bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical effectiveness and economic costs of group versus one‐to‐one education for short‐chain fermentable carbohydrate restriction (low FODMAP diet) in the management of irritable bowel syndrome
Authors: Whigham L. , Joyce T. , Harper G. , Irving P. M. , Staudacher H. M. , Whelan K. , Lomer M. C. E.
Published: April 2015

Background

Restriction of fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) is an effective dietary treatment for irritable bowel syndrome (IBS). Patient dietary education is essential but labour intensive. Group FODMAP education may alleviate this somewhat but has not previously been investigated. The present study aimed to investigate the clinical effectiveness of low FODMAP group education in patients with IBS and to explore the cost of a group pathway.

Methods

Patients with IBS (n = 364) were assessed for their suitability to attend dietitian‐led group education or traditional one‐to‐one education in a novel group pathway. Clinical effectiveness (global symptom question, symptom prevalence, stool output) were compared at baseline and follow‐up using the chi‐squared test. The costs of the novel group pathway were assessed using a decision model.

Results

The global symptom question indicated more patients were satisfied with their symptoms following dietary advice, in both group education [baseline 48/263 (18%) versus follow‐up 142/263 (54%), P < 0.001] and one‐to‐one education [baseline 5/101 (5%) versus follow‐up 61/101 (60%), P < 0.001], with no difference between group and one‐to‐one education at follow‐up (P = 0.271). Overall, there was a significant decrease in symptom severity from baseline to follow‐up (P < 0.001 for both groups) but no difference in symptom response between group and one‐to‐one education. The cost for the group education pathway for all 364 patients was £31 713.36.

Conclusions

The present study shows that dietitian‐led FODMAP group education is clinically effective and the costs associated with a FODMAP group pathway are worthy of further consideration for routine clinical care.
Gene expression and physiological responses to salinity and water stress of contrasting durum wheat genotypes
Authors: Yousfi Salima , Márquez Antonio J. , Betti Marco , Araus José Luis , Serret Maria Dolores
Published: April 2015

Elucidating the relationships between gene expression and the physiological mechanisms remains a bottleneck in breeding for resistance to salinity and drought. This study related the expression of key target genes with the physiological performance of durum wheat under different combinations of salinity and irrigation. The candidate genes assayed included two encoding for the DREB (dehydration responsive element binding) transcription factors TaDREB1A and TaDREB2B, another two for the cytosolic and plastidic glutamine synthetase (TaGS1 and TaGS2), and one for the specific Na+/H+ vacuolar antiporter (TaNHX1). Expression of these genes was related to growth and different trait indicators of nitrogen metabolism (nitrogen content, stable nitrogen isotope composition, and glutamine synthetase and nitrate reductase activities), photosynthetic carbon metabolism (stable carbon isotope composition and different gas exchange traits) and ion accumulation. Significant interaction between genotype and growing conditions occurred for growth, nitrogen content, and the expression of most genes. In general terms, higher expression of TaGS1, TaGS2, TaDREB2B, and to a lesser extent of TaNHX1 were associated with a better genotypic performance in growth, nitrogen, and carbon photosynthetic metabolism under salinity and water stress. However, TaDREB1A was increased in expression under stress compared with control conditions, with tolerant genotypes exhibiting lower expression than susceptible ones.
Social cognitive training in adolescents with chromosome 22q11.2 deletion syndrome: feasibility and preliminary effects of the intervention
Authors: Shashi V. , Harrell W. , Eack S. , Sanders C. , McConkie‐Rosell A. , Keshavan M. S. , Bonner M. J. , Schoch K. , Hooper S. R.
Published: April 2015

Background

Children with chromosome 22q11.2 deletion syndrome (22q11DS) often have deficits in social cognition and social skills that contribute to poor adaptive functioning. These deficits may be of relevance to the later occurrence of serious psychiatric illnesses such as schizophrenia. Yet, there are no evidence‐based interventions to improve social cognitive functioning in children with 22q11DS.

Methods

Using a customised social cognitive curriculum, we conducted a pilot small‐group‐based social cognitive training (SCT) programme in 13 adolescents with 22q11DS, relative to a control group of nine age‐ and gender‐matched adolescents with 22q11DS.

Results

We found the SCT programme to be feasible, with high rates of compliance and satisfaction on the part of the participants and their families. Our preliminary analyses indicated that the intervention group showed significant improvements in an overall social cognitive composite index.

Conclusions

SCT in a small‐group format for adolescents with 22q11DS is feasible and results in gains in social cognition. A larger randomised controlled trial would permit assessment of efficacy of this promising novel intervention.
Acceptance of Vulvovaginal Pain in Women with Provoked Vestibulodynia and Their Partners: Associations with Pain, Psychological, and Sexual Adjustment
Authors: Boerner Katelynn E. , Rosen Natalie O.
Published: April 2015

Introduction

Provoked vestibulodynia (PVD) is a common vulvovaginal pain condition associated with negative psychological and sexual consequences for affected women and their sexual partners. Greater pain acceptance has been found to be associated with better functional and psychological outcomes in individuals with chronic pain, and acceptance-based strategies are being increasingly incorporated into treatment protocols. The present study is a novel investigation of pain acceptance in PVD couples.

Aim

The aim was to examine the associations between acceptance of vulvovaginal pain and women's pain during intercourse, as well as the psychological and sexual adjustment of both women with PVD and their partners.

Methods

Sixty-one couples (Mage for women = 27.95 years, SD = 5.87; Mage for men = 30.48 years, SD = 6.70) in which the woman was diagnosed with PVD completed the Chronic Pain Acceptance Questionnaire, in reference to women's vulvovaginal pain. Women also rated their pain during intercourse, and couples completed measures of anxiety, depression, sexual function, and sexual satisfaction.

Main Outcome Measures

Dependent measures were (i) women's self-reported pain during intercourse on a numerical rating scale; (ii) State-Trait Anxiety Inventory trait subscale; (iii) Beck Depression Inventory-II; (iv) Derogatis Interview for Sexual Functioning; and (v) Global Measure of Sexual Satisfaction Scale.

Results

Women's greater pain acceptance was associated with their lower self-reported pain during intercourse, controlling for partner's pain acceptance. Greater pain acceptance among women was associated with their own lower anxiety and depression, greater sexual functioning, as well as their own and their partner's greater sexual satisfaction, controlling for the partner's pain acceptance. Additionally, greater pain acceptance among male partners was associated with their own lower depression.

Conclusions

Findings suggest that psychological interventions for PVD should target increasing couples' vulvovaginal pain acceptance in order to improve women's pain and the sexual and psychological functioning of both members of the couple.
Youth Training Programs and Their Impact on Career and Spell Duration of Professional Soccer Players
Authors: Radoman Mihailo , Voia Marcel C.
Published: April 2015

A unique data set of post‐war English trained soccer players is used to study the impact of the youth training program they attended on their career and spell duration. Duration models in the spirit of Abbring and van den Berg are employed to estimate local treatment effects of different training programs on players — survival in the top European leagues. The results indicate that the duration patterns of players are dependent on the youth academy they attended. Certain clubs, with a well‐established reputation in developing youth talent, outperform others in terms of producing and evaluating the ability of their youth players to succeed in top European leagues. The spell analysis outlines the nature of the competitive environment in which smaller clubs have a chance to keep up with the larger ones in terms of producing and holding on to homegrown talent. Finally, the results of both analyses addressed unobserved heterogeneity, allowed for nonlinearity of covariates using the cubic spline methodology, and were tested for endogeneity bias using a split sample test.
Labour Market Policies in Times of Crisis: A Reaction Function Approach for the Period 1985–2010
Authors: Erhel Christine , Levionnois Charlotte
Published: April 2015

This article examines the reaction function of labour market expenditure to unemployment in 24 OECD countries, over the period 1985–2010, using the OECD panel data. The level of public debt is also introduced as a factor that is likely to influence these expenditures. Using a fixed‐effect model with interaction terms, this research focuses on two periods of crisis (1992–93 and 2007–09). The results confirm the counter‐cyclical variation of labour market policy expenditures. Nevertheless, the sensitivity of labour market expenditure to the economic cycle has in general decreased and the policy mix has changed. This could result from the important labour market reforms undertaken in the last 20 years.
Adolescents' experiences of using removable functional appliances
Authors: Čirgić E. , Kjellberg H. , Hansen K. , Lepp M.
Published: April 2015

Structured Abstract

Objectives

The aim of this qualitative study was to explore and describe adolescents′ experiences of treatment with removable functional appliances.

Setting and sample population

Public Dental Service, Gothenburg, Sweden.

Material and methods

Individual interviews focusing on adolescents' experiences of using a removable functional appliance were held with 21 adolescents (12 girls and nine boys). The mean age of the participants was 13.2 years (range 11–15, SD 1.25) at the interview occasion. Interviews were transcribed verbatim and analysed according to a qualitative research approach, phenomenography.

Results

Outcomes of data analysis emerged in five categories with totally 12 subcategories that describe the adolescents' various conceptions of the treatment. The adolescent's experiences of using removable functional appliance appeared to have a large variation, comprising of the individual approach, feelings and strategies, the dentist role and receiving external support.

Conclusion

Participants developed their own strategies of measurement to see improvement. An active involvement of the adolescents' in the treatment seems to be needed, supported by the dentist at coming appointments, using overjet measurement as a tool for motivation. Furthermore, efforts should be made by clinicians to listen and understand adolescents' needs and requirement before the treatment start.
Herbivores limit the population size of big‐leaf mahogany trees in an Amazonian forest
Authors: Norghauer Julian M. , Free Christopher M. , Landis R. Matthew , Grogan James , Malcolm Jay R. , Thomas Sean C.
Published: April 2015

The Janzen–Connell hypothesis proposes that specialized herbivores maintain high numbers of tree species in tropical forests by restricting adult recruitment so that host populations remain at low densities. We tested this prediction for the large timber tree species, Swietenia macrophylla, whose seeds and seedlings are preyed upon by small mammals and a host‐specific moth caterpillar Steniscadia poliophaea, respectively. At a primary forest site, experimental seed additions to gaps – canopy‐disturbed areas that enhance seedling growth into saplings – over three years revealed lower survival and seedling recruitment closer to conspecific trees and in higher basal area neighborhoods, as well as reduced subsequent seedling survival and height growth. When we included these Janzen–Connell effects in a spatially explicit individual‐based population model, the caterpillar's impact was critical to limiting Swietenia's adult tree density, with a > 10‐fold reduction estimated at 300 years. Our research demonstrates the crucial but oft‐ignored linkage between Janzen–Connell effects on offspring and population‐level consequences for a long‐lived, potentially dominant tree species.
Congenital syphilis presenting as Jarisch–Herxheimer reaction at birth
Authors: Hori Hideyuki , Sato Yoshitake , Shitara Tosiji
Published: April 2015

We report a rare case of congenital syphilis (CS) presenting as Jarisch–Herxheimer reaction (JHR) at birth. The mother (primigravida) presented in labor and had not received antenatal care. She was given prophylactic ampicillin 2 g i.v. on admission and delivered shortly thereafter. The male infant (2899 g) had normal vital signs, conjunctival congestion, splenohepatomegaly, and maculopapular rash with small blisters over the entire body. Serological tests on the infant and mother confirmed CS. The infant was given i.v. ampicillin for 14 days (50 mg/kg per day until day 3, 100 mg/kg per day thereafter). One hour after the first injection, the infant developed fever (39°C), tachycardia and tachypnea without worsening of rash. Vital signs improved gradually. The rash reduced markedly at postnatal day 1, and disappeared without pigmentation at day 3. This was considered a JHR following ampicillin injection given to the mother before delivery and to the infant after birth.
Radiological improvement by tocilizumab in polyarticular juvenile idiopathic arthritis
Authors: Tozawa Yusuke , Fujita Shouji , Abe Shuji , Kitamura Koichi , Kobayashi Ichiro
Published: April 2015

Recent advances in biologic therapy have enabled reduction of the progression of destructive arthritis in rheumatoid arthritis. Once destroyed, however, the affected bones and cartilage are not fully repaired. We describe the case of an 8‐year‐old girl with anti‐citrullinated peptide antibody (ACPA)‐positive polyarticular juvenile idiopathic arthritis (p‐JIA). Destructive arthritis progressed during combination therapy with infliximab, methotrexate, mizoribine and prednisolone. Clinical remission was achieved, however, after switching the biologic agent to tocilizumab, a humanized monoclonal antibody to interleukin‐6 receptor. Both bone erosion and bone marrow edema on magnetic resonance imaging were repaired in association with restoration of joint spaces. Furthermore, there was no relapse of arthritis on weekly methotrexate alone for 2 years after discontinuation of the tocilizumab. Tocilizumab led to radiological repair of both bone and cartilage destruction and long‐term biologics‐free remission in a patient with ACPA‐positive p‐JIA, and should be considered for tumor necrosis factor inhibitor‐resistant cases.
Autoimmune‐type atypical hemolytic uremic syndrome treated with eculizumab as first‐line therapy
Authors: Hisano Masataka , Ashida Akira , Nakano Eiji , Suehiro Mamiko , Yoshida Yoko , Matsumoto Masanori , Miyata Toshiyuki , Fujimura Yoshihiro , Hattori Motoshi
Published: April 2015

We report a case of atypical hemolytic uremic syndrome (aHUS) in a 4‐year‐old boy. Although the patient had the typical triad of aHUS (microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury), urgent dialysis was not indicated because he had neither oliguria nor severe electrolyte abnormality. He was given eculizumab as first‐line therapy, which led to significant clinical improvement, thus avoiding any risk of complications associated with plasma exchange and central venous catheterization. Retrograde functional analysis of the patient's plasma using sheep erythrocytes indicated an increase in hemolysis, suggesting impairment of host cell protection by complement factor H. The use of eculizumab as first‐line therapy in place of plasma exchange might be reasonable for pediatric patients with aHUS.
Hemophagocytic lymphohistiocytosis secondary to Varicella zoster infection in a child with Henoch–Schönlein purpura
Authors: Gur Gokce , Cakar Nilgun , Uncu Nermin , Ayar Ganime , Basaran Ozge , Taktak Aysel , Koksoy Adem Yasin , Acar Banu , Caycı Fatma Semsa
Published: April 2015

Hemophagocytic lymphohistiocytosis (HLH) is a fatal, hyper‐inflammatory syndrome that is characterized by untimely activation of macrophages, and manifests as cytopenia, organ dysfunction, and coagulopathy. Secondary HLH can be associated with infection, drugs, malignancy, and transplantation, and is mostly triggered by infection. Herein, we report the case of a patient with Henoch–Schönlein purpura (HSP) who developed severe HLH secondary to Varicella zoster infection.
Rituximab‐combination chemotherapy achieves a 10th cycle of remission for Burkitt's lymphoma
Authors: Umeda Katsutsugu , Fujino Hisanori , Saida Satoshi , Kato Itaru , Hiramatsu Hidefumi , Yamada Tomomi , Hori Toshinori , Adachi Souichi , Heike Toshio , Watanabe Ken‐Ichiro
Published: April 2015

A 14‐year‐old girl with multiple intra‐abdominal tumors was diagnosed with stage III Burkitt's lymphoma. She achieved complete remission after multi‐drug chemotherapy, but she relapsed after six courses. Autologous peripheral blood stem cells (PBSC) or allogeneic PBSC harvested from an HLA‐identical sibling were insufficient, and her family did not agree to bone marrow collection from the sibling. Although the patient relapsed nine times (the relapses involved intra‐abdominal organs or bone) during the following 4 years 7 months, treatment with rituximab monotherapy or in combination with ifosphamide, carboplastin, and etoposide, or local irradiation (33.8–40.0 Gy) to treat the bone metastases, proved effective, resulting in complete or partial remission. At the time of writing, the patient was in a 10th cycle of remission lasting 1 year 6 months and had not required transplantation. Thus, a chemotherapy regimen including rituximab might be effective for Burkitt's lymphoma in patients experiencing multiple relapse.
Successful diuretics treatment of protein‐losing enteropathy in Noonan syndrome
Authors: Mizuochi Tatsuki , Suda Kenji , Seki Yoshitaka , Yanagi Tadahiro , Yoshimoto Hironaga , Kudo Yoshiyuki , Iemura Motofumi , Tanikawa Ken , Matsuishi Toyojiro
Published: April 2015

There are few reports on successful high‐dose spironolactone treatment of refractory protein‐losing enteropathy (PLE) caused by Fontan procedure. We report successful diuretics treatment with spironolactone and furosemide at standard dose, of refractory PLE in a patient with Noonan syndrome and repaired congenital heart disease. This is the first successful application of diuretics treatment in a patient with refractory PLE without Fontan procedure. This case illustrates that diuretics treatment can be the first‐line treatment of PLE regardless of the causative physiology, and can be effective in refractory PLE with Noonan syndrome.
The Power of Powerlessness
Authors: Levi Don S.
Published: April 2015

Philosophers should forget what they think they know about divine assistance, power, control, up‐to‐usness, freedom‐from and free will, when it comes to alcoholism, given what Alcoholics Anonymous (AA) says. Alcoholics will never be free of their alcoholism; although it is up to them to acknowledge their powerlessness over alcohol, often that is not possible until they hit bottom, and even then they might not acquire the power of powerlessness without help from a Higher Power. After explaining and defending these insights of AA, the unwarranted assumptions behind how philosophers (and others) criticise them are identified.
Visual search is postponed during the period of the AB: An event‐related potential study
Authors: Lagroix Hayley E. P. , Grubert Anna , Spalek Thomas M. , Di Lollo Vincent , Eimer Martin
Published: April 2015

In the phenomenon known as the attentional blink (AB), perception of the second of two rapidly sequential targets (T2) is impaired when presented shortly after the first (T1). Studies in which T2 consisted of a pop‐out search array provided evidence suggesting that visual search is postponed during the AB. In the present work, we used behavioral and electrophysiological measures to test this postponement hypothesis. The behavioral measure was reaction time (RT) to T2; the electrophysiological measure was the onset latency of an ERP index of attentional selection, known as the N2pc. Consistent with the postponement hypothesis, both measures were delayed during the AB. The delay in N2pc was substantially shorter than that in RT, pointing to multiple sources of delay in the chain of processing events, as distinct from the single source postulated in current theories of the AB. Finally, the finding that the N2pc was delayed during the AB strongly suggests that attention is involved in the processing of pop‐out search arrays.
The challenges of fractionalized property rights in public‐private hybrid organizations: The good, the bad, and the ugly
Authors: Vining Aidan R. , Weimer David L.
Published: April 2015

Policy designers seeking to harness profit‐driven efficiency for public purposes are increasingly creating organizations with fractionalized property rights that distribute “ownership” among public and private actors. The resulting hybrids are quite diverse, including mixed enterprises, public‐private partnerships, social entrepreneurship organizations, government‐sponsored enterprises, and various other hybrid forms. Marrying public purposes to private sector efficiency and strategic flexibility provides a tempting rationale for mixing public and private owners in hybrid organizations. Because public‐private hybrids involve fractionalized property rights, however, they exhibit tension among owners over both strategy and, more importantly, goals. To understand public‐private hybrids, we assess them in terms of six dimensions of property rights: fragmentation of ownership, clarity of allocation, cost of alienation, security from trespass, credibility of persistence, and autonomy (of both owners and managers). The unclear allocation of fractionalized ownership rights facilitates the appropriation of financial residuals and asset ownership opportunistically. Other weaknesses in the property rights configurations of public‐private hybrids create managerial dissonance or opportunistic behavior that typically leads to a narrowing of goals, but sometimes also to organizational failure.
Non‐parametric Copula Estimation Under Bivariate Censoring
Authors: Gribkova Svetlana , Lopez Olivier
Published: April 2015

In this paper, we consider non‐parametric copula inference under bivariate censoring. Based on an estimator of the joint cumulative distribution function, we define a discrete and two smooth estimators of the copula. The construction that we propose is valid for a large range of estimators of the distribution function and therefore for a large range of bivariate censoring frameworks. Under some conditions on the tails of the distributions, the weak convergence of the corresponding copula processes is obtained in l∞([0,1]2). We derive the uniform convergence rates of the copula density estimators deduced from our smooth copula estimators. Investigation of the practical behaviour of these estimators is performed through a simulation study and two real data applications, corresponding to different censoring settings. We use our non‐parametric estimators to define a goodness‐of‐fit procedure for parametric copula models. A new bootstrap scheme is proposed to compute the critical values.
Friendship, Negative Peer Experiences, and Daily Positive and Negative Mood
Authors: Reavis Rachael D. , Donohue Laura J. , Upchurch Mikayla C.
Published: April 2015

We examined the effect of negative peer experiences (NPEs; peer victimization and exclusion) on mood (depressed, angry, positive). Seventy‐seven (43 female) fifth graders from elementary schools located in a small town in the Midwest completed a friendship quality measure, in addition to daily reports (seven school days) of mood and peer experiences. Multilevel modeling showed that children who had NPEs in which no one intervened had more negative and less positive mood. For negative mood, this result was attenuated if the child had a friend who was generally helpful. The results demonstrate the positive role of bystanders during NPEs and highlight the protective role of high‐quality friendships.
Understanding the Accuracy of Parental Perceptions of Child Physical Activity: A Mixed Methods Analysis
Authors: Kesten Joanna M. , Jago Russ , Sebire Simon J. , Edwards Mark J. , Pool Laura , Zahra Jesmond , Thompson Janice L.
Published: April 2015

Background:

Interventions to increase children’s physical activity (PA) have achieved limited success. This may be attributed to inaccurate parental perceptions of their children’s PA and a lack of recognition of a need to change activity levels.

Methods:

Fifty-three parents participated in semistructured interviews to determine perceptions of child PA. Perceptions were compared with children’s measured MVPA (classified as meeting or not meeting UK guidelines) to produce 3 categories: “accurate,” “over-estimate,” and “under-estimate.” Deductive content analysis was performed to understand the accuracy of parental perceptions.

Results:

All parents of children meeting the PA guidelines accurately perceived their child’s PA; while the majority of parents whose child did not meet the guidelines overestimated their PA. Most parents were unconcerned about their child’s PA level, viewing them as naturally active and willing to be active. Qualitative explanations for perceptions of insufficient activity included children having health problems and preferences for inactive pursuits, and parents having difficulty facilitating PA in poor weather and not always observing their child’s PA level. Social comparisons also influenced parental perceptions.

Conclusions:

Strategies to improve parental awareness of child PA are needed. Perceptions of child PA may be informed by child “busyness,” being unaware of activity levels, and social comparisons.
Constitutive production of c-di-GMP is associated with mutations in a variant of
Pseudomonas aeruginosa
with altered membrane composition
Authors: Blanka Andrea , Düvel Juliane , Dötsch Andreas , Klinkert Birgit , Abraham Wolf-Rainer , Kaever Volkhard , Ritter Christiane , Narberhaus Franz , Häussler Susanne
Published: April 2015

Changes in the fatty acid composition of the plasma membrane in an opportunistic pathogen promote biofilm formation.
Science Signaling
Podcast: 14 April 2015
Authors: Häussler Susanne , Blanka Andrea , VanHook Annalisa M.
Published: April 2015

Altered fatty acid metabolism enhances the ability of a disease-associated strain of
Pseudomonas aeruginosa
to form biofilms.
Tailoring talin function
Authors: VanHook Annalisa M.
Published: April 2015

Different configurations of the integrin-talin-vinculin complex may enable talin to sense the different forces in developing tissues.
Giving protein folding a helping hand
Authors: Hurtley Stella M.
Published: April 2015

Sephin1 selectively inhibits a protein phosphatase to prevent two protein misfolding diseases in mice.
Vitamin D lends a helping hand
Authors: Nusinovich Yevgeniya
Published: April 2015

Vitamin D promotes tumoricidal activity of macrophages and improves the efficacy of antibody-dependent cellular cytotoxicity.
Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics
Authors: Vuong Chau , Xie Lisa H. , Potter Brittney M. J. , Zhang Jing , Zhang Ping , Duan Dehui , Nolan Christina K. , Sciotti Richard J. , Zottig Victor E. , Nanayakkara N. P. Dhammika , Tekwani Babu L. , Walker Larry A. , Smith Philip L. , Paris Robert M. , Read Lisa T. , Li Qigui , Pybus Brandon S. , Sousa Jason C. , Reichard Gregory A. , Smith Bryan , Marcsisin Sean R.
Published: April 2015

Cytochrome P450 (CYP) 2D metabolism is required for the liver-stage antimalarial efficacy of the 8-aminoquinoline molecule tafenoquine in mice. This could be problematic for
Plasmodium vivax
radical cure, as the human CYP 2D ortholog (2D6) is highly polymorphic. Diminished CYP 2D6 enzyme activity, as in the poor-metabolizer phenotype, could compromise radical curative efficacy in humans. Despite the importance of CYP 2D metabolism for tafenoquine liver-stage efficacy, the exact role that CYP 2D metabolism plays in the metabolism and pharmacokinetics of tafenoquine and other 8-aminoquinoline molecules has not been extensively studied. In this study, a series of tafenoquine pharmacokinetic experiments were conducted in mice with different CYP 2D metabolism statuses, including wild-type (WT) (reflecting extensive metabolizers for CYP 2D6 substrates) and CYP
mouse
2D knockout (KO) (reflecting poor metabolizers for CYP 2D6 substrates) mice. Plasma and liver pharmacokinetic profiles from a single 20-mg/kg of body weight dose of tafenoquine differed between the strains; however, the differences were less striking than previous results obtained for primaquine in the same model. Additionally, the presence of a 5,6-
ortho
-quinone tafenoquine metabolite was examined in both mouse strains. The 5,6-
ortho
-quinone species of tafenoquine was observed, and concentrations of the metabolite were highest in the WT extensive-metabolizer phenotype. Altogether, this study indicates that CYP 2D metabolism in mice affects tafenoquine pharmacokinetics and could have implications for human tafenoquine pharmacokinetics in polymorphic CYP 2D6 human populations.
Contribution of Stress Responses to Antibiotic Tolerance in Pseudomonas aeruginosa Biofilms
Authors: Stewart Philip S. , Franklin Michael J. , Williamson Kerry S. , Folsom James P. , Boegli Laura , James Garth A.
Published: April 2015

Enhanced tolerance of biofilm-associated bacteria to antibiotic treatments is likely due to a combination of factors, including changes in cell physiology as bacteria adapt to biofilm growth and the inherent physiological heterogeneity of biofilm bacteria. In this study, a transcriptomics approach was used to identify genes differentially expressed during biofilm growth of
Pseudomonas aeruginosa
. These genes were tested for statistically significant overlap, with independently compiled gene lists corresponding to stress responses and other putative antibiotic-protective mechanisms. Among the gene groups tested were those associated with biofilm response to tobramycin or ciprofloxacin, drug efflux pumps, acyl homoserine lactone quorum sensing, osmotic shock, heat shock, hypoxia stress, and stationary-phase growth. Regulons associated with Anr-mediated hypoxia stress, RpoS-regulated stationary-phase growth, and osmotic stress were significantly enriched in the set of genes induced in the biofilm. Mutant strains deficient in
rpoS
,
relA
and
spoT
, or
anr
were cultured in biofilms and challenged with ciprofloxacin and tobramycin. When challenged with ciprofloxacin, the mutant strain biofilms had 2.4- to 2.9-log reductions in viable cells compared to a 0.9-log reduction of the wild-type strain. Interestingly, none of the mutants exhibited a statistically significant alteration in tobramycin susceptibility compared to that with the wild-type biofilm. These results are consistent with a model in which multiple genes controlled by overlapping starvation or stress responses contribute to the protection of a
P. aeruginosa
biofilm from ciprofloxacin. A distinct and as yet undiscovered mechanism protects the biofilm bacteria from tobramycin.
In Vivo
Cluster Formation of Nisin and Lipid II Is Correlated with Membrane Depolarization
Authors: Tol Menno B. , Morales Angeles Danae , Scheffers Dirk-Jan
Published: April 2015

Nisin and related lantibiotics kill bacteria by pore formation or by sequestering lipid II. Some lantibiotics sequester lipid II into clusters, which were suggested to kill cells through delocalized peptidoglycan synthesis. Here, we show that cluster formation is always concomitant with (i) membrane pore formation and (ii) membrane depolarization. Nisin variants that cluster lipid II kill L-form bacteria with similar efficiency, suggesting that delocalization of peptidoglycan synthesis is not the primary killing mechanism of these lantibiotics.
Intrauterine Infection with Plasmid-Free Chlamydia muridarum Reveals a Critical Role of the Plasmid in Chlamydial Ascension and Establishes a Model for Evaluating Plasmid-Independent Pathogenicity
Authors: Chen Jianlin , Yang Zhangsheng , Sun Xin , Tang Lingli , Ding Yiling , Xue Min , Zhou Zhiguang , Baseman Joel , Zhong Guangming
Published: April 2015

Intravaginal infection with plasmid-competent but not plasmid-free
Chlamydia muridarum
induces hydrosalpinx in mouse upper genital tract, indicating a critical role of the plasmid in chlamydial pathogenicity. To evaluate the contribution of the plasmid to chlamydial ascension and activation of tubal inflammation, we delivered plasmid-free
C. muridarum
directly into the endometrium by intrauterine inoculation. We found that three of the six mouse strains tested, including CBA/J, C3H/HeJ, and C57BL/6J, developed significant hydrosalpinges when 1 × 10
7
inclusion-forming units (IFU) of plasmid-free
C. muridarum
were intrauterinally inoculated. Even when the inoculum was reduced to 1 × 10
4
IFU, the CBA/J mice still developed robust hydrosalpinx. The hydrosalpinx development in CBA/J mice correlated with increased organism ascension to the oviduct following the intrauterine inoculation. The CBA/J mice intravaginally infected with the same plasmid-free
C. muridarum
strain displayed reduced ascending infection and failed to develop hydrosalpinx. These observations have demonstrated a critical role of the plasmid in chlamydial ascending infection. The intrauterine inoculation of the CBA/J mice with plasmid-free
C. muridarum
not only resulted in more infection in the oviduct but also stimulated more inflammatory infiltration and cytokine production in the oviduct than the intravaginal inoculation, suggesting that the oviduct inflammation can be induced by plasmid-independent factors, which makes the hydrosalpinx induction in CBA/J mice by intrauterine infection with plasmid-free
C. muridarum
a suitable model for investigating plasmid-independent pathogenic mechanisms.
Variation in Plasmodium falciparum Erythrocyte Invasion Phenotypes and Merozoite Ligand Gene Expression across Different Populations in Areas of Malaria Endemicity
Authors: Bowyer Paul W. , Stewart Lindsay B. , Aspeling-Jones Harvey , Mensah-Brown Henrietta E. , Ahouidi Ambroise D. , Amambua-Ngwa Alfred , Awandare Gordon A. , Conway David J.
Published: April 2015

Plasmodium falciparum
merozoites use diverse alternative erythrocyte receptors for invasion and variably express cognate ligands encoded by the erythrocyte binding antigen (
eba
) and reticulocyte binding-like homologue (
Rh
) gene families. Previous analyses conducted on parasites from single populations in areas of endemicity revealed a wide spectrum of invasion phenotypes and expression profiles, although comparisons across studies have been limited by the use of different protocols. For direct comparisons within and among populations, clinical isolates from three different West African sites of endemicity (in Ghana, Guinea, and Senegal) were cryopreserved and cultured
ex vivo
after thawing in a single laboratory to assay invasion of target erythrocytes pretreated with enzymes affecting receptor subsets. Complete invasion assay data from 67 isolates showed no differences among the populations in the broad range of phenotypes measured by neuraminidase treatment (overall mean, 40.6% inhibition) or trypsin treatment (overall mean, 83.3% inhibition). The effects of chymotrypsin treatment (overall mean, 79.2% inhibition) showed heterogeneity across populations (Kruskall-Wallis
P
= 0.023), although the full phenotypic range was seen in each. Schizont-stage transcript data for a panel of 8 invasion ligand genes (
eba175
,
eba140
,
eba181
,
Rh1
,
Rh2a
,
Rh2b
,
Rh4
, and
Rh5
) were obtained for 37 isolates, showing similar ranges of variation in each population except that
eba175
levels tended to be higher in parasites from Ghana than in those from Senegal (whereas levels of
eba181
and
Rh2b
were lower in parasites from Ghana). The broad diversity in invasion phenotypes and gene expression seen within each local population, with minimal differences among them, is consistent with a hypothesis of immune selection maintaining parasite variation.
The Type VI Secretion System Modulates Flagellar Gene Expression and Secretion in Citrobacter freundii and Contributes to Adhesion and Cytotoxicity to Host Cells
Authors: Liu Liyun , Hao Shuai , Lan Ruiting , Wang Guangxia , Xiao Di , Sun Hui , Xu Jianguo
Published: April 2015

The type VI secretion system (T6SS) as a virulence factor-releasing system contributes to virulence development of various pathogens and is often activated upon contact with target cells.
Citrobacter freundii
strain CF74 has a complete T6SS genomic island (GI) that contains
clpV
,
hcp-2
, and
vgr
T6SS genes. We constructed
clpV
,
hcp-2
,
vgr
, and T6SS GI deletion mutants in CF74 and analyzed their effects on the transcriptome overall and, specifically, on the flagellar system at the levels of transcription and translation. Deletion of the T6SS GI affected the transcription of 84 genes, with 15 and 69 genes exhibiting higher and lower levels of transcription, respectively. Members of the cell motility class of downregulated genes of the CF74ΔT6SS mutant were mainly flagellar genes, including effector proteins, chaperones, and regulators. Moreover, the production and secretion of FliC were also decreased in
clpV
,
hcp-2
,
vgr
, or T6SS GI deletion mutants in CF74 and were restored upon complementation. In swimming motility assays, the mutant strains were found to be less motile than the wild type, and motility was restored by complementation. The mutant strains were defective in adhesion to HEp-2 cells and were restored partially upon complementation. Further, the CF74ΔT6SS, CF74Δ
clpV
, and CF74Δ
hcp-2
mutants induced lower cytotoxicity to HEp-2 cells than the wild type. These results suggested that the T6SS GI in CF74 regulates the flagellar system, enhances motility, is involved in adherence to host cells, and induces cytotoxicity to host cells. Thus, the T6SS plays a wide-ranging role in
C. freundii
.
Biochemical and Functional Characterization of the NurA-HerA Complex from Deinococcus radiodurans
Authors: Cheng Kaiying , Chen Xuanyi , Xu Guangzhi , Wang Liangyan , Xu Hong , Yang Su , Zhao Ye , Hua Yuejin
Published: April 2015

In archaea, the NurA nuclease and HerA ATPase/helicase, together with the Mre11-Rad50 complex, function in 3′ single-stranded DNA (ssDNA) end processing during homologous recombination (HR). However, bacterial homologs of NurA and HerA have not been characterized. From
Deinococcus radiodurans
, we identified the manganese-dependent 5′-to-3′ ssDNA/double-stranded DNA (dsDNA) exonuclease/endonuclease NurA (DrNurA) and the ATPase HerA (DrHerA). These two proteins stimulated each other's activity through direct protein-protein interactions. The N-terminal HAS domain of DrHerA was the key domain for this interaction. Several critical residues of DrNurA and DrHerA were verified by site-directed mutational analysis. Temperature-dependent activity assays confirmed that the two proteins had mesophilic features, with optimum activity temperatures 10°C to 15°C higher than their optimum growth temperatures. Knocking out either
nurA
or
herA
affected cell proliferation by shortening the growth phase, especially for growth at a high temperature (37°C). In addition, both mutant strains displayed almost 10-fold-reduced intermolecular recombination efficiency, indicating that DrNurA and DrHerA might be involved in homologous recombination
in vivo
. However, single- and double-gene deletions did not show significantly decreased radioresistance. Our results confirmed that the biochemical activities of bacterial NurA and HerA proteins were conserved with archaea. Our phenotypical results suggested that these proteins might have different functions in bacteria.

IMPORTANCE
Deinococcus radiodurans
NurA (DrNurA) was identified as a manganese-dependent 5′-to-3′ ssDNA/dsDNA exonuclease/endonuclease, and
Deinococcus radiodurans
HerA (DrHerA) was identified as an ATPase. Physical interactions between DrNurA and DrHerA explained mutual stimulation of their activities. The N-terminal HAS domain on DrHerA was identified as the interaction domain. Several essential functional sites on DrNurA and DrHerA were characterized. Both DrHerA and DrNurA showed mesophilic biochemical features, with their optimum activity temperatures 10°C to 15°C higher than their optimum growth temperatures
in vitro
. Knockout of
nurA
or
herA
led to abnormal cell proliferation and reduced intermolecular recombination efficiency but no obvious effect on radioresistence.
Involvement of the TetR-Type Regulator PaaR in the Regulation of Pristinamycin I Biosynthesis through an Effect on Precursor Supply in Streptomyces pristinaespiralis
Authors: Zhao Yawei , Feng Rongrong , Zheng Guosong , Tian Jinzhong , Ruan Lijun , Ge Mei , Jiang Weihong , Lu Yinhua
Published: April 2015

Pristinamycin I (PI), produced by
Streptomyces pristinaespiralis
, is a streptogramin type B antibiotic, which contains two proteinogenic and five aproteinogenic amino acid precursors. PI is coproduced with pristinamycin II (PII), a member of streptogramin type A antibiotics. The PI biosynthetic gene cluster has been cloned and characterized. However, thus far little is understood about the regulation of PI biosynthesis. In this study, a TetR family regulator (encoded by
SSDG_03033
) was identified as playing a positive role in PI biosynthesis. Its homologue, PaaR, from
Corynebacterium glutamicum
serves as a transcriptional repressor of the
paa
genes involved in phenylacetic acid (PAA) catabolism. Herein, we also designated the identified regulator as PaaR. Deletion of
paaR
led to an approximately 70% decrease in PI production but had little effect on PII biosynthesis. Identical to the function of its homologue from
C. glutamicum
, PaaR is also involved in the suppression of
paa
expression. Given that phenylacetyl coenzyme A (PA-CoA) is the common intermediate of the PAA catabolic pathway and the biosynthetic pathway of
l
-phenylglycine (
l
-Phg), the last amino acid precursor for PI biosynthesis, we proposed that derepression of the transcription of
paa
genes in a Δ
paaR
mutant possibly diverts more PA-CoA to the PAA catabolic pathway, thereby with less PA-CoA metabolic flux toward
l
-Phg formation, thus resulting in lower PI titers. This hypothesis was verified by the observations that PI production of a Δ
paaR
mutant was restored by
l
-Phg supplementation as well as by deletion of the
paaABCDE
operon in the Δ
paaR
mutant. Altogether, this study provides new insights into the regulation of PI biosynthesis by
S. pristinaespiralis
.

IMPORTANCE
A better understanding of the regulation mechanisms for antibiotic biosynthesis will provide valuable clues for
Streptomyces
strain improvement. Herein, a TetR family regulator PaaR, which serves as the repressor of the transcription of
paa
genes involved in phenylacetic acid (PAA) catabolism, was identified as playing a positive role in the regulation of pristinamycin I (PI) by affecting the supply of one of seven amino acid precursors,
l
-phenylglycine, in
Streptomyces pristinaespiralis
. To our knowledge, this is the first report describing the interplay between PAA catabolism and antibiotic biosynthesis in
Streptomyces
strains. Considering that the PAA catabolic pathway and its regulation by PaaR are widespread in antibiotic-producing actinomycetes, it could be suggested that PaaR-dependent regulation of antibiotic biosynthesis might commonly exist.
Trends and social differentials in child mortality in Rwanda 1990–2010: results from three demographic and health surveys
Authors: Musafili Aimable , Essén Birgitta , Baribwira Cyprien , Binagwaho Agnes , Persson Lars-Åke , Selling Katarina Ekholm
Published: April 2015

Background

Rwanda has embarked on ambitious programmes to provide equitable health services and reduce mortality in childhood. Evidence from other countries indicates that advances in child survival often have come at the expense of increasing inequity. Our aims were to analyse trends and social differentials in mortality before the age of 5 years in Rwanda from 1990 to 2010.

Methods

We performed secondary analyses of data from three Demographic and Health Surveys conducted in 2000, 2005 and 2010 in Rwanda. These surveys included 34 790 children born between 1990 and 2010 to women aged 15–49 years. The main outcome measures were neonatal mortality rates (NMR) and under-5 mortality rates (U5MR) over time, and in relation to mother's educational level, urban or rural residence and household wealth. Generalised linear mixed effects models and a mixed effects Cox model (frailty model) were used, with adjustments for confounders and cluster sampling method.

Results

Mortality rates in Rwanda peaked in 1994 at the time of the genocide (NMR 60/1000 live births, 95% CI 51 to 65; U5MR 238/1000 live births, 95% CI 226 to 251). The 1990s and the first half of the 2000s were characterised by a marked rural/urban divide and inequity in child survival between maternal groups with different levels of education. Towards the end of the study period (2005–2010) NMR had been reduced to 26/1000 (95% CI 23 to 29) and U5MR to 65/1000 (95% CI 61 to 70), with little or no difference between urban and rural areas, and household wealth groups, while children of women with no education still had significantly higher U5MR.

Conclusions

Recent reductions in child mortality in Rwanda have concurred with improved social equity in child survival. Current challenges include the prevention of newborn deaths.
High hepatitis C virus prevalence and incidence in a community cohort of young heroin injectors in a context of extensive harm reduction programmes
Authors: Vallejo Fernando , Barrio Gregorio , Brugal M Teresa , Pulido Jose , Toro Carlos , Sordo Luis , Espelt Albert , Bravo María J ,   the Itinere Project Group
Published: April 2015

Background

Cohort studies on hepatitis C virus (HCV) among drug injectors are scarcer than studies on HIV. Combined harm reduction interventions (HRIs) can prevent HCV infection. Spain has a medium–high coverage of HRIs.

Methods

513 young heroin users who injected drugs in the past 12 months (recent injectors) were street-recruited in 2001–2003 and followed until 2006 in three Spanish cities; 137 were anti-HCV seronegative, 77 of whom had ≥1 follow-up visit. Dried blood spots were tested for anti-HCV. HCV incidence and predictors of infection were estimated using Poisson models.

Results

At baseline, 73% were anti-HCV positive. Overall incidence (n=77) of HCV seroconversion was 39.8/100 person-years (py) (95% CI 28.7 to 53.8). Excluding non-injectors during follow-up from the analysis (n=57), HCV incidence was 52.9/100 py (95% CI 37.4 to 72.5). Injecting at least weekly (incidence rate ratio (IRR)=5.2 (95% CI 2.5 to 11.1)) and having ≥2 sexual partners (IRR=2.2 (95% CI 1.1 to 4.7)) were independent predictors of HCV seroconversion; drug-injection history <2 years was marginally associated (IRR=2.4 (95% CI 0.9 to 4.7)). HCV incidence may have been underestimated due to differential attrition.

Conclusions

Despite fairly high HRI coverage among Spanish drug injectors, a distressingly high incidence of HCV in a context of high HCV prevalence was found among young heroin injectors.