bluuebunny/crossref_metadata_2025 huggingface dataset:
Sensitivity Analysis Using Risk Measures
Authors: Tsanakas Andreas , Millossovich Pietro
Published: November 2015

In a quantitative model with uncertain inputs, the uncertainty of the output can be summarized by a risk measure. We propose a sensitivity analysis method based on derivatives of the output risk measure, in the direction of model inputs. This produces a global sensitivity measure, explicitly linking sensitivity and uncertainty analyses. We focus on the case of distortion risk measures, defined as weighted averages of output percentiles, and prove a representation of the sensitivity measure that can be evaluated on a Monte Carlo sample, as a weighted average of gradients over the input space. When the analytical model is unknown or hard to work with, nonparametric techniques are used for gradient estimation. This process is demonstrated through the example of a nonlinear insurance loss model. Furthermore, the proposed framework is extended in order to measure sensitivity to constant model parameters, uncertain statistical parameters, and random factors driving dependence between model inputs.
Regional Trade Agreements and Cross‐border Lobbying: Empirical Evidence from the Canada–US Free Trade Agreement Negotiations
Authors: Stoyanov Andrey
Published: November 2015

This paper documents participation of special interest groups in negotiations of the Canada–US Free Trade Agreement. Using data on the tariff reduction schedules mandated by the agreement, it shows that industries represented by strong lobby groups were faced with more favorable tariff reduction paths in both countries: phase‐out periods were longer at home and shorter in the partner country. This result provides evidence on the involvement of industry lobbying in negotiation of regional trade agreements and suggests that countries negotiating trade agreements are responsive to the interests of lobbying groups from across the border. Both results provide important implications for the political economy theory of trade agreements.
Making Amends: Children's Expectations about and Responses to Apologies
Authors: Drell Marissa B. , Jaswal Vikram K.
Published: November 2015

Two studies investigate children's expectations and actual responses to a transgressor's attempt to make amends. In Study 1, six‐ and seven‐year‐olds (N = 16) participated in a building activity and then imagined how they would respond if a transgressor knocked over their tower and then apologized spontaneously, apologized after prompting, offered restitution, or did nothing. Children forecasted that they would feel better and would share more when a transgressor offered restitution or apologized spontaneously than when the transgressor had to be prompted to apologize or did not apologize at all. In Study 2, six‐ and seven‐year‐olds (N = 64) participated in the same building activity, but then actually had their towers knocked over and received one of the four responses. The only response that actually made children feel better was when the transgressor offered restitution. However, children shared more with a transgressor who offered restitution, a spontaneous apology, or a prompted apology than with one who failed to offer any apology. Restitution can both mitigate hurt feelings and repair relationships in children; apologies serve mainly to repair relationships.
Wage Reimbursement and Minority Voter Turnout*
Authors: Hostetter Joshua D.
Published: November 2015

Objective

In this article, I estimate the conditional effect of racial minorities and women on the relationship between wage reimbursement laws and voter turnout. Scholars have found evidence that voting laws affect demographic segments of the population differently. However, scholars have not considered the theoretical implications of pay incentive structures for different minority groups.

Methods

Using pooled cross‐sectional survey data from the November Supplement Current Population Survey 1996–2012, I test whether paid time off to vote laws increase the likelihood of voting for racial and gender minorities.

Results

The findings indicate that women and Asian Americans are highly responsive to wage reimbursement, Hispanic Americans are relatively unresponsive, and blacks are highly unresponsive relative to whites.

Conclusions

Reimbursing minorities for wages lost while voting decreases the costs of voting and increases turnout for these racial and gender minority groups except for blacks. I suggest the long history of discrimination and mistreatment by economic and political institutions has led to a lower level of blacks willing to engage in wage reimbursement because of mistrust in the delivery system.
Subthreshold vagal stimulation suppresses ventricular arrhythmia and inflammatory response in a canine model of acute cardiac ischaemia and reperfusion
Authors: Zhang Ling , Lu Yanmei , Sun Juan , Zhou Xianhui , Tang Baopeng
Published: November 2015

New Findings

What is the central question of this study?

Vagal stimulation (VS) with heart rate reduction has been performed to protect against ventricular arrhythmias for several decades. Recent studies show that subthreshold VS (SVS) suppresses atrial arrhythmias in both canine models and humans. However, it is unknown whether SVS could decrease ventricular arrhythmia during ischaemia and reperfusion.

What is the main finding and its importance?

Our results show that SVS without heart rate reduction is also capable of suppressing ventricular arrhythmia and inflammatory responses in a canine model of ischaemia and reperfusion. These findings suggest that SVS may serve as a novel therapeutic modality to treat ventricular arrhythmias in patients with acute myocardial infarction.

Subthreshold vagal stimulation (SVS) suppresses atrial arrhythmias in canine models and humans. This study was designed to examine whether SVS could decrease ventricular arrhythmia during ischaemia and reperfusion. Twenty‐four anaesthetized dogs subjected to 1 h of coronary artery occlusion and 3 h of reperfusion were equally assigned into sham and SVS groups. Subthreshold vagal stimulation was initiated 15 min before coronary occlusion and maintained until the end of the reperfusion period using electrical stimulation on bilateral vagal trunks at 50% below the voltage which slowed the sinus rate. Ventricular arrhythmias were recorded during ischaemia and reperfusion periods. Serum concentrations of C‐reactive protein (CRP), interleukin‐6 (IL‐6), tumour necrosis factor‐α (TNF‐α), high‐mobility group box 1 (HMGB1) and noradrenaline were detected at baseline, at the end of ischaemia and at the end of reperfusion. Area at risk and infarct size were evaluated after 3 h of reperfusion. Compared with the sham group, SVS significantly suppressed ischaemia‐ and reperfusion‐induced ventricular arrhythmias and decreased serum concentrations of CRP, IL‐6, TNF‐α, HMGB1 and noradrenaline during both the ischaemia period and the reperfusion period. However, SVS did not affect the area at risk, infarct size or the ratio of infarct size to area at risk. This study demonstrated that SVS exerted antiarrhythmic and anti‐inflammatory effects in a canine model of ischaemia and reperfusion.
Differential signalling and glutamate receptor compositions in the OFF bipolar cell types in the mouse retina
Authors: Ichinose Tomomi , Hellmer Chase B.
Published: November 2015

Key points

Using whole‐cell clamp methods, we characterized the temporal coding in each type of OFF bipolar cell.

We found that type 2 and 3a cells are transient, type 1 and 4 cells are sustained, and type 3b cells are intermediate.

The light‐evoked excitatory postsynaptic potentials in some types were rectified, suggesting that they provide inputs to the non‐linear ganglion cells.

Visual signalling from the photoreceptors was mediated exclusively through the kainate receptors in the transient OFF bipolar cells, whereas both kainate and AMPA receptors contributed in the other cells.

This study demonstrates, for the first time, that parallel visual encoding starts at the OFF bipolar cells in a type‐specific manner.

The retina is the entrance to the visual system, which receives various kinds of image signals and forms multiple encoding pathways. The second‐order retinal neurons, the bipolar cells, are thought to initiate multiple neural streams by encoding various visual signals in different types of cells. However, the functions of each bipolar cell type have not been fully understood. We investigated whether OFF bipolar cells encode visual signals in a type‐dependent manner. We recorded the changes in the bipolar cell voltage in response to two input functions: step and sinusoidal light stimuli. Type 1 and 4 OFF bipolar cells were sustained cells and responded to sinusoidal stimuli over a broad range of frequencies. Type 2 and 3a cells were transient and exhibited band‐pass filtering. Type 3b cells were in the middle of these two groups. The distinct temporal responses might be attributed to different types of glutamate receptors. We examined the AMPA and kainate glutamate receptor composition in each bipolar cell type. The light responses in the transient OFF bipolar cells were exclusively mediated by kainate receptors. Although the kainate receptors mediated the light responses in the sustained cells, the AMPA receptors also mediated a portion of the responses in sustained cells. Furthermore, we found that some types of cells were rectified more than other types. Taken together, we found that the OFF bipolar cells encode diverse temporal image signals in a type‐dependent manner, confirming that each type of OFF bipolar cell initiates diverse temporal visual processing in parallel.
Enhancement on Wingate Anaerobic Test Performance With Hyperventilation
Authors: Leithäuser Renate M. , Böning Dieter , Hütler Matthias , Beneke Ralph
Published: November 2015

Relatively long-lasting metabolic alkalizing procedures such as bicarbonate ingestion have potential for improving performance in long-sprint to middle-distance events. Within a few minutes, hyperventilation can induce respiratory alkalosis. However, corresponding performance effects are missing or equivocal at best.

Purpose:

To test a potential performance-enhancing effect of respiratory alkalosis in a 30-s Wingate Anaerobic Test (WAnT).

Methods:

10 men (mean ± SD age 26.6 ± 4.9 y, height 184.4 ± 6.1 cm, body-mass test 1 80.7 ± 7.7 kg, body-mass test 2 80.4 ± 7.2 kg, peak oxygen uptake 3.95 ± 0.43 L/min) performed 2 WAnTs, 1 with and 1 without a standardized 15-min hyperventilation program pre-WAnT in randomized order separated by 1 wk.

Results:

Compared with the control condition, hyperventilation reduced (all P < .01) pCO2 (40.5 ± 2.8 vs 22.5 ± 1.6 mm Hg) and HCO3− (25.5 ± 1.7 vs 22.7 ± 1.6 mmol/L) and increased (all P < .01) pH (7.41 ± 0.01 vs 7.61 ± 0.03) and actual base excess (1.4 ± 1.4 vs 3.2 ± 1.6 mmol/L) pre-WAnT with an ergogenic effect on WAnT average power (681 ± 41 vs 714 ± 44 W) and total metabolic energy (138 ± 12 vs. 144 ± 13 kJ) based on an increase in glycolytic energy (81 ± 13 vs 88 ± 13 kJ).

Conclusion:

Hyperventilation-induced respiratory alkalosis can enhance WAnT cycling sprint performance well in the magnitude of what is seen after successful bicarbonate ingestion.
Self–Myofascial Release: No Improvement of Functional Outcomes in “Tight” Hamstrings
Authors: Morton Robert W. , Oikawa Sara Y. , Phillips Stuart M. , Devries Michaela C. , Mitchell Cameron J.
Published: November 2015

Purpose:

Self–myofascial release (SMR) is a common exercise and therapeutic modality shown to induce acute improvements in joint range of motion (ROM) and recovery; however, no long-term studies have been conducted. Static stretching (SS) is the most common method used to increase joint ROM and decrease muscle stiffness. It was hypothesized that SMR paired with SS (SMR+SS) compared with SS alone over a 4-wk intervention would yield greater improvement in knee-extension ROM and hamstring stiffness.

Methods:

19 men (22 ± 3 y) with bilateral reduced hamstring ROM had each of their legs randomly assigned to either an SMR+SS or an SS-only group. The intervention consisted of 4 repetitions of SS each for 45 s or the identical amount of SS preceded by 4 repetitions of SMR each for 60 s and was performed on the respective leg twice daily for 4 wk. Passive ROM, hamstring stiffness, rate of torque development (RTD), and maximum voluntary contraction (MVC) were assessed pre- and postintervention.

Results:

Passive ROM (P < .001), RTD, and MVC (P < .05) all increased after the intervention. Hamstring stiffness toward end-ROM was reduced postintervention (P = .02). There were no differences between the intervention groups for any variable.

Conclusion:

The addition of SMR to SS did not enhance the efficacy of SS alone. SS increases joint ROM through a combination of decreased muscle stiffness and increased stretch tolerance.
Lower-Body Muscle Structure and Jump Performance of Stronger and Weaker Surfing Athletes
Authors: Secomb Josh L. , Nimphius Sophia , Farley Oliver R.L. , Lundgren Lina , Tran Tai T. , Sheppard Jeremy M.
Published: November 2015

Purpose:

To identify whether there are any significant differences in the lower-body muscle structure and countermovement-jump (CMJ) and squat-jump (SJ) performance between stronger and weaker surfing athletes.

Methods:

Twenty elite male surfers had their lower-body muscle structure assessed with ultrasonography and completed a series of lower-body strength and jump tests including isometric midthigh pull (IMTP), CMJ, and SJ. Athletes were separated into stronger (n = 10) and weaker (n = 10) groups based on IMTP performance.

Results:

Large significant differences were identified between the groups for vastus lateralis (VL) thickness (P = .02, ES = 1.22) and lateral gastrocnemius (LG) pennation angle (P = .01, ES = 1.20), and a large nonsignificant difference was identified in LG thickness (P = .08, ES = 0.89). Furthermore, significant differences were present between the groups for peak force, relative peak force, and jump height in the CMJ and SJ (P < .01−.05, ES = 0.90−1.47) and eccentric peak velocity, as well as vertical displacement of the center of mass during the CMJ (P < .01, ES = 1.40−1.41).

Conclusion:

Stronger surfing athletes in this study had greater VL and LG thickness and LG pennation angle. These muscle structures may explain their better performance in the CMJ and SJ. A unique finding in this study was that the stronger group appeared to better use their strength and muscle structure for braking as they had significantly higher eccentric peak velocity and vertical displacement during the CMJ. This enhanced eccentric phase may have resulted in a greater production and subsequent utilization of stored elastic strain energy that led to the significantly better CMJ performance in the stronger group.
Relationship Between Fundamental Motor Skill Competence and Physical Activity During Childhood and Adolescence: A Systematic Review
Authors: Logan Samuel W. , Kipling Webster E. , Getchell Nancy , Pfeiffer Karin A. , Robinson Leah E.
Published: November 2015

The purpose of this review is to synthesize the evidence of the relationship between fundamental motor skills (FMS) competence and physical activity by qualitatively describing results from 13 studies that met rigorous inclusion criteria. Inclusion criteria: (a) published in a peer-review journal, (b) participants were between the ages of 3–18, (c) participants were typically developing, (d) FMS was measured by a process-oriented assessment, (e) assessed physical activity, (f) related FMS and physical activity through statistical procedures, and (g) printed in English. Databases were searched for relevant articles using key terms related to FMS and physical activity. Evidence suggested low to moderate relationships between FMS competence and physical activity in early childhood (r = .16 to .48; R2 = 3–23%, 4 studies), low to high relationships in middle to late childhood (r = .24 to .55; R2 = 6–30%, 7 studies), and low to moderate relationships in adolescence (r = .14 to .35; R2 = 2–12.3%, 2 studies). Across ages, object control skills and locomotor skills were more strongly related to physical activity for boys and girls, respectively. Future research should emphasize experimental and longitudinal research designs to provide further understanding of the relationship between FMS competence and physical activity.
Integrating Public Health in Kinesiology: Instruction, Academic Programs, Research, and Outreach
Authors: Freedson Patty , Buchner David M. , Pate Russ , Hatfield Brad , DiPietro Loretta , Dzewaltowski David A. , Gavin Tim , Nessler Jeff
Published: November 2015

This paper provides an overview of several university programs that have integrated various aspects of public health into their kinesiology instruction, research, and outreach efforts. The summaries of these programs provide the historical context that shows the various stages of transformation of their kinesiology and exercise science programs over the last century. Examples of specific academic structural designs and curricula are described, as well as the rationale the faculty used to justify these programs. In addition, advantages, opportunities, and challenges of this integration are highlighted.
University and Community Partnerships to Implement Comprehensive School Physical Activity Programs: Insights and Impacts for Kinesiology Departments
Authors: Brusseau Timothy A. , Bulger Sean M. , Elliott Eloise , Hannon James C. , Jones Emily
Published: November 2015

This paper discusses lessons learned from the process of conducting community-based research with a focus on issues and topics of potential importance to leaders of departments of kinesiology. This paper is written from the perspective of physical education teacher education faculty implementing comprehensive school physical activity programming. Specifically, the paper focuses on the intersection of physical education and public health, the reconceptualization of training physical education teachers, related opportunities for community-engaged learning, and the process of relationship building in schools and communities. It is the authors’ intent that this paper will stimulate discussions relative to these topics among leaders of and faculty within kinesiology departments.
Exciting times for biofilms
Authors: VanHook Annalisa M.
Published: November 2015

Bacterial biofilms can generate propagating waves of potassium ions.
Uncovering the FACTs in neuroblastoma
Authors: Nusinovich Yevgeniya
Published: November 2015

Histone chaperone FACT acts in a positive feedback loop with MYCN and is a therapeutic target in neuroblastoma.
Rubbing sodium in a wound
Authors: Gough Nancy R.
Published: November 2015

Blocking Na
x
reduces scarring and improves dermatitis symptoms in mice by preventing excessive inflammation.
Carriage of Enterobacteria Producing Extended-Spectrum β-Lactamases and Composition of the Gut Microbiota in an Amerindian Community
Authors: Gosalbes María José , Vázquez-Castellanos Jorge F. , Angebault Cécile , Woerther Paul-Louis , Ruppé Etienne , Ferrús María Loreto , Latorre Amparo , Andremont Antoine , Moya Andrés
Published: November 2015

Epidemiological and individual risk factors for colonization by enterobacteria producing extended-spectrum beta-lactamases (E-ESBL) have been studied extensively, but whether such colonization is associated with significant changes in the composition of the rest of the microbiota is still unknown. To address this issue, we assessed in an isolated Amerindian Guianese community whether intestinal carriage of E-ESBL was associated with specificities in gut microbiota using metagenomic and metatranscriptomic approaches. While the richness of taxa of the active microbiota of carriers was similar to that of noncarriers, the taxa were less homogeneous. In addition, species of four genera,
Desulfovibrio
,
Oscillospira
,
Parabacteroides
, and
Coprococcus
, were significantly more abundant in the active microbiota of noncarriers than in the active microbiota of carriers, whereas such was the case only for species of
Desulfovibrio
and
Oscillospira
in the total microbiota. Differential genera in noncarrier microbiota could either be associated with resistance to colonization or be the consequence of the colonization by E-ESBL.
Ertapenem-Containing Double-Carbapenem Therapy for Treatment of Infections Caused by Carbapenem-Resistant Klebsiella pneumoniae
Authors: Cprek Jessica B. , Gallagher Jason C.
Published: November 2015

We describe outcomes of patients with infections with carbapenem-resistant
Klebsiella pneumoniae
(CRKP) who received ertapenem-containing double-carbapenem therapy (ECDCT). Clinical success was observed in 7/18 (39%) patients overall: bloodstream infections, 3/7 (43%); pneumonia, 1/5 (20%); intraabdominal infections, 0/2 (0%); urinary tract infections, 2/3 (67%); and a skin and skin structure infection, 1/1 (100%). Microbiologic success was observed in 11/14 (79%) evaluable patients; 5/18 (28%) patients died. ECDCT may be effective for CRKP infections with limited treatment options.
Inhibition of Calcium-Dependent Protein Kinase 1 (CDPK1)
In Vitro
by Pyrazolopyrimidine Derivatives Does Not Correlate with Sensitivity of Cryptosporidium parvum Growth in Cell Culture
Authors: Kuhlenschmidt Theresa B. , Rutaganira Florentine U. , Long Shaojun , Tang Keliang , Shokat Kevan M. , Kuhlenschmidt Mark S. , Sibley L. David
Published: November 2015

Cryptosporidiosis is a serious diarrheal disease in immunocompromised patients and malnourished children, and treatment is complicated by a lack of adequate drugs. Recent studies suggest that the natural occurrence of a small gatekeeper residue in serine threonine calcium-dependent protein kinase 1 (CDPK1) of
Cryptosporidium parvum
might be exploited to target this enzyme and block parasite growth. Here were explored the potency with which a series of pyrazolopyrimidine analogs, which are selective for small gatekeeper kinases, inhibit
C. parvum
CDPK1 and block
C. parvum
growth in tissue culture
in vitro
. Although these compounds potently inhibited kinase activity
in vitro
, most had no effect on parasite growth. Moreover, among those that were active against parasite growth, there was a very poor correlation with their 50% inhibitory concentrations against the enzyme. Active compounds also had no effect on cell invasion, unlike the situation in
Toxoplasma gondii
, where these compounds block CDPK1, prevent microneme secretion, and disrupt cell invasion. These findings suggest that CPDK1 is not essential for
C. parvum
host cell invasion or growth and therefore that it is not the optimal target for therapeutic intervention. Nonetheless, several inhibitors with low micromolar 50% effective concentrations were identified, and these may affect other essential targets in
C. parvum
that are worthy of further exploration.
Interactions of OP0595, a Novel Triple-Action Diazabicyclooctane, with β-Lactams against OP0595-Resistant Enterobacteriaceae Mutants
Authors: Livermore David M. , Warner Marina , Mushtaq Shazad , Woodford Neil
Published: November 2015

OP0595 is a novel diazabicyclooctane which, like avibactam, inhibits class A and C β-lactamases. In addition, unlike avibactam, it has antibacterial activity, with MICs of 0.5 to 4 μg/ml for most members of the family
Enterobacteriaceae
, owing to inhibition of PBP2; moreover, it acts synergistically with PBP3-active β-lactams independently of β-lactamase inhibition, via an “enhancer effect.”
Enterobacteriaceae
mutants stably resistant to 16 μg/ml OP0595 were selected on agar at frequencies of approximately 10
−7
. Unsurprisingly, OP0595 continued to potentiate substrate β-lactams against mutants derived from
Enterobacteriaceae
with OP0595-inhibited class A and C β-lactamases. Weaker potentiation of partners, especially aztreonam, cefepime, and piperacillin—less so meropenem—remained frequent for OP0595-resistant
Enterobacteriaceae
mutants lacking β-lactamases or with OP0595-resistant metallo-β-lactamases (MBLs), indicating that the enhancer effect is substantially retained even when antibiotic activity is lost.
Insights into the Molecular Mechanism of Polymerization and Nucleoside Reverse Transcriptase Inhibitor Incorporation by Human PrimPol
Authors: Mislak Andrea C. , Anderson Karen S.
Published: November 2015

Human PrimPol is a newly identified DNA and RNA primase-polymerase of the archaeo-eukaryotic primase (AEP) superfamily and only the second known polymerase in the mitochondria. Mechanistic studies have shown that interactions of the primary mitochondrial DNA polymerase γ (mtDNA Pol γ) with nucleoside reverse transcriptase inhibitors (NRTIs), key components in treating HIV infection, are a major source of NRTI-associated toxicity. Understanding the interactions of host polymerases with antiviral and anticancer nucleoside analog therapies is critical for preventing life-threatening adverse events, particularly in AIDS patients who undergo lifelong treatment. Since PrimPol has only recently been discovered, the molecular mechanism of polymerization and incorporation of natural nucleotide and NRTI substrates, crucial for assessing the potential for PrimPol-mediated NRTI-associated toxicity, has not been explored. We report for the first time a transient-kinetic analysis of polymerization for each nucleotide and NRTI substrate as catalyzed by PrimPol. These studies reveal that nucleotide selectivity limits chemical catalysis while the release of the elongated DNA product is the overall rate-limiting step. Remarkably, PrimPol incorporates four of the eight FDA-approved antiviral NRTIs with a kinetic profile distinct from that of mtDNA Pol γ that may manifest in toxicity.
Heterologous Expression and Functional Characterization of the Exogenously Acquired Aminoglycoside Resistance Methyltransferases RmtD, RmtD2, and RmtG
Authors: Corrêa Laís L. , Witek Marta A. , Zelinskaya Natalia , Picão Renata C. , Conn Graeme L.
Published: November 2015

The exogenously acquired 16S rRNA methyltransferases RmtD, RmtD2, and RmtG were cloned and heterologously expressed in
Escherichia coli
, and the recombinant proteins were purified to near homogeneity. Each methyltransferase conferred an aminoglycoside resistance profile consistent with m
7
G1405 modification, and this activity was confirmed by
in
vitro
30S methylation assays. Analyses of protein structure and interaction with
S
-adenosyl-
l
-methionine suggest that the molecular mechanisms of substrate recognition and catalysis are conserved across the 16S rRNA (m
7
G1405) methyltransferase family.
Suppression of CD4+Effector Responses by Naturally Occurring CD4+CD25+Foxp3+Regulatory T Cells Contributes to Experimental Cerebral Malaria
Authors: Blanc Anne-Laurence , Keswani Tarun , Gorgette Olivier , Bandeira Antonio , Malissen Bernard , Cazenave Pierre-André , Pied Sylviane
Published: November 2015

The role of naturally occurring CD4+CD25+Foxp3+regulatory T cells (nTreg) in the pathogenesis of cerebral malaria (CM), which involves both pathogenic T cell responses and parasite sequestration in the brain, is still unclear. To assess the contribution and dynamics of nTreg during the neuropathogenesis, we unbalanced the ratio between nTreg and naive CD4+T cells in an attenuated model ofPlasmodium bergheiANKA-induced experimental CM (ECM) by using a selective cell enrichment strategy. We found that nTreg adoptive transfer accelerated the onset and increased the severity of CM in syngeneic C57BL/6 (B6)P. bergheiANKA-infected mice without affecting the level of parasitemia. In contrast, naive CD4+T cell enrichment prevented CM and promoted parasite clearance. Furthermore, early during the infection nTreg expanded in the spleen but did not efficiently migrate to the site of neuroinflammation, suggesting that nTreg exert their pathogenic action early in the spleen by suppressing the protective naive CD4+T cell response toP. bergheiANKA infectionin vivoin both CM-susceptible (B6) and CM-resistant (B6-CD4−/−) mice. However, their sole transfer was not sufficient to restore CM susceptibility in two CM-resistant congenic strains tested. Altogether, these results demonstrate that nTreg are activated and functional duringP. bergheiANKA infection and that they contribute to the pathogenesis of CM. They further suggest that nTreg may represent an early target for the modulation of the immune response to malaria.
Global Changes in Mycoplasma gallisepticum Phase-Variable Lipoprotein Gene
vlhA
Expression during
In Vivo
Infection of the Natural Chicken Host
Authors: Pflaum K. , Tulman E. R. , Beaudet J. , Liao X. , Geary S. J.
Published: November 2015

Mycoplasma gallisepticum
is the primary etiologic agent of chronic respiratory disease in poultry, a disease largely affecting the respiratory tract and causing significant economic losses worldwide. Immunodominant proteins encoded by members of the variable lipoprotein and hemagglutinin (
vlhA
) gene family are thought to be important for mechanisms of
M. gallisepticum
-host interaction, pathogenesis, and immune evasion, but their exact role and the overall nature of their phase variation are unknown. To better understand these mechanisms, we assessed global transcriptomic
vlhA
gene expression directly from
M. gallisepticum
populations present on tracheal mucosae during a 7-day experimental infection in the natural chicken host. Here we report differences in both dominant and minor
vlhA
gene expression levels throughout the first week of infection and starting as early as day 1 postinfection, consistent with a functional role not dependent on adaptive immunity for driving phase variation. Notably, data indicated that, at given time points, specific
vlhA
genes were similarly dominant in multiple independent hosts, suggesting a nonstochastic temporal progression of dominant
vlhA
gene expression in the colonizing bacterial population. The dominant expression of a given
vlhA
gene was not dependent on the presence of 12-copy GAA trinucleotide repeats in the promoter region and did not revert to the predominate
vlhA
gene when no longer faced with host pressures. Overall, these data indicate that
vlhA
phase variation is dynamic throughout the earliest stages of infection and that the pattern of dominant
vlhA
expression may be nonrandom and regulated by previously unrecognized mechanisms.
Accumulation of Regulatory T Cells and Chronic Inflammation in the Middle Ear in a Mouse Model of Chronic Otitis Media with Effusion Induced by Combined Eustachian Tube Blockage and Nontypeable Haemophilus influenzae Infection
Authors: Hirano Takashi , Kodama Satoru , Kawano Toshiaki , Suzuki Masashi
Published: November 2015

NontypeableHaemophilus influenzae(NTHi) is associated with chronic otitis media (COM). In this study, we generated a murine model of COM by using eustachian tube (ET) obstruction and NTHi (107CFU) inoculation into the tympanic bulla, and we investigated the relationship between regulatory T cells (Treg) and chronic inflammation in the middle ear. Middle ear effusions (MEEs) and middle ear mucosae (MEM) were collected at days 3 and 14 and at 1 and 2 months after inoculation. Untreated mice served as controls. MEEs were used for bacterial counts and to measure the concentrations of cytokines. MEM were collected for histological evaluation and flow cytometric analysis. Inflammation of the MEM was prolonged throughout this study, and the incidence of NTHi culture-positive MEE was 38% at 2 months after inoculation. The levels of interleukin-1β (IL-β), tumor necrosis factor alpha, IL-10, and transforming growth factor β were increased in the middle ear for up to 2 months after inoculation. CD4+CD25+FoxP3+Treg accumulated in the middle ear, and the percentage of Treg in the MEM increased for up to 2 months after inoculation. Treg depletion induced a 99.9% reduction of bacterial counts in MEEs and also significantly reduced the ratio of NTHi culture-positive MEE. The levels of these cytokines were also reduced in MEEs. In summary, we developed a murine model of COM, and our findings indicate that Treg confer infectious tolerance to NTHi in the middle ear.
The Stringent Response Regulator DksA Is Required for Salmonella enterica Serovar Typhimurium Growth in Minimal Medium, Motility, Biofilm Formation, and Intestinal Colonization
Authors: Azriel Shalhevet , Goren Alina , Rahav Galia , Gal-Mor Ohad
Published: November 2015

Salmonella enterica
serovar Typhimurium is a facultative intracellular human and animal bacterial pathogen posing a major threat to public health worldwide.
Salmonella
pathogenicity requires complex coordination of multiple physiological and virulence pathways. DksA is a conserved Gram-negative regulator that belongs to a distinct group of transcription factors that bind directly to the RNA polymerase secondary channel, potentiating the effect of the signaling molecule ppGpp during a stringent response. Here, we established that in
S.
Typhimurium,
dksA
is induced during the logarithmic phase and DksA is essential for growth in minimal defined medium and plays an important role in motility and biofilm formation. Furthermore, we determined that DksA positively regulates the
Salmonella
pathogenicity island 1 and motility-chemotaxis genes and is necessary for
S.
Typhimurium invasion of human epithelial cells and uptake by macrophages. In contrast, DksA was found to be dispensable for
S.
Typhimurium host cell adhesion. Finally, using the colitis mouse model, we found that
dksA
is spatially induced at the midcecum during the early stage of the infection and required for gastrointestinal colonization and systemic infection
in vivo
. Taken together, these data indicate that the ancestral stringent response regulator DksA coordinates various physiological and virulence
S.
Typhimurium programs and therefore is a key virulence regulator of
Salmonella
.
Expression and Genetic Activation of Cyclic Di-GMP-Specific Phosphodiesterases in Escherichia coli
Authors: Reinders Alberto , Hee Chee-Seng , Ozaki Shogo , Mazur Adam , Boehm Alex , Schirmer Tilman , Jenal Urs
Published: November 2015

Intracellular levels of the bacterial second messenger cyclic di-GMP (c-di-GMP) are controlled by antagonistic activities of diguanylate cyclases and phosphodiesterases. The phosphodiesterase PdeH was identified as a key regulator of motility in
Escherichia coli
, while deletions of any of the other 12 genes encoding potential phosphodiesterases did not interfere with motility. To analyze the roles of
E. coli
phosphodiesterases, we demonstrated that most of these proteins are expressed under laboratory conditions. We next isolated suppressor mutations in six phosphodiesterase genes, which reinstate motility in the absence of PdeH by reducing cellular levels of c-di-GMP. Expression of all mutant alleles also led to a reduction of biofilm formation. Thus, all of these proteins are
bona fide
phosphodiesterases that are capable of interfering with different c-di-GMP-responsive output systems by affecting the global c-di-GMP pool. This argues that
E. coli
possesses several phosphodiesterases that are inactive under laboratory conditions because they lack appropriate input signals. Finally, one of these phosphodiesterases, PdeL, was studied in more detail. We demonstrated that this protein acts as a transcription factor to control its own expression. Motile suppressor alleles led to a strong increase of PdeL activity and elevated
pdeL
transcription, suggesting that enzymatic activity and transcriptional control are coupled. In agreement with this, we showed that overall cellular levels of c-di-GMP control
pdeL
transcription and that this control depends on PdeL itself. We thus propose that PdeL acts both as an enzyme and as a c-di-GMP sensor to couple transcriptional activity to the c-di-GMP status of the cell.

IMPORTANCE
Most bacteria possess multiple diguanylate cyclases and phosphodiesterases. Genetic studies have proposed that these enzymes show signaling specificity by contributing to distinct cellular processes without much cross talk. Thus, spatial separation of individual c-di-GMP signaling units was postulated. However, since most cyclases and phosphodiesterases harbor N-terminal signal input domains, it is equally possible that most of these enzymes lack their activating signals under laboratory conditions, thereby simulating signaling specificity on a genetic level. We demonstrate that a subset of
E. coli
phosphodiesterases can be activated genetically to affect the global c-di-GMP pool and thus influence different c-di-GMP-dependent processes. Although this does not exclude spatial confinement of individual phosphodiesterases, this study emphasizes the importance of environmental signals for activation of phosphodiesterases.
SepM, a Streptococcal Protease Involved in Quorum Sensing, Displays Strict Substrate Specificity
Authors: Biswas Saswati , Cao Luyang , Kim Albert , Biswas Indranil
Published: November 2015

Streptococcus mutans
, a causative agent of dental caries, relies on multiple quorum-sensing (QS) pathways that coordinate the expression of factors needed for colonization in the oral cavity.
S. mutans
uses small peptides as QS signaling molecules that typically are secreted into the outside milieu. Competence-stimulating peptide (CSP) is one such QS signaling molecule that functions through the ComDE two-component signal transduction pathway. CSP is secreted through NlmTE, a dedicated ABC transporter that cleaves off the N-terminal leader peptide to generate a mature peptide that is 21 residues long (CSP-21). We recently identified a surface-localized protease, SepM, which further cleaves the CSP-21 peptide at the C-terminal end and removes the last 3 residues to generate CSP-18. CSP-18 is the active QS molecule that interacts with the ComD sensor kinase to activate the QS pathway. In this study, we show that SepM specifically cleaves CSP-21 between the Ala18 and Leu19 residues. We also show that SepM recognizes only Ala at position 18 and Leu at position 19, although some CSP-18 variants with a substitution at position 18 can function equally as well as the QS peptide. Furthermore, we demonstrate that SepM homologs from other streptococci are capable of processing CSP-21 to generate functional CSP-18.

IMPORTANCE
SepM is a membrane-associated streptococcal protease that processes competence-stimulating peptide (CSP) to generate an active quorum-sensing molecule in
S. mutans
. SepM belongs to the S16 family of serine proteases, and in this study, we found that SepM behaves as an endopeptidase. SepM displays strict substrate specificity and cleaves the peptide bond between the Ala and Leu residues. This is the first report of an endopeptidase that specifically cleaves these two residues.
Management of Crohn's disease
Authors: Kammermeier Jochen , Morris Mary-Anne , Garrick Vikki , Furman Mark , Rodrigues Astor , Russell Richard K ,   BSPGHAN IBD Working Group
Published: November 2015

Crohn's disease (CD) is rapidly increasing in children so an up to date knowledge of diagnosis, investigation and management is essential. Exclusive enteral nutrition is the first line treatment for active disease. The vast majority of children will need immunosuppressant treatment and around 20% will need treatment with biologics. Recent guidelines have helped make best use of available therapies.
The effects of malnutrition on cardiac function in African children
Authors: Silverman Jonathan A , Chimalizeni Yamikani , Hawes Stephen E , Wolf Elizabeth R , Batra Maneesh , Khofi Harriet , Molyneux Elizabeth M
Published: November 2015

Objective

Cardiac dysfunction may contribute to high mortality in severely malnourished children. Our objective was to assess the effect of malnutrition on cardiac function in hospitalised African children.

Design

Prospective cross-sectional study.

Setting

Public referral hospital in Blantyre, Malawi.

Patients

We enrolled 272 stable, hospitalised children ages 6–59 months, with and without WHO-defined severe acute malnutrition.

Main outcome measures

Cardiac index, heart rate, mean arterial pressure, stroke volume index and systemic vascular resistance index were measured by the ultrasound cardiac output monitor (USCOM, New South Wales, Australia). We used linear regression with generalised estimating equations controlling for age, sex and anaemia.

Results

Our primary outcome, cardiac index, was similar between those with and without severe malnutrition: difference=0.22 L/min/m2 (95% CI −0.08 to 0.51). No difference was found in heart rate or stroke volume index. However, mean arterial pressure and systemic vascular resistance index were lower in children with severe malnutrition: difference=−8.6 mm Hg (95% CI −12.7 to −4.6) and difference=−200 dyne s/cm5/m2 (95% CI −320 to −80), respectively.

Conclusions

In this largest study to date, we found no significant difference in cardiac function between hospitalised children with and without severe acute malnutrition. Further study is needed to determine if cardiac function is diminished in unstable malnourished children.
Is cost-related non-collection of prescriptions associated with a reduction in health? Findings from a large-scale longitudinal study of New Zealand adults
Authors: Jatrana Santosh , Richardson Ken , Norris Pauline , Crampton Peter
Published: November 2015

Objective

To investigate whether cost-related non-collection of prescription medication is associated with a decline in health.

Settings

New Zealand Survey of Family, Income and Employment (SoFIE)-Health.

Participants

Data from 17 363 participants with at least two observations in three waves (2004–2005, 2006–2007, 2008–2009) of a panel study were analysed using fixed effects regression modelling.

Primary outcome measures

Self-rated health (SRH), physical health (PCS) and mental health scores (MCS) were the health measures used in this study.

Results

After adjusting for time-varying confounders, non-collection of prescription items was associated with a 0.11 (95% CI 0.07 to 0.15) unit worsening in SRH, a 1.00 (95% CI 0.61 to 1.40) unit decline in PCS and a 1.69 (95% CI 1.19 to 2.18) unit decline in MCS. The interaction of the main exposure with gender was significant for SRH and MCS. Non-collection of prescription items was associated with a decline in SRH of 0.18 (95% CI 0.11 to 0.25) units for males and 0.08 (95% CI 0.03 to 0.13) units for females, and a decrease in MCS of 2.55 (95% CI 1.67 to 3.42) and 1.29 (95% CI 0.70 to 1.89) units for males and females, respectively. The interaction of the main exposure with age was significant for SRH. For respondents aged 15–24 and 25–64 years, non-collection of prescription items was associated with a decline in SRH of 0.12 (95% CI 0.03 to 0.21) and 0.12 (95% CI 0.07 to 0.17) units, respectively, but for respondents aged 65 years and over, non-collection of prescription items had no significant effect on SRH.

Conclusion

Our results show that those who do not collect prescription medications because of cost have an increased risk of a subsequent decline in health.
Feedback on SMS reminders to encourage adherence among patients taking antipsychotic medication: a cross-sectional survey nested within a randomised trial
Authors: Kannisto Kati Anneli , Adams Clive E , Koivunen Marita , Katajisto Jouko , Välimäki Maritta
Published: November 2015

Objectives

To explore feedback on tailored SMS reminders to encourage medication adherence and outpatient treatment among patients taking antipsychotic medication, and associations related to the feedback.

Design

A cross-sectional survey nested within a nationwide randomised clinical trial (“Mobile.Net”ISRCTN27704027).

Setting

Psychiatric outpatient care in Finland.

Participants

Between September 2012 and December 2013, 403 of 558 adults with antipsychotic medication responded after 12 months of SMS intervention.

Main outcome measure

Feedback was gathered with a structured questionnaire based on Technology Acceptance Model theory. Data were analysed by Pearson's χ2test, binary logistic regression and stepwise multiple regression analyses.

Results

Almost all participants (98%) found the SMS reminders easy to use and 87% felt that the SMS did not cause harm. About three-quarters (72%) were satisfied with the SMS received, and 61% found it useful. Divorced people were particularly prone to find SMS reminders useful (χ2=13.17, df=6, p=0.04), and people seeking employment were more often ‘fully satisfied’ with the SMS compared with other groups (χ2=10.82, df=4, p=0.029). People who were older at first contact with psychiatric services were more often ‘fully satisfied’ than younger groups (OR=1.02, 95% CI 1.01 to 1.04, p=0.007).

Conclusions

The feedback of patients taking antipsychotic medication on SMS services was generally positive. Overall, people were quite satisfied despite considerable variation in their sociodemographic background and illness history. Our results endorse that the use of simple easy-to-use existing technology, such as mobile phones and SMS, is acceptable in psychiatric outpatient services. Moreover, people using psychiatric outpatient services are able to use this technology. This acceptable and accessible technology can be easily tailored to each patient's needs and could be customised to the needs of the isolated or jobless. This is an area in which much careful evaluation is needed.
A nationwide study of patients hospitalised for poisoning in Korea based on Korea National Hospital Discharge In-Depth Injury Survey data from 2005 to 2009
Authors: Kim Kyunghee , Choi Jae Wook , Park Miso , Kim Min Soo , Lee Eun Sun
Published: November 2015

Objectives

In light of the need to develop an integrated database on poisoning incidents in Korea, this study seeks to determine the characteristics of poisoning incidents in Korea by age, gender, location of incident, causative substance and patient prognosis.

Data sources

The Korea National Hospital Discharge In-Depth Injury Survey results (2005–2009) from the Korea Centers for Disease Control and Prevention were used.

Participants

3826 participants in the survey who had been hospitalised for poisoning incidents.

Results

The poisoning hospitalisation rate per 100 000 population was higher in women (1.735) than in men (1.372) and increased with age: the rate was 0.458 among individuals aged ≤9 years, 0.481 among those aged 10–19 years, 1.584 among those aged 20–64 years and 4.053 among those aged ≥65 years. The intentional poisoning hospitalisation rate differed by gender and age group. Women aged ≤19 years and 20–64 years showed a higher hospitalisation rate than men, while men aged ≥65 years showed a higher hospitalisation rate than women in the same age group. The most common poisoning substance was pesticides (33.6%), while antiepileptic, sedative-hypnotic and antiparkinsonism drugs and psychotropic drugs, not elsewhere classified were also very common. Poisoning in those aged ≤9 years usually involved other drugs, while pesticides were the most common substances in those aged 20–64 years and ≥65 years.

Conclusions

This study analysed poisoning incidents in Korea from 2005 to 2009, by age and gender, causative substance, and characteristics. The results of this study may serve as evidence for new strategies in Korea to prevent poisoning.