bluuebunny/crossref_metadata_2025 huggingface dataset:
Resistin Gene Expression is Downregulated in CD4+ T Helper Lymphocytes and CD14+ Monocytes in Rheumatoid Arthritis Responding to TNF‐α Inhibition
Authors: Nagaev I. , Andersen M. , Olesen M. K. , Nagaeva O. , Wikberg J. , Mincheva‐Nilsson L. , Andersen G. N.
Published: July 2016

Rheumatoid arthritis (RA) is caused by complex interactions between immune cells and sustained by Th1 response cytokines. Resistin [resistance to insulin; (RETN)] is an inflammatory cytokine, first discovered in murine adipocytes. In man, RETN is mainly secreted by monocytes. The distinct role of RETN in the immune reaction is uncertain; however, RETN has pro‐inflammatory, pro‐fibrotic and possibly tolerogenic properties. The aim was to assess the reaction of RETN gene expression to TNF‐α inhibition (I) in pathogenetic immune cell subsets in RA, in the context of Th1, inflammatory and regulatory cytokine gene expressions. Accordingly, we measured RETN, IFN‐γ, TNF‐β, IL‐1β, TNF‐α, TGF‐β and IL‐10 gene expressions in CD14+ monocytes, CD4+ T helper (Th) lymphocytes (ly), CD8+ T cytotoxic (Tc) ly and CD19+ B ly in active RA before and 3 months after start of TNF‐αI. Leucocyte subsets were separated by specific monoclonal antibody‐covered beads, RNA extracted and levels of RETN, Th1 response, inflammatory and regulatory cytokine mRNAs measured by quantitative reverse transcription‐polymerase chain reaction technique. We found that TNF‐αI caused a significant downregulation of RETN gene expression in CD14+ monocytes and CD4+ Th ly and was unchanged in CD8+ Tc ly and CD19+ B ly. Both in active RA and during TNF‐αI, RETN mRNA levels were significantly higher in CD14+ monocytes than in all other examined cell types. In monocytes, fold change in RETN and TGF‐β gene expressions upon TNF‐αI correlated significantly. Our findings indicate that RETN has pro‐inflammatory as well as proresolving roles in active RA.
The impact of remote ischemic preconditioning on cardiac biomarker and functional response to endurance exercise
Authors: Cocking S. , Landman T. , Benson M. , Lord R. , Jones H. , Gaze D. , Thijssen D. H. J. , George K.
Published: July 2016

Remote ischemic preconditioning (RIPC; repeated short reversible periods of ischemia) protects the heart against subsequent ischemic injury. We explored whether RIPC can attenuate post‐exercise changes in cardiac troponin T (cTnT) and cardiac function in healthy individuals. In a randomized, crossover design, 14 participants completed 1‐h cycling time trials (TT) on two separate visits; preceded by RIPC (arms/legs, 4 × 5‐min 220 mmHg), or SHAM‐RIPC (20 mmHg). Venous blood was sampled before and 0‐, 1‐, and 3‐h post‐exercise to assess high sensitivity (hs‐)cTnT and brain natriuretic peptide (NT‐proBNP). Echocardiograms were performed at the same time points to assess left and right ventricular systolic (ejection fraction; EF and right ventricular fractional area change; RVFAC, respectively) and diastolic (early transmitral flow velocities; E) function. Baseline hs‐cTnT was not different between RIPC and SHAM. Post‐exercise hs‐cTnT levels were consistently lower following RIPC (18 ± 3 vs 21 ± 3; 19 ± 3 vs 23 ± 3; and 20 ± 2 vs 25 ± 2 ng/L at 0, 1 and 3‐h post‐exercise, respectively; P < 0.05). There was no main effect of time, trial, or interaction for NT‐proBNP and left ventricular EF or RVFAC (all P < 0.05). A main effect of time was evident for E which transiently declined immediately after exercise to a similar level in both trials (0.85 ± 0.04 vs 0.74 ± 0.04 m/s, respectively; P < 0.05). In summary, RIPC was associated with lower hs‐cTnT levels after exercise but there was no independent effect of RIPC for NT‐proBNP or LV systolic and diastolic function. The lower hs‐cTnT levels after RIPC suggests that further research should evaluate the role of ischemia in exercise‐induced elevation in hs‐cTnT.
Epidemiology of injury in male collegiate Gaelic footballers in one season
Authors: O'Connor S. , McCaffrey N. , Whyte E. F. , Moran K. A.
Published: July 2016

Despite the popularity of collegiate Gaelic football in Ireland and the recent expansion into the United Kingdom and United States, no previous study has examined injury incidence. A prospective epidemiological study was implemented to establish injury incidence in 217 (19.3 ± 1.9 years) male collegiate Gaelic footballers from two collegiate institutions in one season. An injury was defined as any injury sustained during training or competition resulting in time lost from play or athlete reported restricted performance. Athletic therapy and training students, alongside a certified athletic and rehabilitation therapist, attended all training/matches over one season, and injuries were recorded using a standardized injury report form. The match injury rate was 25.1 injuries per 1000 h, with a significantly higher match injury rate noted in fresher players (players in their 1st year of higher education) (41.6 injuries per 1000 h) than senior players (12.7 injuries per 1000 h). Lower limb injuries were predominant (71.1%), particularly in the hamstring (15.5%), knee (14.1%), and ankle (11.3%). Soft‐tissue injuries predominated, particularly strains (32.4%) and sprains (27.5%). A scan and surgery was required in 31% and 12% of injuries, respectively. Thus, injuries are prevalent in male collegiate Gaelic football, and injury prevention programs are required.
Racial Threat and the Influence of Latino Turnout on State Immigration Policy*
Authors: Avery James M. , Fine Jeffrey A. , Márquez Timothy
Published: July 2016

Objective

We examine how Latino constituencies—their percentage of the population and their percentage of voters—influence the propensity of states to pass restrictive immigration policy, testing two competing theories.

Method

Using state‐level data from 2009 through 2012, we examine the influence of Latino constituency size and Latino electoral strength on the number of restrictive immigration laws enacted by U.S. state legislatures.

Results

We find that states with larger Latino populations pass more restrictive laws, but greater Latino electoral strength leads states to pass fewer restrictive policies. This relationship is interactive such that increases in Latino turnout act to mitigate the positive effect of Latino population size on restrictive policies. Finally, we show that the positive effect of Latino mobilization is indirect, meditated by their electoral influence on the partisan and ethnic composition of state legislatures.

Conclusions

Our findings emphasize the importance of voting for minority substantive representation.
Bacterial survival and distribution during buffy coat platelet production
Authors: Taha M. , Kalab M. , Yi Q.‐L. , Maurer E. , Jenkins C. , Schubert P. , Ramirez‐Arcos S.
Published: July 2016

Background and Objectives

At Canadian Blood Services, buffy coat (BC) platelet concentrates (BC‐PCs) show a generally lower bacterial contamination rate than apheresis PCs. This study investigated whether the PC production method contributes to this observation.

Materials and Methods

Whole blood (WB) inoculated with eight bacterial strains was processed using the BC method. Bacteria were enumerated throughout BC‐PC production and subsequent PC storage. Endotoxin production and bacterial adhesion to PC bags were evaluated during PC storage. PC quality was monitored by CD62P expression (flow cytometry) and changes in dynamic light scattering (ThromboLUX®).

Results

During overnight WB hold, Staphylococcus epidermidis titres remained unchanged, commercial Escherichia coli and Klebsiella pneumoniae were eliminated and the remaining organisms proliferated to high concentrations. Through BC‐PC production, bacteria segregated preferentially towards the cellular fractions compared to plasma (P < 0·05). During PC storage, most bacteria adhered to the PC bags and Gram negatives produced clinically significant endotoxin levels. Changes in CD62P expression or ThromboLUX scoring did not consistently reflect bacterial contamination in BC‐PCs.

Conclusion

WB hold during BC‐PC production does not have a broad‐spectrum bactericidal effect, and therefore, other factors contribute to low rates of contamination in BC‐PCs.
Implications of a switch to a 100% apheresis platelet supply for patients and for blood donors: a risk benefit analysis
Authors: Thiele T. , Alt‐Mayer T. , Greinacher A. , Bux J.
Published: July 2016

Background

A 100% apheresis platelet supply is considered to increase transfusion safety by lowering donor exposures for transfusion recipients. We performed a risk benefit analysis to contrast the reduction of donor exposures and the risk of contaminated blood products in the nation‐wide inventory with the donor risks associated with a switch to a 100% apheresis platelet supply in Germany.

Methods

Donor exposures and the number of contaminated blood products resulting from HIV‐like, HBV‐like, HCV‐like pathogens and two theoretical agents with infection rates of 10 and 1000 in 100 000, respectively, were calculated for a 100% apheresis platelet supply in Germany based on the 2006–2012 hemovigilance reports. These numbers were compared with the current mixed platelet supply of pooled and apheresis platelets. Moreover, additional donation time and apheresis donor complications resulting from a 100% apheresis platelet supply were estimated.

Results

Per million total blood products (red cells, platelets, fresh frozen plasma), a 100% apheresis platelet supply would reduce donor exposures by 87 100 and the number of contaminated blood products ranging from 0·8 to 871·1. On the other hand, this requires additional 29 478 apheresis donations, 3·4 years additional donor time, and would be associated with 58 additional donor complications, respectively.

Conclusions

A 100% apheresis platelet supply would reduce donor exposures and the number of contaminated blood products in the inventory, but would increase apheresis complications in donors. Potential risks for patients must be carefully weighed against the risks for donors, dependent on the specific pathogen scenario.
Structure and optical band gaps of (Ba,Sr)SnO3 films grown by molecular beam epitaxy
Authors: Schumann Timo , Raghavan Santosh , Ahadi Kaveh , Kim Honggyu , Stemmer Susanne
Published: July 2016

Epitaxial growth of (BaxSr1−x)SnO3 films with 0 ≤ x ≤ 1 using molecular beam epitaxy is reported. It is shown that SrSnO3 films can be grown coherently strained on closely lattice and symmetry matched PrScO3 substrates. The evolution of the optical band gap as a function of composition is determined by spectroscopic ellipsometry. The direct band gap monotonously decreases with x from to 4.46 eV (x = 0) to 3.36 eV (x = 1). A large Burnstein-Moss shift is observed with La-doping of BaSnO3 films. The shift corresponds approximately to the increase in Fermi level and is consistent with the low conduction band mass.
SiO2 nanohole arrays with high aspect ratio for InGaN/GaN nanorod-based phosphor-free white light-emitting-diodes
Authors: Lim Wantae , Kum Hyun , Choi Young-Jin , Sim Sung-Hyun , Yeon Ji-Hye , Kim Jung-Sub , Seong Han-Kyu , Cha Nam-Goo , Kim Yong-Il , Park Young-Soo , Yoo Geonwook , Pearton Stephen J.
Published: July 2016

Vertically aligned InGaN/GaN nanorod (NR)-based phosphor-free light emitting diodes (LEDs) using SiO2 nanohole patterns are demonstrated. The highly ordered SiO2 nanoholes were realized on a 2 μm-thick n+GaN template by a two-step dry etching process. The use of C4F8/O2/Ar plasma chemistries under the low pressure is found to greatly enlarge the bottom diameter of each hole, exhibiting high aspect ratio (AR ∼ 9) and vertical etch profile (∼89°). SAG technique was used to define the height of the GaN NRs while the width is determined by the trimethylgallium flow rate and growth temperature. An LED structure consisted of three-pairs of InGaN/GaN quantum well and AlGaN electron blocking layer on the sidewall of the nanorod in a core-shell structure. The wavelengths were successfully tuned by controlling pitches of the rods, which was caused by the different growth rate and indium incorporation of conformally overgrown InGaN multiquantum wells. At the operating current density of 1.5 A/cm2 (65 mA), NR-based single-chip phosphor-free white LEDs with the dimension of 630 × 970 μm2 show highly stable white emission characteristics which are attractive for future solid-state lighting and full-color display applications.
Effectiveness of a loudness model for time-varying sounds in equating the loudness of sentences subjected to different forms of signal processing
Authors: Zorilă Tudor-Cătălin , Stylianou Yannis , Flanagan Sheila , Moore Brian C. J.
Published: July 2016

A model for the loudness of time-varying sounds [Glasberg and Moore (2012). J. Audio. Eng. Soc. 50, 331–342] was assessed for its ability to predict the loudness of sentences that were processed to either decrease or increase their dynamic fluctuations. In a paired-comparison task, subjects compared the loudness of unprocessed and processed sentences that had been equalized in (1) root-mean square (RMS) level; (2) the peak long-term loudness predicted by the model; (3) the mean long-term loudness predicted by the model. Method 2 was most effective in equating the loudness of the original and processed sentences.
Spectral and temporal cues for perception of material and action categories in impacted sound sources
Authors: Hjortkjær Jens , McAdams Stephen
Published: July 2016

In two experiments, similarity ratings and categorization performance with recorded impact sounds representing three material categories (wood, metal, glass) being manipulated by three different categories of action (drop, strike, rattle) were examined. Previous research focusing on single impact sounds suggests that temporal cues related to damping are essential for material discrimination, but spectral cues are potentially more efficient for discriminating materials manipulated by different actions that include multiple impacts (e.g., dropping, rattling). Perceived similarity between material categories across different actions was correlated with the distribution of long-term spectral energy (spectral centroid). Similarity between action categories was described by the temporal distribution of envelope energy (temporal centroid) or by the density of impacts. Moreover, perceptual similarity correlated with the pattern of confusion in categorization judgments. Listeners tended to confuse materials with similar spectral centroids, and actions with similar temporal centroids and onset densities. To confirm the influence of these different features, spectral cues were removed by applying the envelopes of the original sounds to a broadband noise carrier. Without spectral cues, listeners retained sensitivity to action categories but not to material categories. Conversely, listeners recognized material but not action categories after envelope scrambling that preserved long-term spectral content.
Flirting With the Judges: Bikini Fitness Competitors’ Negotiations of Femininity in Bodybuilding Competitions
Authors: Tajrobehkar Bahar
Published: July 2016

Women’s bodybuilding manifestly challenges hegemonic understandings of the female body as weak, fragile, and limited. Because it has acquired characteristics that are traditionally deemed masculine, the muscular woman is thought to be in need of having her femininity “restored”. Perhaps for this reason, in bodybuilding competitions, female competitors are required to display femininity and implied heterosexuality on stage through their attitude, gestures, posing, make-up, hairstyle, and adornments. The aim of this study was to examine the experiences of competitors in the Bikini category to understand the ways in which they perceive and negotiate the expectations of idealized femininity within bodybuilding competitions. Semi-structured interviews, supplemented with ethnographic fieldwork, were conducted with nine female bodybuilding competitors. The data gathered indicated the contradictory views that some female bodybuilders hold of female muscularity and of femininity. The participants were able to negotiate the judging criteria, albeit at times reluctantly and with frequent expressions of criticism and disapproval.
Queering the Gaze: Calgary Hockey Breasts, Dynamics of Desire, and Colonial Hauntings
Authors: Davidson Judy , Helstein Michelle
Published: July 2016

This paper compares two hockey-related breast-flashing events that occurred in Calgary, Alberta, Canada. The first was performed by Calgary Flames fans, the ‘Flamesgirls’, in the 2004 NHL Stanley Cup final, and the second flashing event occurred when members and fans of the Booby Orr hockey team participated in lifting their shirts and jerseys at a lesbian hockey tournament at the 2007 Outgames/Western Cup held in Calgary. We deploy an analysis of visual psychic economies to highlight psychoanalytic framings of masculinized and feminized subject positions in both heteronormative and lesbigay-coded sporting spaces. We suggest there is a queer twist to the Booby Orr flashing context, which we read as disruptive and potentially resistive. The paper ends by turning to Avery Gordon’s (1997) Ghostly Matters, to consider how even in its queer transgression, the Booby Orr flashing scene is simultaneously haunted and saturated by the absent presence of colonial technologies of visuality and sexual violence. It is argued that in this case, openings for transgressive gender dynamics might be imaginable—even as those logics themselves are disciplined and perhaps made possible through racialized colonial framings of appropriate desire.
Pore-forming death signal
Authors: Foley John F. , Gough Nancy R.
Published: July 2016

The N-terminal domain of gasdermin D oligomerizes and forms plasma membrane pores to kill cells by pyroptosis.
Cancer reactivated by collagen
Authors: Ferrarelli Leslie K.
Published: July 2016

The tetraspanin TM4SF1 mediates type I collagen–triggered reactivation of dormant breast cancer cells.
Papers of note in
Science
Authors: VanHook Annalisa M.
Published: July 2016

This week’s articles highlight a regulatory interaction between organelles, a mechanism that controls neural stem cell quiescence, epigenetic regulation of neural activity, and the structural basis of glutamatergic signaling.
Family planning for worms
Authors: VanHook Annalisa M.
Published: July 2016

Dietary nutrients and developmental timing mechanisms control germline development in nematodes.
Shutting down oxygen use
Authors: Gough Nancy R.
Published: July 2016

Cancer cells can shut down nonmitochondrial oxygen use with PTP1B to survive hypoxic conditions.
Daptomycin Improves Outcomes Regardless of Vancomycin MIC in a Propensity-Matched Analysis of Methicillin-Resistant Staphylococcus aureus Bloodstream Infections
Authors: Claeys Kimberly C. , Zasowski Evan J. , Casapao Anthony M. , Lagnf Abdalhamid M. , Nagel Jerod L. , Nguyen Cynthia T. , Hallesy Jessica A. , Compton Mathew T. , Kaye Keith S. , Levine Donald P. , Davis Susan L. , Rybak Michael J.
Published: July 2016

Vancomycin remains the mainstay treatment for methicillin-resistant
Staphylococcus aureus
(MRSA) bloodstream infections (BSIs) despite increased treatment failures. Daptomycin has been shown to improve clinical outcomes in patients with BSIs caused by MRSA isolates with vancomycin MICs of >1 mg/liter, but these studies relied on automated testing systems. We evaluated the outcomes of BSIs caused by MRSA isolates for which vancomycin MICs were determined by standard broth microdilution (BMD). A retrospective, matched cohort of patients with MRSA BSIs treated with vancomycin or daptomycin from January 2010 to March 2015 was completed. Patients were matched using propensity-adjusted logistic regression, which included age, Pitt bacteremia score, primary BSI source, and hospital of care. The primary endpoint was clinical failure, which was a composite endpoint of the following metrics: 30-day mortality, bacteremia with a duration of ≥7 days, or a change in anti-MRSA therapy due to persistent or worsening signs or symptoms. Secondary endpoints included MRSA-attributable mortality and the number of days of MRSA bacteremia. Independent predictors of failure were determined through conditional backwards-stepwise logistic regression with vancomycin BMD MIC forced into the model. A total of 262 patients were matched. Clinical failure was significantly higher in the vancomycin cohort than in the daptomycin cohort (45.0% versus 29.0%;
P
= 0.007). All-cause 30-day mortality was significantly higher in the vancomycin cohort (15.3% versus 6.1%;
P
= 0.024). These outcomes remained significant when stratified by vancomycin BMD MIC. There was no significant difference in the length of MRSA bacteremia. Variables independently associated with treatment failure included vancomycin therapy (adjusted odds ratio [aOR] = 2.16, 95% confidence interval [CI] = 1.24 to 3.76), intensive care unit admission (aOR = 2.46, 95% CI = 1.34 to 4.54), and infective endocarditis as the primary source (aOR = 2.33, 95% CI = 1.16 to 4.68). Treatment of MRSA BSIs with daptomycin was associated with reduced clinical failure and 30-day mortality; these findings were independent of vancomycin BMD MIC.
Structural and Biochemical Characterization of Rm3, a Subclass B3 Metallo-β-Lactamase Identified from a Functional Metagenomic Study
Authors: Salimraj Ramya , Zhang Lihong , Hinchliffe Philip , Wellington Elizabeth M. H. , Brem Jürgen , Schofield Christopher J. , Gaze William H. , Spencer James
Published: July 2016

β-Lactamase production increasingly threatens the effectiveness of β-lactams, which remain a mainstay of antimicrobial chemotherapy. New activities emerge through both mutation of previously known β-lactamases and mobilization from environmental reservoirs. The spread of metallo-β-lactamases (MBLs) represents a particular challenge because of their typically broad-spectrum activities encompassing carbapenems, in addition to other β-lactam classes. Increasingly, genomic and metagenomic studies have revealed the distribution of putative MBLs in the environment, but in most cases their activity against clinically relevant β-lactams and, hence, the extent to which they can be considered a resistance reservoir remain uncharacterized. Here we characterize the product of one such gene,
bla
Rm3
, identified through functional metagenomic sampling of an environment with high levels of biocide exposure.
bla
Rm3
encodes a subclass B3 MBL that, when expressed in a recombinant
Escherichia coli
strain, is exported to the bacterial periplasm and hydrolyzes clinically used penicillins, cephalosporins, and carbapenems with an efficiency limited by high

K
m

values. An Rm3 crystal structure reveals the MBL superfamily αβ/βα fold, which more closely resembles that in mobilized B3 MBLs (AIM-1 and SMB-1) than other chromosomal enzymes (L1 or FEZ-1). A binuclear zinc site sits in a deep channel that is in part defined by a relatively extended N terminus. Structural comparisons suggest that the steric constraints imposed by the N terminus may limit its affinity for β-lactams. Sequence comparisons identify Rm3-like MBLs in numerous other environmental samples and species. Our data suggest that Rm3-like enzymes represent a distinct group of B3 MBLs with a wide distribution and can be considered an environmental reservoir of determinants of β-lactam resistance.
Single-Ascending-Dose Pharmacokinetic Study of Tribendimidine in Opisthorchis viverrini-Infected Patients
Authors: Duthaler Urs , Sayasone Somphou , Vanobbergen Fiona , Penny Melissa A. , Odermatt Peter , Huwyler Jörg , Keiser Jennifer
Published: July 2016

Praziquantel is the only drug available for the treatment of
Opisthorchis viverrini
infections. Tribendimidine has emerged as a potential treatment alternative; however, its pharmacokinetic (PK) properties have not been sufficiently studied to date. Via two phase IIa dose-finding studies, 68
O. viverrini
patients were treated with 25- to 600-mg doses of tribendimidine using 50- and 200-mg tablet formulations. Plasma, blood, and dried blood spots (DBS) were sampled at selected time points. The two main metabolites of tribendimidine, active deacetylated amidantel (dADT) and acetylated dADT (adADT), were analyzed in plasma, blood, and DBS. PK parameters were estimated by noncompartmental analysis. An acceptable agreement among plasma and DBS concentrations was observed, with a mean bias of ≤10%, and 60% dADT and 74% adADT concentrations being within ±20% margins. We found that 200-mg tribendimidine tablets possess immediate floating characteristics, which led to variable time to maximal concentration of drug (
T
max
) values (2 to 24 h) between individuals. Dose proportionality was observed for dADT from 25 to 200 mg using 50-mg tablets, but at higher dosages (200 to 600 mg), saturation occurred. The median ratio of the area under the plasma concentration-time curve from 0 to 24 h (AUC
0–24
) of dADT to the AUC
0–
24
of adADT ranged from 0.8 to 26.4, suggesting substantial differences in acetylation rates. Cure rates ranged from 11% (25-mg dose) to 100% (400-mg dose). Cured patients showed significantly higher dADT maximal serum concentrations (
C
max
) and AUC
0–24
values than uncured patients. Tribendimidine is a promising drug for the treatment of opisthorchiasis. However, the tablet formulation should be optimized to achieve consistent absorption among patients. Further studies are warranted to assess the large differences between individuals in the rate of metabolic turnover of dADT to adADT. (This study has been registered with the ISRCTN Registry under no. ISRCTN96948551.)
Epidemiology and Molecular Characterizations of Azole Resistance in Clinical and Environmental Aspergillus fumigatus Isolates from China
Authors: Chen Yong , Lu Zhongyi , Zhao Jingjun , Zou Ziying , Gong Yanwen , Qu Fen , Bao Zhiyao , Qiu Guangbin , Song Mingsheng , Zhang Qing , Liu Lin , Hu Mandong , Han Xuelin , Tian Shuguang , Zhao Jingya , Chen Fangyan , Zhang Changjian , Sun Yansong , Verweij Paul E. , Huang Liuyu , Han Li
Published: July 2016

Azole resistance in
Aspergillus fumigatus
has emerged as a worldwide public health problem. We sought here to demonstrate the occurrence and characteristics of azole resistance in
A. fumigatus
from different parts of China. A total of 317 clinical and 144 environmental
A. fumigatus
isolates from 12 provinces were collected and subjected to screening for azole resistance. Antifungal susceptibility,
cyp51A
gene sequencing, and genotyping were carried out for all suspected azole-resistant isolates and a subset of azole-susceptible isolates. As a result, 8 (2.5%) clinical and 2 (1.4%) environmental
A. fumigatus
isolates were identified as azole resistant. Five azole-resistant strains exhibit the TR
34
/L98H mutation, whereas four carry the TR
34
/L98H/S297T/F495I mutation in the
cyp51A
gene. Genetic typing and phylogenetic analysis showed that there was a worldwide clonal expansion of the TR
34
/L98H isolates, while the TR
34
/L98H/S297T/F495I isolates from China harbored a distinct genetic background with resistant isolates from other countries. High polymorphisms existed in the
cyp51A
gene that produced amino acid changes among azole-susceptible
A. fumigatus
isolates, with N248K being the most common mutation. These data suggest that the wide distribution of azole-resistant
A. fumigatus
might be attributed to the environmental resistance mechanisms in China.
An Aromatic Diamidine That Targets Kinetoplast DNA, Impairs the Cell Cycle in Trypanosoma cruzi, and Diminishes Trypomastigote Release from Infected Mammalian Host Cells
Authors: Girard Richard M. B. M. , Crispim Marcell , Stolić Ivana , Damasceno Flávia Silva , Santos da Silva Marcelo , Pral Eizabeth Mieko Furusho , Elias Maria Carolina , Bajić Miroslav , Silber Ariel Mariano
Published: July 2016

Trypanosoma cruzi
is the etiological agent of Chagas disease, affecting approximately 10 million people in the Americas and with some 40 million people at risk. The objective of this study was to evaluate the anti-
T. cruzi
activity of three new diamidines that have a 3,4-ethylenedioxy extension of the thiophene core, designated MB17, MB19, and MB38. All three diamidines exhibited dose-dependent inhibition of epimastigote replication. The mechanisms of action of these diamidines were investigated. Unlike MB17 and MB19, MB38 exhibited a significant increase in the number of annexin-propidium iodide double-labeled cells compared to levels in control parasites. As MB17 had shown a lower 50% inhibitory concentration (IC
50
) against epimastigote growth, the mechanism of action of this drug was studied in more detail. MB17 triggered a decrease in the intracellular ATP levels. As a consequence, MB17 affected the genomic DNA and kinetoplast DNA (kDNA) and impaired the parasite cell cycle. Moreover, MB17 caused DNA fragmentation, with a more severe effect on kDNA than on nuclear DNA, resulting in dyskinetoplastic cells. MB17 was tested for toxicity and effectiveness for the treatment of infected CHO-K
1
cells, exhibiting a 50% cytotoxic concentration (CC
50
) of 13.47 ± 0.37 μM and an IC
50
of 0.14 ± 0.12 μM against trypomastigote release. MB17 also diminished the infection index by 60% at 0.5 μM. In conclusion, despite belonging to the same family, these diamidines have different efficiencies. To summarize, MB17 was the most potent of these diamidines against epimastigotes, producing DNA damage preferentially in kDNA, impairing the parasite cell cycle, and decreasing the infection index and trypomastigote release from infected mammalian host cells, with a high selectivity index (SI) (<90). These data suggest that MB17 could be an interesting lead compound against
T. cruzi
.
Personalized Therapeutic Cocktail of Wild Environmental Phages Rescues Mice from Acinetobacter baumannii Wound Infections
Authors: Regeimbal James M. , Jacobs Anna C. , Corey Brendan W. , Henry Matthew S. , Thompson Mitchell G. , Pavlicek Rebecca L. , Quinones Javier , Hannah Ryan M. , Ghebremedhin Meron , Crane Nicole J. , Zurawski Daniel V. , Teneza-Mora Nimfa C. , Biswas Biswajit , Hall Eric R.
Published: July 2016

Multidrug-resistant bacterial pathogens are an increasing threat to public health, and lytic bacteriophages have reemerged as a potential therapeutic option. In this work, we isolated and assembled a five-member cocktail of wild phages against
Acinetobacter baumannii
and demonstrated therapeutic efficacy in a mouse full-thickness dorsal infected wound model. The cocktail lowers the bioburden in the wound, prevents the spread of infection and necrosis to surrounding tissue, and decreases infection-associated morbidity. Interestingly, this effective cocktail is composed of four phages that do not kill the parent strain of the infection and one phage that simply delays bacterial growth
in vitro
via a strong but incomplete selection event. The cocktail here appears to function in a combinatorial manner, as one constituent phage targets capsulated
A. baumannii
bacteria and selects for loss of receptor, shifting the population to an uncapsulated state that is then sensitized to the remaining four phages in the cocktail. Additionally, capsule is a known virulence factor for
A. baumannii
, and we demonstrated that the emergent uncapsulated bacteria are avirulent in a
Galleria mellonella
model. These results highlight the importance of anticipating population changes during phage therapy and designing intelligent cocktails to control emergent strains, as well as the benefits of using phages that target virulence factors. Because of the efficacy of this cocktail isolated from a limited environmental pool, we have established a pipeline for developing new phage therapeutics against additional clinically relevant multidrug-resistant pathogens by using environmental phages sourced from around the globe.
Replacement of GroEL in Escherichia coli by the Group II Chaperonin from the Archaeon Methanococcus maripaludis
Authors: Shah Riddhi , Large Andrew T. , Ursinus Astrid , Lin Bevan , Gowrinathan Preethy , Martin Jörg , Lund Peter A.
Published: July 2016

Chaperonins are required for correct folding of many proteins. They exist in two phylogenetic groups: group I, found in bacteria and eukaryotic organelles, and group II, found in archaea and eukaryotic cytoplasm. The two groups, while homologous, differ significantly in structure and mechanism. The evolution of group II chaperonins has been proposed to have been crucial in enabling the expansion of the proteome required for eukaryotic evolution. In an archaeal species that expresses both groups of chaperonins, client selection is determined by structural and biochemical properties rather than phylogenetic origin. It is thus predicted that group II chaperonins will be poor at replacing group I chaperonins. We have tested this hypothesis and report here that the group II chaperonin from
Methanococcus maripaludis
(Mm-cpn) can partially functionally replace GroEL, the group I chaperonin of
Escherichia coli
. Furthermore, we identify and characterize two single point mutations in Mm-cpn that have an enhanced ability to replace GroEL function, including one that allows
E. coli
growth after deletion of the
groEL
gene. The biochemical properties of the wild-type and mutant Mm-cpn proteins are reported. These data show that the two groups are not as functionally diverse as has been thought and provide a novel platform for genetic dissection of group II chaperonins.

IMPORTANCE
The two phylogenetic groups of the essential and ubiquitous chaperonins diverged approximately 3.7 billion years ago. They have similar structures, with two rings of multiple subunits, and their major role is to assist protein folding. However, they differ with regard to the details of their structure, their cofactor requirements, and their reaction cycles. Despite this, we show here that a group II chaperonin from a methanogenic archaeon can partially substitute for the essential group I chaperonin GroEL in
E. coli
and that we can easily isolate mutant forms of this chaperonin with further improved functionality. This is the first demonstration that these two groups, despite the long time since they diverged, still overlap significantly in their functional properties.
Characterization of Key Helicobacter pylori Regulators Identifies a Role for ArsRS in Biofilm Formation
Authors: Servetas Stephanie L. , Carpenter Beth M. , Haley Kathryn P. , Gilbreath Jeremy J. , Gaddy Jennifer A. , Merrell D. Scott
Published: July 2016

Helicobacter pylorimust be able to rapidly respond to fluctuating conditions within the stomach. Despite this need for constant adaptation,H. pyloriencodes few regulatory proteins. Of the identified regulators, the ferric uptake regulator (Fur), the nickel response regulator (NikR), and the two-component acid response system (ArsRS) are each paramount to the success of this pathogen. While numerous studies have individually examined these regulatory proteins, little is known about their combined effect. Therefore, we constructed a series of isogenic mutant strains that contained all possible single, double, and triple regulatory mutations in Fur, NikR, and ArsS. A growth curve analysis revealed minor variation in growth kinetics across the strains; these were most pronounced in the triple mutant and in strains lacking ArsS. Visual analysis showed that strains lacking ArsS formed large aggregates and a biofilm-like matrix at the air-liquid interface. Biofilm quantification using crystal violet assays and visualization via scanning electron microscopy (SEM) showed that all strains lacking ArsS or containing a nonphosphorylatable form of ArsR (ArsR-D52N mutant) formed significantly more biofilm than the wild-type strain. Molecular characterization of biofilm formation showed that strains containing mutations in the ArsRS pathway displayed increased levels of cell aggregation and adherence, both of which are key to biofilm development. Furthermore, SEM analysis revealed prevalent coccoid cells and extracellular matrix formation in the ArsR-D52N, ΔnikRΔarsS, and ΔfurΔnikRΔarsSmutant strains, suggesting that these strains may have an exacerbated stress response that further contributes to biofilm formation. Thus,H. pyloriArsRS has a previously unrecognized role in biofilm formation.

IMPORTANCEDespite a paucity of regulatory proteins, adaptation is key to the survival ofH. pyloriwithin the stomach. While prior studies have focused on individual regulatory proteins, such as Fur, NikR, and ArsRS, few studies have examined the combined effect of these factors. Analysis of isogenic mutant strains that contained all possible single, double, and triple regulatory mutations in Fur, NikR, and ArsS revealed a previously unrecognized role for the acid-responsive two-component system ArsRS in biofilm formation.
New insights into environmental enteric dysfunction
Authors: Trehan Indi , Kelly Paul , Shaikh Nurmohammad , Manary Mark J
Published: July 2016

Environmental enteric dysfunction (EED) has been recognised as an important contributing factor to physical and cognitive stunting, poor response to oral vaccines, limited resilience to acute infections and ultimately global childhood mortality. The aetiology of EED remains poorly defined but the epidemiology suggests a multifactorial combination of prenatal and early-life undernutrition and repeated infectious and/or toxic environmental insults due to unsanitary and unhygienic environments. Previous attempts at medical interventions to ameliorate EED have been unsatisfying. However, a new generation of imaging and ‘-omics’ technologies hold promise for developing a new understanding of the pathophysiology of EED. A series of trials designed to decrease EED and stunting are taking novel approaches, including improvements in sanitation, hygiene and nutritional interventions. Although many challenges remain in defeating EED, the global child health community must redouble their efforts to reduce EED in order to make substantive improvements in morbidity and mortality worldwide.
Does well-child care education improve consultations and medication management for childhood fever and common infections? A systematic review
Authors: Peetoom Kirsten K B , Smits Jacqueline J M , Ploum Luc J L , Verbakel Jan Y , Dinant Geert-Jan , Cals Jochen W L
Published: July 2016

Background

Fever is common in preschool children and is often caused by benign self-limiting infections. Parents' lack of knowledge and fever phobia leads to high healthcare consumption.

Objective

To systematically review the effect of providing educational interventions about childhood fever and common infections in well-child clinics (WCCs), prior to illness episodes, on parental practices: healthcare-seeking behaviour (frequency of physician consultations, appropriateness of consultations) and medication management.

Design

Medline, Embase, CINAHL, PsycINFO, Cochrane Library, Web of Science were searched. We included randomised controlled trials evaluating interventions in WCC settings focusing on educating parents prior to new illness episodes to improve parental practices during episodes of childhood fever and common infections. Data were extracted on study design, sample characteristics, type of intervention, outcome measures and results.

Results

Eight studies were eligible for data extraction. Educating parents, in WCCs, prior to new episodes of childhood fever and common infections reduces daytime physician consultations of parents, home visits and telephone consultations, and enhances medication management. However, single and multicomponent interventions vary in effectiveness in reducing the frequency of daytime physician consultations and differ in their potential to reduce the number of home visits and general practitioner out-of-hours contacts. Only multicomponent interventions achieved a reduction in telephone consultations and improved medication management.

Conclusions

Educating parents in WCCs prior to episodes of childhood fever and common infections showed potential to improve parental practices in terms of healthcare-seeking behaviour and medication management.
Right atrial spindle cell sarcoma as a rare cause of tricuspid stenosis
Authors: Shewale Sunil D , Bhat Prabhavathi , Gupta Anshul Kumar , Manjunath Cholenahally Nanjappa
Published: July 2016

Spindle cell sarcomas of the right atrium are extremely rare primary cardiac tumours with very few cases reported in the medical literature. The prognosis of this malignant neoplasm remains poor due to delay in diagnosis, early metastasis and few available therapeutic options. It responds poorly to chemotherapy and radiotherapy. Surgical excision is the mainstay of treatment. We report a 42-year-old man, who presented to emergency room with dyspnoea and fatigue (New York Heart Association classification II) since 1 month. Transthoracic echocardiogram showed massive pericardial effusion with tamponade. The patient underwent emergency pericardiocentesis; postpericardiocentesis echocardiogram showed large right atrial mass involving the right ventricle and the tricuspid valve causing tricuspid stenosis. Findings were confirmed by cardiac CT scan. Percutaneous transvenous biopsy was carried out which revealed spindle cell sarcoma.
Medication usage, treatment intensification, and medical cost in patients with type 2 diabetes: a retrospective database study
Authors: Bonafede Machaon , Chandran Arthi , DiMario Stefan , Saltiel-Berzin Rita , Saliu Drilon
Published: July 2016

Objective

The goal of this study was to describe medication usage patterns in patients with type 2 diabetes mellitus (T2DM) initiating treatment with non-insulin antidiabetic drugs (NIADs), basal insulin, or prandial/mixed insulin using real-world data.

Research design and methods

A retrospective analysis using the Truven Health MarketScan Research Databases was conducted to identify adults (≥18 years) with T2DM from 2006 to 2012. Patients were categorized into four cohorts based on diabetes treatment. Cohort 1 (n=597 664) consisted of newly diagnosed patients who did not receive any treatment, cohort 2 (n=342 511) included NIAD initiators, cohort 3 (n=99 578) included basal insulin initiators, and cohort 4 (n=62 876) included prandial/mixed insulin initiators. Patients transitioned out of a cohort once they met the criteria for the next one.

Results

Patients in cohort 2 were younger (56.2 years, SD±12.1) than patients in cohorts 1, 3, and 4 (58 years, SD±0.75). Metformin was the most commonly prescribed drug in cohort 2 patients. Basal insulin usage decreased from 71% in year 1 to 47% in year 4, in cohort 3 patients. Approximately one-third of these patients switched to prandial/mixed insulin each year. In cohort 4, the usage of prandial/mixed insulin decreased to 61% by year 4. Use of basal insulin and NIAD remained common in this group. Mean glycosylated hemoglobin (HbA1c) values decreased by ∼1% for each of the treatment cohorts following treatment initiation and remained stable during follow-up. All-cause and diabetes-related medical costs were highest for patients in cohorts 3 and 4.

Conclusions

Overall, our findings demonstrate that treatment intensification was low in all study cohorts despite elevated HbA1c levels during preindex and follow-up period.
Prevalence of disability in Manikganj district of Bangladesh: results from a large-scale cross-sectional survey
Authors: Moniruzzaman Mohammad , Zaman M Mostafa , Mashreky Saidur Rahman , Rahman A K M Fazlur
Published: July 2016

Objective

To conduct a comprehensive survey on disability to determine the prevalence and distribution of cause-specific disability among residents of the Manikganj district in Bangladesh.

Methods

The survey was conducted in Manikganj, a typical district in Bangladesh, in 2009. Data were collected from 37 030 individuals of all ages. Samples were drawn from 8905 households from urban and rural areas proportionate to population size. Three sets of interviewer-administered questionnaires were used separately for age groups 0–1 years, 2–10 years and 11 years and above to collect data. For the age groups 0–1 years and 2–10 years, the parents or the head of the household were interviewed to obtain the responses. Impairments, activity limitations and restriction of participation were considered in defining disability consistent with the International Classification of Functioning, Disability and Health framework.

Results

Overall, age-standardised prevalence of disability per 1000 was 46.5 (95% CI 44.4 to 48.6). Prevalence was significantly higher among respondents living in rural areas (50.2; 95% CI 47.7 to 52.7) than in urban areas (31.0; 95% CI 27.0 to 35.0). Overall, female respondents had more disability (50.0; 95% CI 46.9 to 53.1) than male respondents (43.4; 95% CI 40.5 to 46.3). Educational deprivation was closely linked to higher prevalence of disability. Commonly reported prevalences (per 1000) for underlying causes of disability were 20.2 for illness, followed by 9.4 for congenital causes and 6.8 for injury, and these were consistent in males and females.

Conclusions

Disability is a common problem in this typical district of Bangladesh, which is largely generalisable. Interventions at community level with special attention to the socioeconomically deprived are warranted.
Invasiveness of pharmacokinetic studies in children: a systematic review
Authors: Altamimi Mohammed I , Choonara Imti , Sammons Helen
Published: July 2016

Objectives

To explore whether pharmacokinetic (PK) studies in paediatric patients are becoming less invasive. This will be evaluated by analysing the number of samples and volume of blood collected for each study within four different decades.

Methods

A systematic literature review was performed to identify PK papers describing number of samples and volume of blood collected in studies of children aged 0–18 years. The following databases were searched: MEDLINE (1946 to December 2015), EMBASE (1974 to December 2015), International Pharmaceutical Abstracts (1970 to December 2015), CINAHL and Cochrane Library.

Results

A total of 549 studies were identified between 1974 and 2015. There were 52 studies between 1976 and 1985, 105 between 1986 and 1995, 201 between 1996 and 2005 and 191 between 2006 and 2015. The number of blood samples collected per participant increased between the first two decades (p=0.013), but there was a decrease in the number of samples in the subsequent two decades (p=0.044 and p<0.001, respectively). Comparing the first and last decades, there has been no change in the number of blood samples collected. There were no significant differences in volume collected per sample or total volume per child in any of the age groups. There was however a significant difference in the frequency of blood sampling between population PK studies (median 5 (IQR 3–7)) and non-population PK studies (median 8 (IQR 6–10); p=<0.001).

Conclusions

The number of blood samples collected for PK studies in children rose in 1985–1995 and subsequently declined. There was no overall change in the volume of blood collected over the 4 decades. The usage of population PK methods reduces the frequency of blood sampling in children.