre Tiziano , Cassina Tiziano
Published: September 2017

Left atrial appendage (LAA) closure prevents thromboembolic risk and avoids lifelong anticoagulation due to atrial fibrillation (AF). Nowadays, AtriClip, a modern epicardial device approved in June 2010, allows external and safe closure of LAA in patients undergoing cardiac surgery during other open‐chest cardiac surgical procedures. Such a surgical approach and its epicardial deployment differentiates LAA closure with AtriClip from percutaneous closure techniques such as Watchman (Boston Scientific, Marlborough, MA, USA), Lariat (SentreHEART Inc., Redwood City, CA, USA), and Amplatzer Amulet (St. Jude Medical, St. Paul, MN, USA) device procedures. AtriClip positioning must consider perioperative transesophageal echocardiography (TEE) to confirm LAA anatomical features, to explore the links with neighboring structures, and finally to assess its successful closure. We report a sequence of images to document the role of intraoperative TEE during an elective aortic valve replacement and LAA external closure with AtriClip.
Analyses of N‐linked glycans of PrPSc revealed predominantly 2,6‐linked sialic acid residues
Authors: Katorcha Elizaveta , Baskakov Ilia V.
Published: September 2017

Mammalian prions (PrPSc) consist of misfolded, conformationally altered, self‐replicating states of the sialoglycoprotein called prion protein or PrPC. Recent studies revealed that the sialylation status of PrPSc plays a major role in evading innate immunity and infecting a host. Establishing the type of linkage by which sialic acid residues are attached to galactose is important, as it helps to identify the sialyltransferases responsible for sialylating PrPC and outline strategies for manipulating the sialyation status of PrPSc. Using enzymatic treatment with sialidases and lectin blots, this study demonstrated that in N‐linked glycans of PrPSc, the sialic acid residues are predominantly alpha 2,6‐linked. High percentages of alpha 2,6‐linked sialic acids were observed in PrPSc of three prion strains 22L, RML, and ME7, as well as PrPSc from brain, spleen, or N2a cells cultured in vitro. Moreover, the variation in the percentage of alpha 2,3‐ versus 2,6‐linked sialic acid was found to be relatively minor between brain‐, spleen‐, or cell‐derived PrPSc, suggesting that the type of linkage is independent of tissue type. Based on the current results, we propose that sialyltransferases of St6Gal family, which is responsible for attaching sialic acids via alpha 2,6‐linkages to N‐linked glycans, controls sialylation of PrPC and PrPSc.
Investigating creep rupture and damage behaviour in notched P92 steel specimen using a microscale modelling approach
Authors: Zhao L. , Alang N. , Nikbin K.
Published: September 2017

Idealized random grains separated by pseudo grain boundaries were generated by using Voronoi tessellation to simulate the polycrystalline microstructure. Combined with finite element analyses, this approach made it possible to addressing crack initiation and progressive failure due to crack growth in notched bar geometries of P92 steel at high temperature. The calculations provided good predictions for creep rupture lives of notched specimen with different notch radii and external stress. Simultaneously, irregular crack growth shape, intergranular crack mode, and wedge cracks at triple grain interaction were captured in the model. The crack initiation positions were found to be influenced by notch radius and applied stress causing high stress triaxiality at the subgrain level. Furthermore, the preferential crack growth directions were changed as the notch varied from sharp to blunt.
The Economic Effect of Refugee Crises on Neighbouring Host Countries: Empirical Evidence from Pakistan
Authors: Baloch Amdadullah , Shah Said Zamin , Noor Zaleha Mohd , Lacheheb Miloud
Published: September 2017

There is a considerable debate in terms of opportunities and challenges about the presence of refugees in the neighbouring host countries. Most of the existing discourse has focused only on their humanitarian and security implications. This article, on the other hand, seeks to uncover this issue through a purely economic lens, focusing on the economic impact of more than three million Afghan refugees in Pakistan. Utilizing data for the period 1979–2014 and the ARDL bounds testing approach, we arrive at few important conclusions. The empirical results indicate that Afghan refugees have a strong negative impact on economic growth in Pakistan. The effect holds in both the short run and the long run, suggesting that the influx of refugees lowers real economic activity in the country. Ultimately, the study implies that hosting refugees can never be a boon to Pakistan's economy.
Quality of life measurement in acne. Position Paper of the European Academy of Dermatology and Venereology Task Forces on Quality of Life and Patient Oriented Outcomes and Acne, Rosacea and Hidradenitis Suppurativa
Authors: Chernyshov P.V. , Zouboulis C.C. , Tomas‐Aragones L. , Jemec G.B. , Manolache L. , Tzellos T. , Sampogna F. , Evers A.W.M. , Dessinioti C. , Marron S.E. , Bettoli V. , van Cranenburgh O.D. , Svensson A. , Liakou A.I. , Poot F. , Szepietowski J.C. , Salek M.S. , Finlay A.Y.
Published: September 2017

Acne causes profound negative psychological and social effects on the quality of life (QoL) of patients. The European Dermatology Forum S3‐Guideline for the Treatment of Acne recommended adopting a QoL measure as an integral part of acne management. Because of constantly growing interest in health‐related QoL assessment in acne and because of the high impact of acne on patients’ lives, the European Academy of Dermatology and Venereology Task Force on QoL and Patient Oriented Outcomes and the Task Force on Acne, Rosacea and Hidradenitis Suppurativa have documented the QoL instruments that have been used in acne patients, with information on validation, purposes of their usage, description of common limitations and mistakes in their usage and overall recommendations.
The Design, Development, and Evaluation of a Qualitative Data Collection Application for Pregnant Women
Authors: Keedle Hazel , Schmied Virginia , Burns Elaine , Dahlen Hannah
Published: September 2017

Purpose

This article explores the development and evaluation of a smartphone mobile software application (app) to collect qualitative data. The app was specifically designed to capture real‐time qualitative data from women planning a vaginal birth after caesarean delivery. This article outlines the design and development of the app to include funding, ethics, and the recruitment of an app developer, as well as the evaluation of using the app by seven participants.

Organizing Construct

Data collection methods used in qualitative research include interviews and focus groups (either online, face‐to‐face, or by phone), participant diaries, or observations of interactions. This article identifies an alternative data collection methodology using a smartphone app to collect real‐time data.

Conclusions

The app provides real‐time data and instant access to data alongside the ability to access participants from a variety of locations. This allows the researcher to gain insight into the experiences of participants through audio or video recordings in longitudinal studies without the need for constant interactions or interviews with participants.

Clinical Relevance

Using smartphone applications can allow researchers to access participants who are traditionally hard to reach and access their data in real time. Evaluating these apps before use in research is invaluable.
The dental therapist movement in the United States: A critique of current trends
Authors: Nash David A. , Mathu‐Muju Kavita R. , Friedman Jay W.
Published: September 2017

Dental therapists are members of the oral health workforce in over 50 countries in the world typically caring for children in publically funded school‐based programs. A movement has developed in the United States to introduce dental therapists to the oral health workforce in an attempt to improve access to care and to reduce disparities in oral health. This article critiques trends in the United States movement in the context of the history and success of dental therapists practicing internationally. While supporting the dental therapist movement, we challenge: a) the use of dental therapists treating adults, versus focusing on children; b) the use of dental therapists in the private versus the public/not‐for‐profit sector; and c) requirements that a dental therapist must also be credentialed as a dental hygienist.
A review of escape behaviour in orthopterans
Authors: Lagos P. A.
Published: September 2017

In most situations, escaping from a predator may not be a simple decision to make, mainly because of the number and complexity of factors that might influence escape behaviour. There is rich literature on how different factors affect escape behaviour, and on the mechanisms involved, but to date, very little synthesis exist, with the exception for escape behaviour in vertebrates. Little is known about the general patterns affecting the escape decisions in arthropod taxa, even though vast research exists describing how different variables affect their escape behaviour. Here, I’ll summarize the main factors that influence the escape decisions in a particular group of arthropods, the orthopterans. I decided to focus on this taxon because we have a good understanding of the neural bases for their escape response as well as their sensory systems. Thus, my objective is to connect general patterns of the escape decisions with the mechanisms explaining how escape behaviour operates.
Growth differentiation factor 15 predicts advanced fibrosis in biopsy‐proven non‐alcoholic fatty liver disease
Authors: Koo Bo Kyung , Um Sung Hee , Seo Dong Soo , Joo Sae Kyung , Bae Jeong Mo , Park Jeong Hwan , Chang Mee Soo , Kim Jung Ho , Lee Jieun , Jeong Won‐Il , Kim Won
Published: September 2017

Background & Aims

We explored whether growth differentiation factor 15 (GDF15) affects the histological severity of non‐alcoholic fatty liver disease (NAFLD) independent of insulin resistance.

Methods

In a biopsy‐proven NAFLD cohort, we measured serum GDF15 levels using enzyme‐linked immunosorbent assays.

Results

Among 190 subjects (mean age, 53 ± 14 years; men, 52.1%), 72 (men, 65.3%) and 78 (men, 44.9%) were diagnosed with biopsy‐proven non‐alcoholic fatty liver (NAFL) and non‐alcoholic steatohepatitis (NASH) respectively. GDF15 levels were significantly higher in NASH patients than in controls (P = .010) or NAFL patients (P = .001). Subjects with advanced fibrosis (≥F3) also showed higher GDF15 levels compared to the others (F0‐2; P < .001). Among NAFLD patients, the highest quartile of GDF15 levels was significantly associated with a risk of advanced fibrosis even after adjustment for age, gender, body mass index, smoking status, hypertension, diabetes, aspartate aminotransferase, platelet, albumin, insulin resistance and low skeletal muscle mass (odds ratio, 4.27; 95% confidence interval, 1.04‐17.63), but not with NASH risk. GDF15 levels showed a significant positive correlation with liver stiffness (Spearman's ρ, .525; P < .001). Palmitate treatment increased the GDF15 mRNA expression level significantly in Kupffer cells, but not in hepatocytes. In LX‐2 cells, GDF15 treatment resulted in enhanced expression of α‐smooth muscle actin and collagen I, as well as phosphorylation of SMAD2 and SMAD3.

Conclusions

Our findings suggest that GDF15 may serve as a novel biomarker of advanced fibrosis in NAFLD, thereby indicating the need for urgent anti‐fibrotic pharmacotherapy.
Role of closed loop stimulation pacing (CLS) in vasovagal syncope
Authors: Ruzieh Mohammed , Ammari Zaid , Dasa Osama , Karim Saima , Grubb Blair
Published: September 2017

Vasovagal syncope (VVS) or neurocardiogenic syncope is defined by transient loss of consciousness with spontaneous and rapid recovery. Recently, a closed loop stimulation (CLS) pacing system has emerged as a new strategy which appears superior to conventional pacing for patients with refractory syncope. However, its efficacy remains of considerable debate and large randomized controlled clinical trials are needed. Between 2002 and 2017, 12 total studies evaluated the use of CLS pacing in patients with refractory VVS, and are summarized in this article.
Product Portfolio Restructuring: Methodology and Application at Caterpillar
Authors: Shunko Masha , Yunes Tallys , Fenu Giulio , Scheller‐Wolf Alan , Tardif Valerie , Tayur Sridhar
Published: September 2017

We develop a three‐step methodology to restructure a product line by quantifying the restructuring's likely effects on revenues and costs: (i) Constructing migration lists to capture customer preferences and willingness to substitute; (ii) Explicitly capturing the (positive and negative) cost of complexity across different functional areas, using statistical analysis of cost data; and (iii) Integrating these tools within a mathematical optimization program to produce a final product line, incorporating the possibility of differentiating products by lead‐time (into different lanes). Our methodology is highly flexible—each step can be tailored to a company's particular setting, data availability and strategic needs, so long as it produces the necessary output for the next step. We report on the successful application of our methodology to the Backhoe Loader product line at Caterpillar: In collaboration with Caterpillar, we were able to significantly simplify this line, reducing the number of configurations from 37,920 to 135, in three lanes, while increasing sales by almost 7%.
Aligning nature conservation and agriculture: the search for new regimes
Authors: van der Windt Henny J. , Swart Jac. A.A.
Published: September 2017

In addition to the protection of nature in reserves, known as the land‐sparing approach, another strategy is often suggested, the land‐sharing approach, which implies the integration of nature protection with other human activities. Especially in Europe, a rich variety of sharing approaches have been practiced. Using the theoretical concepts of the multilevel perspective on sustainable transitions, we will analyze two experimental cases in the Netherlands, in which the development of a sustainable, nature‐friendly form of agriculture was attempted. In these experiments, new concepts of biodiversity monitoring, self‐governance, and agriculture were developed in order to enhance biodiversity and the quality of nature on a regional scale. Our conclusion is that this sharing strategy has proved to be promising, at least in terms of relatively extensive use of agricultural areas. It should, however, not only include sharing of land use but also of responsibilities, knowledge development, aims, and means. Moreover, our study revealed that such an approach is possible only if governmental and market structures also change, and if based on new integrating concepts.
Our Lives Matter: The Racialized Violence of Poverty among Homeless Mothers of Color,
Authors: Roschelle Anne R.
Published: September 2017

Intimate partner and community violence are an unrelenting presence in the lives of homeless Latinaand African American women and their children. Impoverished neighborhoods are inundated with public acts of violence that impact daily life in profound ways. Sexual violence, drug use, gang violence, child abuse, and hypermasculinity are enacted visibly for all to see. Based on a four‐year ethnography of homeless families in San Francisco, this research examines the gendered and racialized violence of poverty experienced by homeless mothers in San Francisco. Women in this research have endured physical and sexual violence as children and are typically victims of adult intimate partner violence. This research presents the excruciating narratives of violence and degradation suffered by homeless women of color. Their lived experiences illustrate that for many women of color, becoming homeless is a direct result of racialized poverty and chronic family violence. Framed within the intersectionality perspective, these women's stories advance our understanding of the interlocking nature of race, gender, and class oppression.
Critical Appraisal Tools and Reporting Guidelines for Evidence‐Based Practice
Authors: Buccheri Robin K. , Sharifi Claire
Published: September 2017

Background

Nurses engaged in evidence‐based practice (EBP) have two important sets of tools: Critical appraisal tools and reporting guidelines. Critical appraisal tools facilitate the appraisal process and guide a consumer of evidence through an objective, analytical, evaluation process. Reporting guidelines, checklists of items that should be included in a publication or report, ensure that the project or guidelines are reported on with clarity, completeness, and transparency.

Purpose

The primary purpose of this paper is to help nurses understand the difference between critical appraisal tools and reporting guidelines. A secondary purpose is to help nurses locate the appropriate tool for the appraisal or reporting of evidence.

Methods

A systematic search was conducted to find commonly used critical appraisal tools and reporting guidelines for EBP in nursing.

Rationale

This article serves as a resource to help nurse navigate the often‐overwhelming terrain of critical appraisal tools and reporting guidelines, and will help both novice and experienced consumers of evidence more easily select the appropriate tool(s) to use for critical appraisal and reporting of evidence. Having the skills to select the appropriate tool or guideline is an essential part of meeting EBP competencies for both practicing registered nurses and advanced practice nurses (Melnyk & Gallagher‐Ford, 2015; Melnyk, Gallagher‐Ford, & Fineout‐Overholt, 2017).

Results

Nine commonly used critical appraisal tools and eight reporting guidelines were found and are described in this manuscript. Specific steps for selecting an appropriate tool as well as examples of each tool's use in a publication are provided.

Linking Evidence to Action

Practicing registered nurses and advance practice nurses must be able to critically appraise and disseminate evidence in order to meet EBP competencies. This article is a resource for understanding the difference between critical appraisal tools and reporting guidelines, and identifying and accessing appropriate tools or guidelines.
Nosocomial Outbreak of Extensively Drug-Resistant Acinetobacter baumannii Isolates Containing
bla
OXA-237
Carried on a Plasmid
Authors: Hujer Andrea M. , Higgins Paul G. , Rudin Susan D. , Buser Genevieve L. , Marshall Steven H. , Xanthopoulou Kyriaki , Seifert Harald , Rojas Laura J. , Domitrovic T. Nicholas , Cassidy P. Maureen , Cunningham Margaret C. , Vega Robert , Furuno Jon P. , Pfeiffer Christopher D. , Beldavs Zintars G. , Wright Meredith S. , Jacobs Michael R. , Adams Mark D. , Bonomo Robert A.
Published: September 2017

Carbapenem antibiotics are among the mainstays for treating infections caused by
Acinetobacter baumannii
, especially in the Northwest United States, where carbapenem-resistant
A. baumannii
remains relatively rare. However, between June 2012 and October 2014, an outbreak of carbapenem-resistant
A. baumannii
occurred in 16 patients from five health care facilities in the state of Oregon. All isolates were defined as extensively drug resistant. Multilocus sequence typing revealed that the isolates belonged to sequence type 2 (international clone 2 [IC2]) and were >95% similar as determined by repetitive-sequence-based PCR analysis. Multiplex PCR revealed the presence of a
bla
OXA
carbapenemase gene, later identified as
bla
OXA-237
. Whole-genome sequencing of all isolates revealed a well-supported separate branch within a global
A. baumannii
phylogeny. Pacific Biosciences (PacBio) SMRT sequencing was also performed on one isolate to gain insight into the genetic location of the carbapenem resistance gene. We discovered that
bla
OXA-237
, flanked on either side by IS
Aba1
elements in opposite orientations, was carried on a 15,198-bp plasmid designated pORAB01-3 and was present in all 16 isolates. The plasmid also contained genes encoding a TonB-dependent receptor, septicolysin, a type IV secretory pathway (VirD4 component, TraG/TraD family) ATPase, an integrase, a RepB family plasmid DNA replication initiator protein, an alpha/beta hydrolase, and a BrnT/BrnA type II toxin-antitoxin system. This is the first reported outbreak in the northwestern United States associated with this carbapenemase. Particularly worrisome is that
bla
OXA-237
was carried on a plasmid and found in the most prominent worldwide clonal group IC2, potentially giving pORAB01-3 great capacity for future widespread dissemination.
Dual Mechanism of Action of 5-Nitro-1,10-Phenanthroline against Mycobacterium tuberculosis
Authors: Kidwai Saqib , Park Chan-Yong , Mawatwal Shradha , Tiwari Prabhakar , Jung Myung Geun , Gosain Tannu Priya , Kumar Pradeep , Alland David , Kumar Sandeep , Bajaj Avinash , Hwang Yun-Kyung , Song Chang Sik , Dhiman Rohan , Lee Ill Young , Singh Ramandeep
Published: September 2017

New chemotherapeutic agents with novel mechanisms of action are urgently required to combat the challenge imposed by the emergence of drug-resistant mycobacteria. In this study, a phenotypic whole-cell screen identified 5-nitro-1,10-phenanthroline (5NP) as a lead compound. 5NP-resistant isolates harbored mutations that were mapped to
fbiB
and were also resistant to the bicyclic nitroimidazole PA-824. Mechanistic studies confirmed that 5NP is activated in an F
420
-dependent manner, resulting in the formation of 1,10-phenanthroline and 1,10-phenanthrolin-5-amine as major metabolites in bacteria. Interestingly, 5NP also killed naturally resistant intracellular bacteria by inducing autophagy in macrophages. Structure-activity relationship studies revealed the essentiality of the nitro group for
in vitro
activity, and an analog, 3-methyl-6-nitro-1,10-phenanthroline, that had improved
in vitro
activity and
in vivo
efficacy in mice compared with that of 5NP was designed. These findings demonstrate that, in addition to a direct mechanism of action against
Mycobacterium tuberculosis
, 5NP also modulates the host machinery to kill intracellular pathogens.
Development and Validation of a High-Resolution Melting Assay To Detect Azole Resistance in Aspergillus fumigatus
Authors: Bernal-Martínez L. , Gil H. , Rivero-Menéndez O. , Gago S. , Cuenca-Estrella M. , Mellado E. , Alastruey-Izquierdo A.
Published: September 2017

The global emergence of azole-resistant
Aspergillus fumigatus
strains is a growing public health concern. Different patterns of azole resistance are linked to mutations in
cyp51A
. Therefore, accurate characterization of the mechanisms underlying azole resistance is critical to guide selection of the most appropriate antifungal agent for patients with aspergillosis. This study describes a new sequencing-free molecular screening tool for early detection of the most frequent mutations known to be associated with azole resistance in
A. fumigatus
. PCRs targeting
cyp51A
mutations at positions G54, Y121, G448, and M220 and targeting different tandem repeats (TRs) in the promoter region were designed. All PCRs were performed simultaneously, using the same cycling conditions. Amplicons were then distinguished using a high-resolution melting assay. For standardization, 30 well-characterized azole-resistant
A. fumigatus
strains were used, yielding melting curve clusters for different resistance mechanisms for each target and allowing detection of the most frequent azole resistance mutations, i.e., G54E, G54V, G54R, G54W, Y121F, M220V, M220I, M220T, M220K, and G448S, and the tandem repeats TR
34
, TR
46
, and TR
53
. Validation of the method was performed using a blind panel of 80
A. fumigatus
azole-susceptible or azole-resistant strains. All strains included in the blind panel were properly classified as susceptible or resistant with the developed method. The implementation of this screening method can reduce the time needed for the detection of azole-resistant
A. fumigatus
isolates and therefore facilitate selection of the best antifungal therapy in patients with aspergillosis.
Chemical Genetic Interaction Profiling Reveals Determinants of Intrinsic Antibiotic Resistance in Mycobacterium tuberculosis
Authors: Xu Weizhen , DeJesus Michael A. , Rücker Nadine , Engelhart Curtis A. , Wright Meredith G. , Healy Claire , Lin Kan , Wang Ruojun , Park Sae Woong , Ioerger Thomas R. , Schnappinger Dirk , Ehrt Sabine
Published: September 2017

Chemotherapy for tuberculosis (TB) is lengthy and could benefit from synergistic adjuvant therapeutics that enhance current and novel drug regimens. To identify genetic determinants of intrinsic antibiotic susceptibility in
Mycobacterium tuberculosis
, we applied a chemical genetic interaction (CGI) profiling approach. We screened a saturated transposon mutant library and identified mutants that exhibit altered fitness in the presence of partially inhibitory concentrations of rifampin, ethambutol, isoniazid, vancomycin, and meropenem, antibiotics with diverse mechanisms of action. This screen identified the
M. tuberculosis
cell envelope to be a major determinant of antibiotic susceptibility but did not yield mutants whose increase in susceptibility was due to transposon insertions in genes encoding efflux pumps. Intrinsic antibiotic resistance determinants affecting resistance to multiple antibiotics included the peptidoglycan-arabinogalactan ligase Lcp1, the mycolic acid synthase MmaA4, the protein translocase SecA2, the mannosyltransferase PimE, the cell envelope-associated protease CaeA/Hip1, and FecB, a putative iron dicitrate-binding protein. Characterization of a deletion mutant confirmed FecB to be involved in the intrinsic resistance to every antibiotic analyzed. In contrast to its predicted function, FecB was dispensable for growth in low-iron medium and instead functioned as a critical mediator of envelope integrity.
Pharmacokinetics and Tissue Penetration of Ceftolozane-Tazobactam in Diabetic Patients with Lower Limb Infections and Healthy Adult Volunteers
Authors: Monogue Marguerite L. , Stainton Sean M. , Baummer-Carr Arlinda , Shepard Ashley K. , Nugent James F. , Kuti Joseph L. , Nicolau David P.
Published: September 2017

Ceftolozane-tazobactam displays potent activity against Gram-negative bacteria that can cause diabetic foot infections (DFI), making it an attractive treatment option when few alternatives exist. The pharmacokinetics and tissue penetration of ceftolozane-tazobactam at 1.5 g every 8 h (q8h) in patients (
n
= 10) with DFI were compared with those in healthy volunteers (
n
= 6) using
in vivo
microdialysis. In the patient participants, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: maximum concentration (
C
max
), 55.2 μg/ml (range, 40.9 to 169.3 μg/ml); half-life (
t
1/2
), 3.5 h (range, 2.3 to 4.7 h); and area under the concentration-time curve (AUC) from time zero to 8 h (AUC
0–8
), 191.6 μg · h/ml (range, 147.1 to 286.6 μg · h/ml). The median AUC for tissue (AUC
tissue
; where AUC
tissue
was the AUC
0–8
for tissue for ceftolozane)/AUC for plasma for each antibiotic corrected by the fraction of free drug (
f
AUC
plasma
) was 0.75 (range, 0.35 to 1.00), resulting in a mean free time above 4 μg/ml (the
Pseudomonas aeruginosa
susceptibility breakpoint) in tissue of 99.8% (range, 87.5 to 100%). In the patient participants, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows:
C
max
, 14.2 μg/ml (range, 7.6 to 64.2 μg/ml);
t
1/2
, 2.0 h (range, 0.7 to 2.4 h); and AUC
0–8
, 27.1 μg · h/ml (range, 15.0 to 70.0 μg · h/ml). The AUC
tissue
(where AUC
tissue
was the AUC from time zero to the time of the last measureable concentration in tissue for tazobactam)/
f
AUC
plasma
for tazobactam was 1.18 (range, 0.54 to 1.44). In the healthy volunteers, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows:
C
max
, 91.5 μg/ml (range, 65.7 to 110.7 μg/ml);
t
1/2
, 1.9 h (range, 1.6 to 2.1 h); and AUC
0–8
, 191.3 μg · h/ml (range, 118.1 to 274.3 μg · h/ml). The median AUC
tissue
/
f
AUC
plasma
was 0.87 (range, 0.54 to 2.20), resulting in a mean free time above 4 μg/ml in tissue of 93.8% (range, 87.5 to 100%). In the healthy volunteers, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows:
C
max
, 17.5 μg/ml (range, 15.4 to 27.3 μg/ml);
t
1/2
, 0.7 h (range, 0.6 to 0.8 h); and AUC
0–8
, 22.2 μg · h/ml (range, 19.2 to 36.4 μg · h/ml). The AUC
tissue
/
f
AUC
plasma
for tazobactam was 0.85 (range, 0.63 to 2.10). Both ceftolozane and tazobactam penetrated into subcutaneous tissue with exposures similar to those of free drug in plasma in both patients with DFI and healthy volunteers. These data suggest that ceftolozane-tazobactam at 1.5 g q8h can achieve the optimal exposure with activity against susceptible Gram-negative pathogens in the tissue of patients with DFI. (This study has been registered at ClinicalTrials.gov under identifier NCT02620774.)
In Vitro
Activity of the Novel Pleuromutilin Lefamulin (BC-3781) and Effect of Efflux Pump Inactivation on Multidrug-Resistant and Extensively Drug-Resistant Neisseria gonorrhoeae
Authors: Jacobsson Susanne , Paukner Susanne , Golparian Daniel , Jensen Jörgen S. , Unemo Magnus
Published: September 2017

We evaluated the activity of the novel semisynthetic pleuromutilin lefamulin, inhibiting protein synthesis and growth, and the effect of efflux pump inactivation on clinical gonococcal isolates and reference strains (
n
= 251), including numerous multidrug-resistant and extensively drug-resistant isolates. Lefamulin showed potent activity against all gonococcal isolates, and no significant cross-resistance to other antimicrobials was identified. Further studies of lefamulin are warranted, including
in vitro
selection and mechanisms of resistance, pharmacokinetics/pharmacodynamics, optimal dosing, and performance in randomized controlled trials.
Interleukin-17A-Deficient Mice Are Highly Susceptible to Toxoplasma gondii Infection Due to Excessively Induced T. gondii HSP70 and Interferon Gamma Production
Authors: Moroda Masataka , Takamoto Masaya , Iwakura Yoichiro , Nakayama Jun , Aosai Fumie
Published: September 2017

Interleukin17A (IL-17A) is known to be involved in the host defense against pathogens and the pathogenesis of autoimmune diseases. Previously, we showed that excessive amounts of interferon gamma (IFN-γ) play an important role in the pathogenesis of the lethal effects of
Toxoplasma gondii
by inducing anaphylactic responses. In the study described in this report, we examined the effects of IL-17A deficiency on murine host defense against oral
T. gondii
infection. IL-17A-deficient C57BL/6 (B6) mice exhibited higher rates of mortality than wild-type (WT) mice during the acute phase of
T. gondii
infection. CD4
+
T cells in the mesenteric lymph nodes (mLNs) and ileum of
T. gondii
-infected IL-17A-deficient mice produced higher levels of IFN-γ than did those of WT mice. In addition, the level of
T. gondii
HSP70 (
T.g
.HSP70) expression was also significantly increased in the ileum, mLNs, liver, and spleen of infected IL-17A-deficient mice compared with that in WT mice. These elevated levels of expression of
T.g
.HSP70 and IFN-γ in infected IL-17A-deficient mice were presumably linked to the IL-17A defect since they decreased to WT levels after treatment with recombinant IL-17A. Furthermore, IL-17A-deficient mice were highly susceptible to the anaphylactic effect of
T.g
.HSP70, and the survival of IL-17A-deficient mice during the acute phase was improved by treatment with an anti-
T.g
.HSP70 monoclonal antibody. These results suggest that IL-17A plays an important role in host survival against
T. gondii
infection by protecting the host from an anaphylactic reaction via the downregulation of
T.g
.HSP70 and IFN-γ production.
Brainstem encephalitis and acute polyneuropathy associated with hepatitis E infection
Authors: Salim Omar Jabbar , Davidson Amy , Li Kathy , Leach John Paul , Heath Craig
Published: September 2017

A 59-year-old man presented with feverish illness. His Glasgow Coma Scale was 15, had reduced visual acuity in the left eye with partial left ptosis and mild left hemiparesis with an extensor left plantar. Over 48 hours, he accrued multiple cranial nerves palsies and progressed to a flaccid paralysis necessitating admission to an intensive care unit.

Cerebrospinal fluid (CSF) study showed 20 lymphocytes and raised protein. Viral and bacterial PCRs were negative. Samples for Lyme, blood-borne viruses, syphilis and autoantibodies were also negative. MRI brain showed T2 abnormalities within the brainstem. Nerve conduction studies revealed an acute motor and sensory axonal neuropathy pattern of Guillian Barre Syndrome (GBS). The patient was treated for both infective and inflammatory causes of brainstem encephalitis and GBS.

Retrospective studies confirmed the presence of hepatitis E virus (HEV) RNA in CSF and serum studies showed positive HEV IgG and IgM prior to intravenous infusion. After 3 months of intensive rehabilitation, the patient was discharged home walking with a frame.
Effectiveness of expanding annual mass azithromycin distribution treatment coverage for trachoma in Niger: a cluster randomised trial
Authors: Amza Abdou , Kadri Boubacar , Nassirou Beido , Cotter Sun Y , Stoller Nicole E , West Sheila K , Bailey Robin L , Porco Travis C , Gaynor Bruce D , Keenan Jeremy D , Lietman Thomas M , Oldenburg Catherine E
Published: September 2017

Background/aims

The WHO recommends 3–5 years of annual mass azithromycin distribution with at least 80% treatment coverage to districts with active trachoma prevalence over 10% among children. Here, we assess the efficacy of expanding the coverage target to at least 90% for trachoma control in a mesoendemic region of Niger.

Methods

Twenty-four communities were randomised to a single day of azithromycin distribution with a coverage target of 80% of the community or up to 4 days of treatment, aiming for greater than 90% coverage. Distributions were annual and individuals above 6 months of age were treated. Children under 5 years of age were monitored for ocular chlamydia infection and active trachoma.

Results

At baseline, ocular chlamydia prevalence was 20.5% (95% CI 9.8% to 31.2%) in the standard coverage arm and 21.9% (95% CI 11.3% to 32.5%) in the enhanced coverage arm, which reduced to 4.6% (95% CI 0% to 9.5%, p=0.008) and 7.1% (95% CI 2.7% to 11.4%, p<0.001) at 36 months, respectively. There was no significant difference in 36-month ocular chlamydia prevalence between the two arms (p=0.21). There was no difference in the rate of decline in ocular chlamydia between the two arms in a repeated measures model (p=0.80).

Conclusions

For annual mass azithromycin distribution programme to an entire community, there may be no additional benefit of increasing antibiotic coverage above the WHO’s 80% target.

Trial registration number

NCT00792922, post-results.
Close observation versus upfront treatment in hepatocellular carcinoma: are the exception points worth the risk?
Authors: Tholey Danielle M , Hornung Ben , Enestvedt Charles K , Chen Yiyi , Naugler Willscott S , Farsad Khashayar , Nabavizadeh Nima , Schlansky Barry , Ahn Joseph , Jou Janice H
Published: September 2017

Introduction

To assess the outcomes of immediate LDT versus observation strategies for T1 hepatocellular carcinoma (HCC) with respect to progression beyond Milan and survival.

Method

T1 HCCs were retrospectively reviewed from a multidisciplinary tumour board database between September 2007 and May 2015. In the observation group, T1 lesions were observed until the tumour grew to meet T2 criteria (=2 cm). The treatment group consisted of T1 lesions treated at diagnosis with liver directed therapy (LDT). Kaplan-Meier plots were constructed for tumour progression beyond Milan and overall survival.

Results

87 patients (observation n=56; LDT n=31) were included in the study. A total of 22% (n=19) of patients progressed beyond Milan with no difference in progression between treatment and observation groups (19% vs 23%, p=0.49). Median time to progression beyond Milan was 16 months. Overall transplantation rate was 22% (observation group n=16; treatment group n=3, p=0.04). Median survival was 55 months with LDT versus 36 months in the observation group (p=0.22). In patients who progressed to T2 (n=60), longer time to T2 progression was a predictor of improved survival (HR=0.94, 95% CI 0.88 to 0.99, p=0.03).

Conclusions

Immediate LDT of T1 lesions was not associated with increased risk of progression beyond Milan criteria when compared with an observation approach. Longer time to T2 progression was associated with increased survival and may be a surrogate for favourable tumour biology.
Adrenal venous sampling for primary aldosteronism: laboratory medicine best practice
Authors: Kline Gregory , Holmes Daniel T
Published: September 2017

Primary aldosteronism (PA) is the most common form of secondary hypertension and is critical to identify because when caused by an aldosterone-producing adenoma (APA) or another unilateral form, it is potentially curable, and even when caused by bilateral disease, antihypertensives more specific to PA treatment can be employed (ie, aldosterone antagonists). Identification of unilateral forms is not generally accomplished with imaging because APAs may be small and elude detection, and coincidental identification of a non-functioning incidentaloma contralateral to an APA may lead to removal of an incorrect gland. For this reason, the method of choice for identifying unilateral forms of PA is selective adrenal venous sampling (AVS) followed by aldosterone and cortisol analysis on collected samples. This procedure is technically difficult from a radiological standpoint and, from the laboratory perspective, is fraught with opportunities for preanalytical, analytical and postanalytical error. We review the process of AVS collection, analysis and reporting. Suggestions are made for patient preparation, specimen labelling practices and nomenclature, analytical dilution protocols, which numerical results to report, and the necessary subsequent calculations. We also identify and explain frequent sources of confusion in the aldosterone and cortisol results and provide an example of tabular reporting to facilitate interpretation and communication between laboratorian, radiologist and clinician.
Cross‐sectional study of antimicrobials used for surgical prophylaxis by bovine veterinary practitioners in Australia
Authors: Hardefeldt Laura Y , Browning Glenn F , Thursky Karin A , Gilkerson James R , Billman‐Jacobe Helen , Stevenson Mark A , Bailey Kirsten E
Published: September 2017

Antimicrobials are widely used in veterinary practices, but there has been no investigation of antimicrobial classes used or the appropriateness of their use in bovine practice. This study investigated antimicrobial use for surgical prophylaxis in bovine practice in Australia. A cross‐sectional study of veterinarian antimicrobial usage patterns was conducted using an online questionnaire. Information solicited included respondent's details, the frequency with which antimicrobials were used for specific surgical conditions (including the dose, timing and duration of therapy) and details of practice antimicrobial use policies and sources of information about antimicrobials. In total, 212 members of the Australian veterinary profession working in bovine practice completed the survey. Antimicrobials were always or frequently used by more than 75 per cent of respondents in all scenarios. Generally, antimicrobial drug choice was appropriate for the reported surgical conditions. Procaine penicillin and oxytetracycline accounted for 93 per cent of use. However, there was a wide range of doses used, with underdosing and inappropriate timing of administration being common reasons for inappropriate prophylactic treatment. There was very low use of critically important antimicrobials (3.3 per cent of antimicrobials reported). Antimicrobial use guidelines need to be developed and promoted to improve the responsible use of antimicrobials in bovine practice.
The antioxidant and antiapoptotic effect of boric acid on hepatoxicity in chronic alcohol-fed rats
Authors: Sogut Ibrahim , Paltun Sıla Ozlem , Tuncdemir Matem , Ersoz Melike , Hurdag Canan
Published: September 2017

The harmful use of alcohol is a worldwide problem involving all ages. This study aims to investigate chronic alcohol exposure related hepatotoxicity on the rat liver and possible hepatoprotective effects of boric acid. Rats were separated into 4 different groups: control, ethanol, ethanol+boric acid, and boric acid. We measured (i) malondialdehyde (MDA), total sialic acid (TSA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) levels, which are known to be the markers of alcohol damage; and also (ii) caspase-3, tumor necrosis factor-alpha (TNF-α), and the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) as the markers of apoptosis. In the ethanol group, MDA, TSA, and TNF-α levels increased whereas SOD and CAT levels decreased compared with the control group. Ethanol+boric acid group MDA, TSA, caspase-3, and TNF-α levels decreased whereas SOD and CAT levels increased compared with the ethanol group. Using histopathological evaluation of light microscope images, immunohistochemical caspase-3 and TNF-α activity in the ethanol+boric acid group were shown to be decreased compared with that in the ethanol group. Our results revealed that ethanol is capable of triggering oxidative stress and apoptosis in the rat liver. We propose that boric acid is an effective compound in protecting the rat liver against ethanol.
Solitary waves, rogue waves and homoclinic breather waves for a (2 + 1)-dimensional generalized Kadomtsev–Petviashvili equation
Authors: Dong Min-Jie , Tian Shou-Fu , Yan Xue-Wei , Zou Li , Li Jin
Published: September 2017

We study a (2 + 1)-dimensional generalized Kadomtsev–Petviashvili (gKP) equation, which characterizes the formation of patterns in liquid drops. By using Bell’s polynomials, an effective way is employed to succinctly construct the bilinear form of the gKP equation. Based on the resulting bilinear equation, we derive its solitary waves, rogue waves and homoclinic breather waves, respectively. Our results can help enrich the dynamical behavior of the KP-type equations.
Exponential nonlinear electrodynamics and backreaction effects on holographic superconductor in the Lifshitz black hole background
Authors: Sherkatghanad Z. , Mirza B. , Lalehgani Dezaki F.
Published: September 2017

We analytically describe the properties of the s-wave holographic superconductor with the exponential nonlinear electrodynamics in the Lifshitz black hole background in four-dimensions. Employing an assumption the scalar and gauge fields backreact on the background geometry, we calculate the critical temperature as well as the condensation operator. Based on Sturm–Liouville method, we show that the critical temperature decreases with increasing exponential nonlinear electrodynamics and Lifshitz dynamical exponent, [Formula: see text], indicating that condensation becomes difficult. Also we find that the effects of backreaction has a more important role on the critical temperature and condensation operator in small values of Lifshitz dynamical exponent, while [Formula: see text] is around one. In addition, the properties of the upper critical magnetic field in Lifshitz black hole background using Sturm–Liouville approach is investigated to describe the phase diagram of the corresponding holographic superconductor in the probe limit. We observe that the critical magnetic field decreases with increasing Lifshitz dynamical exponent, [Formula: see text], and it goes to zero at critical temperature, independent of the Lifshitz dynamical exponent, [Formula: see text].