bluuebunny/crossref_metadata_2025 huggingface dataset:
The importance of pollinators and autonomous self‐fertilisation in the early stages of plant invasions:BanksiaandHakea(Proteaceae) as case studies
Authors: Moodley D. , Geerts S. , Richardson D. M. , Wilson J. R. U.
Published: April 2015

Reproduction is a crucial stage in the naturalisation of introduced plant species. Here, using breeding system experiments and observations of floral visitors, we investigate whether a lack of pollinators or an inability to autonomously self‐fertilise limits naturalisation in five AustralianBanksiaspecies and the co‐familialHakea salicifoliain South Africa.Banksiaspecies were heavily utilised by native insects and nectar‐feeding birds. AlthoughBanksiaproduced fruit when pollinators were excluded, pollinators significantly increased seed set in four of the five species.H. salicifoliaflowers were visited by 11 insect species; honeybees (Apis mellifera) were the main visitors. Flowers in naturalisedH. salicifoliapopulations received almost four times the number of visits as flowers in non‐naturalised populations; the latter showed both pollen limitation (PLI0.40) and partial self‐incompatibility. This should not prevent invasion, sinceH. salicifoliaproduces fruitsviaautonomous selfing in the absence of pollinators. The results suggest a limited role of breeding systems in mediating naturalisation of introduced Proteaceae species. Other factors, such as features of the recipient environments, appear to be more important. Spatial variation in rates of reproduction might, however, explain variation in the extent and rate of naturalisation of different populations.
The Effect of Land Restitution on Poverty Reduction among the Khomani San “Bushmen” in South Africa
Authors: Dikgang Johane , Muchapondwa Edwin
Published: April 2015

This paper looks at the impact of land restitution involving the Khomani San “bushmen” in the Kgalagadi area of South Africa. It seeks to investigate the effect of land restitution on poverty reduction among the beneficiaries. We run two‐stage least squares models of access to nature, per capita income and poverty status on the use of restituted land, among other variables. Our results suggest that the Khomani San beneficiaries have gotten more access to natural resources but that the use of restituted land has neither increased per capita income nor reduced poverty. In fact, the use of restituted land has contributed to increased poverty. Therefore, land restitution should become part of a broader, carefully crafted rural developmental strategy for it to be effective in reducing poverty. Otherwise, land restitution risks enabling indigenous communities to continue with their “traditional” way of life, and in fact thereby keep them poor.
Gender, Race, and Dissensus on State Supreme Courts*
Authors: Szmer John , Christensen Robert K. , Kaheny Erin B.
Published: April 2015

Objectives

The objectives of this study were to integrate multiple streams of research on judicial dissensus to better understand the causes of state court of last resort justices’ decisions to dissent. The study particularly focused on the relationship between dissent and gender and race (and their intersection) at the individual and panel level.

Methods

We employed probit regression with clustered standard errors of the population of state court of last resort cases from 1995 to 1998.

Results

Women and minorities were more likely to dissent in cases involving issues that are particularly salient to those particular groups. We also find evidence of the intersectionality of race and gender: while white women and African‐American males were less likely to dissent than white males, African‐American women were the most likely to cast dissenting votes.

Conclusions

Our results suggest that, in addition to small‐group (panel) and institutional characteristics, individual attributes such as race and gender (and their intersection) matter in the decision to dissent.
Longing for a Better American Dream: Homeowners in Trouble Evaluate Shared Equity Alternatives
Authors: Saegert Susan , Greer Andrew , Thaden Emily P. , Anthony Donald L.
Published: April 2015

Objective

We investigated how households with histories of mortgage default, including foreclosure, view traditional homeownership and how shared equity homeownership (SEH), an alternative housing tenure, would be evaluated.

Method

Focus groups and individual interviews with households who had contacted foreclosure counseling organizations were analyzed for themes relating to perceptions of homeownership and renting. After explaining the SEH concept, interviewees compared this form of tenure to both traditional homeownership and renting.

Findings

Interviewees associated homeownership with increased ontological security and financial stability, but the associations were reversed when mortgage delinquency and foreclosure were discussed. Nonetheless, they strongly preferred owning to renting. Participants were interested in SEH and found it a potentially valuable form of homeownership if practical details were properly addressed.

Conclusions

SEH offers the benefits that interviewees associated with homeownership. Those with histories of mortgage default expressed strong interest in SEH as an alternative to traditional homeownership and renting. Policy implications are discussed.
Improving red blood cell orders, utilization, and management with point‐of‐care clinical decision support
Authors: McKinney Zeke J. , Peters Jessica M. , Gorlin Jed B. , Perry Elizabeth H.
Published: April 2015

BACKGROUND

The computerized order for red blood cell (RBC) transfusion within our electronic health record was redesigned with integrated clinical decision support (CDS) to reinforce our restrictive transfusion policy. These changes encouraged 1‐unit (1U) RBC orders, clarified hemoglobin (Hb) transfusion triggers, and discouraged unnecessary orders. This study assessed whether these changes resulted in durable effects on provider practices.

STUDY DESIGN AND METHODS

The study compared three 1‐year subperiods from August 2011 to August 2014, with each year corresponding to a historical control period, preintervention and postintervention years. This study analyzed ratios of 1U versus 2‐unit (2U) orders and the absolute rate of RBC orders, units charged, Hb transfusion triggers, repeat transfusion orders, and selected clinical indications both institution‐wide and across several subpopulations.

RESULTS

Our institution‐wide ratio of 1U versus 2U orders increased from 0.50 to 1.20 (p < 0.0001) in the pre‐ to postintervention subperiods, respectively. The number of units charged per day decreased from 15.68 to 13.53 (p < 0.001), while rates of initial and repeat orders remained stable. Proportion of clinical indications used and mean Hb triggers demonstrated generally positive results. The changes observed between the pre‐ and postintervention years were far greater than changes between historical control versus preintervention years, reinforcing attribution of results to computerized physician order entry changes.

CONCLUSION

Use of computerized orders and CDS encouraged a restrictive transfusion policy, which was highly successful in changing provider practices. We also succeeded in decreasing mean Hb triggers and overall utilization of RBCs. These findings persisted across many subpopulations.
Mobilization of hematopoietic progenitor stem cells in allogeneic setting with lenograstim by subcutaneous injection, in daily or twice‐daily dosing: a single‐center prospective study with historical control
Authors: Martino Massimo , Moscato Tiziana , Barillà Santina , Dattola Antonia , Pontari Antonella , Fedele Roberta , Furlò Giuseppe , Marzia Stilo Carmen , Alberto Gallo Giuseppe , Tripepi Giovanni
Published: April 2015

BACKGROUND

Although the mobilization of hematopoietic progenitor stem cells from healthy donors (HDs) using granulocyte–colony‐stimulating factor is widely used, the ideal method for the administration of the cytokine has not yet been determined.

STUDY DESIGN AND METHODS

Seventy‐five consecutive HDs received lenograstim (LENO) as mobilization agent. LENO was given subcutaneously at a dose of 10 µg/kg in a once‐daily dose (ODD) every 24 hours. Results were compared with a historical control group of 181 HDs treated with 5 µg/kg LENO twice‐daily dose (TDD) with a time interval of 12 hours.

RESULTS

CD34+ cell concentrations evaluated on Day 4 and on Day 5 were 45 × 106 (range, 6 × 106‐217 × 106)/L and 75 × 106 (range, 7 × 106‐279 × 106)/L with ODD versus 36 × 106 (range, 3 × 106‐200 × 106)/L and 55 × 106 (range, 3 × 106‐738 × 106)/L with TDD (p = 0.067 and p = 0.001). The collected CD34+ cell counts in first apheresis procedure were 5.6 × 106 ± 2.9 × 106 and 5.7 × 106 ± 3 × 106/kg donor and recipient body weight in the ODD versus 5.4 × 106 ± 3.8 × 106 and 5.3 × 106 ± 3.5 × 106/kg in the TDD cohort, respectively (p = 0.08 and p = 0.02). Five HDs (6.7%) mobilized CD34+ cells of fewer than 2 × 106/kg recipient body weight in the ODD group compared with seven HDs (3.9%) in the TDD group (p = 0.3).

CONCLUSIONS

Once‐daily administration of LENO is at least as effective as twice‐daily administration for the mobilization of CD34+ cells in HDs.
Dehydration of blood platelets by zeodration: in vitro characterization and hemostatic properties in vivo
Authors: Donnet Thibault , Ravanat Catherine , Eckly Anita , Maurer Eric , Alame Ghina , Ziessel Catherine , Mangin Pierre H. , Freund Monique , Cazenave Jean‐Pierre , Gachet Christian , Rendu Francine
Published: April 2015

BACKGROUND

Platelets (PLTs) are currently stored at room temperature (RT) for 5 to 7 days. So far, there exists no validated method for the preparation and long‐term storage of dehydrated PLTs suitable for transfusion after rehydration. In this study, a desiccation process, zeodration, was applied to PLTs.

STUDY DESIGN AND METHODS

A complete procedure of dehydration at RT by zeodration was employed. Zeodrated human and mouse PLTs were characterized in vitro. Zeodrated mouse PLTs were transfused into clopidogrel‐treated mice to evaluate their hemostatic properties.

RESULTS

The optimal conditions for dehydration of PLTs at RT in a laboratory scale zeodrator were defined as 145 mbar and 20.2 ± 1.5°C. The recovery rate was 85 ± 2% and the dryness of zeodrated PLTs (Z_PLTs) indicated that they were sufficiently stable for long‐term storage. Rehydrated Z_PLTs were round, were not aggregated, and expressed the glycoproteins required for PLT function. Z_PLTs agglutinated in the presence of von Willebrand factor (VWF) and aggregated in response to thrombin or collagen independently of an active metabolism. In a flow system, Z_PLTs could adhere to VWF and form aggregates on a collagen matrix. Thrombin was generated at the surface of Z_PLTs as efficiently as on fresh PLTs. In clopidogrel‐treated mice, which exhibited a severely prolonged bleeding time, continuous perfusion of Z_PLTs restored normal hemostasis.

CONCLUSION

Zeodration represents a new strategy to prepare PLTs with partly preserved aggregative properties after storage and rehydration. Z_PLTs have potential hemostatic properties provided it is possible to improve their transfusion efficacy.
The external microenvironment of healing skin wounds
Authors: Kruse Carla R. , Nuutila Kristo , Lee Cameron C.Y. , Kiwanuka Elizabeth , Singh Mansher , Caterson Edward J. , Eriksson Elof , Sørensen Jens A.
Published: April 2015

The skin wound microenvironment can be divided into two main components that influence healing: the external wound microenvironment, which is outside the wound surface; and the internal wound microenvironment, underneath the surface, to which the cells within the wound are exposed. Treatment methods that directly alter the features of the external wound microenvironment indirectly affect the internal wound microenvironment due to the exchange between the two compartments. In this review, we focus on the effects of temperature, pressure (positive and negative), hydration, gases (oxygen and carbon dioxide), pH, and anti‐microbial treatment on the wound. These factors are well described in the literature and can be modified with treatment methods available in the clinic. Understanding the roles of these factors in wound pathophysiology is of central importance in wound treatment.
Crosstalk between the renal sympathetic nerve and intrarenal angiotensin II modulates proximal tubular sodium reabsorption
Authors: Pontes Roberto B. , Girardi Adriana C. C. , Nishi Erika E. , Campos Ruy R. , Bergamaschi Cássia T.
Published: April 2015

New Findings

What is the topic of this review?

The sympathetic control of renal sodium tubular reabsorption is dependent on activation of the intrarenal renin–angiotensin system and activation of the angiotensin II type 1 (AT1) receptor by angiotensin II.

What advances does it highlight?

Despite the fact that the interaction between the sympathetic nervous system and angiotensin II regarding salt reabsorption is a well‐known classical mechanism for the maintenance of extracellular volume homeostasis, the underlying molecular signalling is not clearly understood. It has been shown recently that renal nerve stimulation increases intrarenal angiotensin II and activates the AT1 receptor, triggering a signalling cascade that leads to elevations of Na+–H+ exchanger isoform 3‐mediated tubular transport. In this short review, the crosstalk between intrarenal angiotensin II and renal nerve activity and its effect on sodium reabsorption is addressed.

In this review, we address the importance of the interaction between the sympathetic nervous system and intrarenal renin–angiotensin system in modulating renal tubular handling of sodium and water. We have recently shown that increased Na+–H+ exchanger isoform 3 (NHE3) activity induced by renal nerve stimulation (RNS) depends on the activation of the angiotensin II type 1 (AT1) receptor by angiotensin II (Ang II). Low‐frequency RNS resulted in higher levels of intrarenal angiotensinogen and Ang II independent of changes in blood pressure, the glomerular filtration rate and systemic angiotensinogen. Angiotensin II, via the AT1 receptor, triggered an intracellular pathway activating NHE3 in the renal cortex, leading to antinatriuresis and antidiuresis. Pharmacological blockade of the AT1 receptor with losartan prior to RNS abolished both the functional and the molecular responses, suggesting that intrarenal Ang II acting via the AT1 receptor is a major factor for NHE3‐mediated sodium and water reabsorption induced by RNS.
Genetic disruption of Smad7 impairs skeletal muscle growth and regeneration
Authors: Cohen Tatiana V. , Kollias Helen D. , Liu Naili , Ward Christopher W. , Wagner Kathryn R.
Published: April 2015

Key points

Smad7 is an intracellular antagonist of transforming growth factor‐β signalling pathways and modulates muscle growth in vivo.

Loss of Smad7 results in decreased muscle mass, reduced force generation, fibre type switching from glycolytic towards oxidative type and delayed recovery from injury.

Upregulated Smad2/3 signalling in Smad7−/− muscle results in reduced myoblast proliferation and differentiation.

Smad7 is an important regulator of muscle growth and may be a potential intracellular therapeutic target for muscle disorders.

The transforming growth factor‐β (TGF‐β) family of growth factors plays an essential role in mediating cellular growth and differentiation. Myostatin is a muscle‐specific member of the TGF‐β superfamily and a negative regulator of muscle growth. Myostatin inhibitors are currently being pursued as therapeutic options for muscle disorders. Smad7 inhibits intracellular myostatin signalling via Smad2/3, and thus presents a means of regulating myostatin and potentiating muscle growth. We investigated the functional loss of Smad7 on muscle in vivo by examining muscle growth and differentiation in mice deficient in Smad7 (Smad7−/−). Smad7−/− mice showed reduced muscle mass, hypotrophy and hypoplasia of muscle fibres, as well as an increase in oxidative fibre types. Examination of muscle strength showed reduced force generation in vivo and ex vivo compared to wild‐type controls. Analysis of muscle regeneration showed a delay in recovery, probably as a result of decreased activation, proliferation and differentiation of satellite cells, as confirmed in vitro. Additionally, myostatin expression was upregulated in Smad7−/− muscle. Our findings suggest that increased Smad2/3 signalling in the absence of Smad7 inhibition impedes muscle growth and regeneration. Taken together, our experiments demonstrate that Smad7 is an important mediator of muscle growth in vivo. Our studies enhance our understanding of in vivo TGF‐β pathway modulation and suggest that Smad7 may be an important therapeutic target for muscle disorders.
Specificity of the anaphase-promoting complex: A single-molecule study
Authors: Lu Ying , Wang Weiping , Kirschner Marc W.
Published: April 2015

Single-molecule assay of ubiquitylation

Many biological processes in cells are regulated by ubiquitin peptides that are attached to proteins. Measurement of single fluorescent molecules in cell extracts can be used to trace the kinetics of such reactions. Lu
et al.
refined assay conditions to follow ubiquitination by an E3 ubiquitin ligase (see the Perspective by Komander). They visualized the activity of the anaphase-promoting complex (APC), a ubiquitin ligase critical for control of the cell division cycle. The processive initial reaction catalyzed by the APC was replaced by slower reactions. The results show how small, commonly occurring recognition motifs can guide specific and highly controlled enzymatic events. In a companion paper, Lu
et al.
explored how the number and arrangement of added ubiquitin chains affected the interaction of ubiquitylated proteins with the proteasome (a protein complex that recognizes ubiquitylated proteins and degrades them). The extent of ubiquitylation determined the strength of interaction of a substrate protein with the proteasome, and the arrangement of the ubiquitin chains determined the movement of the protein into the proteasome and thus the rate of degradation.

Science
, this issue
10.1126/science.1248737
,
10.1126/science.1250834
; see also p.
183
Startup liftoff
Authors: Hand Eric
Published: April 2015

How flocks of small, cheap satellites, hatched in Silicon Valley, will constantly monitor a changing Earth.
The principle of antagonism ensures protein targeting specificity at the endoplasmic reticulum
Authors: Gamerdinger Martin , Hanebuth Marie Anne , Frickey Tancred , Deuerling Elke
Published: April 2015

Sorting out cell sorting

The sorting of proteins into appropriate compartments is vital for proper cell function. After its discovery 20 years ago, various potential roles for nascent chain-associated complex (NAC) in the specificity of intracellular protein sorting have been proposed. Until now, no clear phenotypes have been discovered. Gamerdinger
et al.
explored the role of NAC in protein translocation in
Caenorhabditis elegans
(see the Perspective by Kramer
et al.
). They found that NAC prevents the importation of incorrect cargo, such as mitochondrial proteins, into the endoplasmic reticulum.

Science
, this issue p.
201
; see also p.
182
Speaking of science
Scientific Babel How Science Was Done Before and After Global English
Michael D. Gordin
University of Chicago Press, 2015. 421 pp.
Authors: Nyhart Lynn K.
Published: April 2015

How English became the language of science.
Cyber crime 2.0
Future Crimes Everything Is Connected, Everyone Is Vulnerable, and What We Can Do About It
Marc Goodman
Doubleday, 2015. 462 pp.
Authors: Greenbaum Dov
Published: April 2015

In a world where everything is connected, how will we balance security and privacy?
A chaotic approach clears up imaging
Authors: Schwefel Harald G. L. , Türeci Hakan E.
Published: April 2015

A laser that emits bright, incoherent light provides an ideal light source for imaging
Details of destruction, one molecule at a time
Authors: Komander David
Published: April 2015

Protein ubiquitination and destruction by the proteasome is examined at the single-molecule level

[Also see Reports by

Lu
et al.

and

Lu
et al.

]
NIH research: Think globally
Authors: Fauci Anthony S. , Collins Francis S.
Published: April 2015

The U.S. National Institutes of Health (NIH) has for more than 60 years supported research to improve the health and prolong the lives of people in the United States and around the world. Mean life expectancy worldwide has doubled to more than 70 years, due in large part to medical and public health interventions developed with NIH funding. Now, in the face of serious fiscal constraints, the idea has reemerged from some congressional leaders and disease constituency groups to more closely align NIH funding for disease research with disease burden in the United States. Although the nation must maintain robust research support for diseases that cause illness and death among large numbers of Americans, it would be unwise to deemphasize diseases that exact their largest toll elsewhere in the world. The United States has a vital interest in the health of people around the globe, rooted in an enduring tradition of humanitarian concern as well as in enlightened self-interest. Engagement in global health protects the nation's citizens, enhances the economy, and advances U.S. interests abroad.
Effects of Serial Skin Testing with Purified Protein Derivative on the Level and Quality of Antibodies to Complex and Defined Antigens in Mycobacterium bovis-Infected Cattle
Authors: Waters W. Ray , Palmer Mitchell V. , Stafne Molly R. , Bass Kristin E. , Maggioli Mayara F. , Thacker Tyler C. , Linscott Rick , Lawrence John C. , Nelson Jeffrey T. , Esfandiari Javan , Greenwald Rena , Lyashchenko Konstantin P.
Published: April 2015

Several serological tests designed to detect antibodies to immunodominant
Mycobacterium bovis
antigens have recently emerged as ancillary tests for the detection of bovine tuberculosis in cattle, particularly when used after the injection of purified protein derivative (PPD) for skin testing, which significantly boosts
M. bovis
-specific antibody responses. The present findings demonstrate the onset and duration of boosted antibody responses after the injection of
M. bovis
PPD for the caudal fold test (CFT) and
Mycobacterium avium
and
M. bovis
PPDs for the comparative cervical test (CCT), administered in series in cattle experimentally infected with
M. bovis
. While skin tests boosted the responses to certain antigens (i.e., MPB83 and MPB70), they did not affect the responses to other antigens (e.g., ESAT-6, CFP10, MPB59, and MPB64). Administration of the CCT 105 days after the CFT resulted in an even greater secondary boost in antibody responses to MPB83 and MPB70 and to a proteinase K-digested whole-cell sonicate (WCS-PK) of
M. bovis
. Both IgM and IgG contributed to the initial boost in the MPB83/MPB70-specific antibody response after the CFT. The secondary boost after the CCT was primarily due to increased IgG levels. Also, the avidity of antibodies to MPB83 and MPB70 increased after the CCT in
M. bovis
-infected cattle. The avidity of antibodies to the WCS-PK antigens increased in the interval between the CFT and the CCT but did not increase further after the CCT. Together, these findings demonstrate that the administration of PPDs for skin tests results in additive enhancement (i.e., when the CFT and CCT are performed in series), both qualitative and quantitative, of MPB83/MPB70-specific antibody responses.
PhyResSE: a Web Tool Delineating Mycobacterium tuberculosis Antibiotic Resistance and Lineage from Whole-Genome Sequencing Data
Authors: Feuerriegel Silke , Schleusener Viola , Beckert Patrick , Kohl Thomas A. , Miotto Paolo , Cirillo Daniela M. , Cabibbe Andrea M. , Niemann Stefan , Fellenberg Kurt
Published: April 2015

Antibiotic-resistant tuberculosis poses a global threat, causing the deaths of hundreds of thousands of people annually. While whole-genome sequencing (WGS), with its unprecedented level of detail, promises to play an increasingly important role in diagnosis, data analysis is a daunting challenge. Here, we present a simple-to-use web service (free for academic use at
http://phyresse.org
). Delineating both lineage and resistance, it provides state-of-the-art methodology to life scientists and physicians untrained in bioinformatics. It combines elaborate data processing and quality control, as befits human diagnostics, with a treasure trove of validated resistance data collected from well-characterized samples in-house and worldwide.
Genetics, Receptor Binding, and Virulence in Mice of H10N8 Influenza Viruses Isolated from Ducks and Chickens in Live Poultry Markets in China
Authors: Deng Guohua , Shi Jianzhong , Wang Jing , Kong Huihui , Cui Pengfei , Zhang Fang , Tan Dan , Suzuki Yasuo , Liu Liling , Jiang Yongping , Guan Yuntao , Chen Hualan
Published: April 2015

We analyzed eight H10N8 viruses isolated from ducks and chickens in live poultry markets from 2009 to 2013 in China. These viruses showed distinct genetic diversity and formed five genotypes: the four duck isolates formed four different genotypes, whereas the four chicken viruses belong to a single genotype. The viruses bound to both human- and avian-type receptors, and four of the viruses caused 12.7% to 22.5% body weight loss in mice.
CD8
+
T Cells Can Mediate Short-Term Protection against Heterotypic Dengue Virus Reinfection in Mice
Authors: Zellweger Raphaël M. , Tang William W. , Eddy William E. , King Kevin , Sanchez Marisa C. , Shresta Sujan
Published: April 2015

Dengue virus (DENV) is a major public health threat worldwide. Infection with one of the four serotypes of DENV results in a transient period of protection against reinfection with all serotypes (cross-protection), followed by lifelong immunity to the infecting serotype. While a protective role for neutralizing antibody responses is well established, the contribution of T cells to reinfection is less clear, especially during heterotypic reinfection. This study investigates the role of T cells during homotypic and heterotypic DENV reinfection. Mice were sequentially infected with homotypic or heterotypic DENV serotypes, and T cell subsets were depleted before the second infection to assess the role of DENV-primed T cells during reinfection. Mice primed nonlethally with DENV were protected against reinfection with either a homotypic or heterotypic serotype 2 weeks later. Homotypic priming induced a robust neutralizing antibody response, whereas heterotypic priming elicited binding, but nonneutralizing antibodies. CD8
+
T cells were required for protection against heterotypic, but not homotypic, reinfection. These results suggest that T cells can contribute crucially to protection against heterotypic reinfection in situations where humoral responses alone may not be protective. Our findings have important implications for vaccine design, as they suggest that inducing both humoral and cellular responses during vaccination may maximize protective efficacy across all DENV serotypes.

IMPORTANCE
Dengue virus is present in more than 120 countries in tropical and subtropical regions. Infection with dengue virus can be asymptomatic, but it can also progress into the potentially lethal severe dengue disease. There are four closely related dengue virus serotypes. Infection with one serotype results in a transient period of resistance against all serotypes (cross-protection), followed by lifelong resistance to the infecting serotype, but not the other ones. The duration and mechanisms of the transient cross-protection period remain elusive. This study investigates the contribution of cellular immunity to cross-protection using mouse models of DENV infection. Our results demonstrate that cellular immunity is crucial to mediate cross-protection against reinfection with a different serotype, but not for protection against reinfection with the same serotype. A better understanding of the mediators responsible for the cross-protection period is important for vaccine design, as an ideal vaccine against dengue virus should efficiently protect against all serotypes.
Interleukin-2 from Adaptive T Cells Enhances Natural Killer Cell Activity against Human Cytomegalovirus-Infected Macrophages
Authors: Wu Zeguang , Frascaroli Giada , Bayer Carina , Schmal Tatjana , Mertens Thomas
Published: April 2015

Control of human cytomegalovirus (HCMV) requires a continuous immune surveillance, thus HCMV is the most important viral pathogen in severely immunocompromised individuals. Both innate and adaptive immunity contribute to the control of HCMV. Here, we report that peripheral blood natural killer cells (PBNKs) from HCMV-seropositive donors showed an enhanced activity toward HCMV-infected autologous macrophages. However, this enhanced response was abolished when purified NK cells were applied as effectors. We demonstrate that this enhanced PBNK activity was dependent on the interleukin-2 (IL-2) secretion of CD4
+
T cells when reexposed to the virus. Purified T cells enhanced the activity of purified NK cells in response to HCMV-infected macrophages. This effect could be suppressed by IL-2 blocking. Our findings not only extend the knowledge on the immune surveillance in HCMV—namely, that NK cell-mediated innate immunity can be enhanced by a preexisting T cell antiviral immunity—but also indicate a potential clinical implication for patients at risk for severe HCMV manifestations due to immunosuppressive drugs, which mainly suppress IL-2 production and T cell responsiveness.

IMPORTANCE
Human cytomegalovirus (HCMV) is never cleared by the host after primary infection but instead establishes a lifelong latent infection with possible reactivations when the host′s immunity becomes suppressed. Both innate immunity and adaptive immunity are important for the control of viral infections. Natural killer (NK) cells are main innate effectors providing a rapid response to virus-infected cells. Virus-specific T cells are the main adaptive effectors that are critical for the control of the latent infection and limitation of reinfection. In this study, we found that IL-2 secreted by adaptive CD4
+
T cells after reexposure to HCMV enhances the activity of NK cells in response to HCMV-infected target cells. This is the first direct evidence that the adaptive T cells can help NK cells to act against HCMV infection.
Interaction between TIM-1 and NPC1 Is Important for Cellular Entry of Ebola Virus
Authors: Kuroda Makoto , Fujikura Daisuke , Nanbo Asuka , Marzi Andrea , Noyori Osamu , Kajihara Masahiro , Maruyama Junki , Matsuno Keita , Miyamoto Hiroko , Yoshida Reiko , Feldmann Heinz , Takada Ayato
Published: April 2015

Multiple host molecules are known to be involved in the cellular entry of filoviruses, including Ebola virus (EBOV); T-cell immunoglobulin and mucin domain 1 (TIM-1) and Niemann-Pick C1 (NPC1) have been identified as attachment and fusion receptors, respectively. However, the molecular mechanisms underlying the entry process have not been fully understood. We found that TIM-1 and NPC1 colocalized and interacted in the intracellular vesicles where EBOV glycoprotein (GP)-mediated membrane fusion occurred. Interestingly, a TIM-1-specific monoclonal antibody (MAb), M224/1, prevented GP-mediated membrane fusion and also interfered with the binding of TIM-1 to NPC1, suggesting that the interaction between TIM-1 and NPC1 is important for filovirus membrane fusion. Moreover, MAb M224/1 efficiently inhibited the cellular entry of viruses from all known filovirus species. These data suggest a novel mechanism underlying filovirus membrane fusion and provide a potential cellular target for antiviral compounds that can be universally used against filovirus infections.

IMPORTANCE
Filoviruses, including Ebola and Marburg viruses, cause rapidly fatal diseases in humans and nonhuman primates. There are currently no approved vaccines or therapeutics for filovirus diseases. In general, the cellular entry step of viruses is one of the key mechanisms to develop antiviral strategies. However, the molecular mechanisms underlying the entry process of filoviruses have not been fully understood. In this study, we demonstrate that TIM-1 and NPC1, which serve as attachment and fusion receptors for filovirus entry, interact in the intracellular vesicles where Ebola virus GP-mediated membrane fusion occurs and that this interaction is important for filovirus infection. We found that filovirus infection and GP-mediated membrane fusion in cultured cells were remarkably suppressed by treatment with a TIM-1-specific monoclonal antibody that interfered with the interaction between TIM-1 and NPC1. Our data provide new insights for the development of antiviral compounds that can be universally used against filovirus infections.
Interaction between Shadoo and PrP Affects the PrP-Folding Pathway
Authors: Ciric Danica , Richard Charles-Adrien , Moudjou Mohammed , Chapuis Jérôme , Sibille Pierre , Daude Nathalie , Westaway David , Adrover Miguel , Béringue Vincent , Martin Davy , Rezaei Human
Published: April 2015

Prion diseases are characterized by conformational changes of a cellular prion protein (PrP
C
) into a β-sheet-enriched and aggregated conformer (PrP
Sc
). Shadoo (Sho), a member of the prion protein family, is expressed in the central nervous system (CNS) and is highly conserved among vertebrates. On the basis of histoanatomical colocalization and sequence similarities, it is suspected that Sho and PrP may be functionally related. The downregulation of Sho expression during prion pathology and the direct interaction between Sho and PrP, as revealed by two-hybrid analysis, suggest a relationship between Sho and prion replication. Using biochemical and biophysical approaches, we demonstrate that Sho forms a 1:1 complex with full-length PrP with a dissociation constant in the micromolar range, and this interaction consequently modifies the PrP-folding pathway. Using a truncated PrP that mimics the C-terminal C1 fragment, an allosteric binding behavior with a Hill number of 4 was observed, suggesting that at least a tetramerization state occurs. A cell-based prion titration assay performed with different concentrations of Sho revealed an increase in the PrP
Sc
conversion rate in the presence of Sho. Collectively, our observations suggest that Sho can affect the prion replication process by (i) acting as a holdase and (ii) interfering with the dominant-negative inhibitor effect of the C1 fragment.

IMPORTANCE
Since the inception of the prion theory, the search for a cofactor involved in the conversion process has been an active field of research. Although the PrP interactome presents a broad landscape, candidates corresponding to specific criteria for cofactors are currently missing. Here, we describe for the first time that Sho can affect PrP structural dynamics and therefore increase the prion conversion rate. A biochemical characterization of Sho-PrP indicates that Sho acts as an ATP-independent holdase.
Potentially harmful excipients in neonatal medicines: a pan-European observational study
Authors: Nellis Georgi , Metsvaht Tuuli , Varendi Heili , Toompere Karolin , Lass Jana , Mesek Inge , Nunn Anthony J , Turner Mark A , Lutsar Irja
Published: April 2015

Objectives

We aimed to describe administration of eight potentially harmful excipients of interest (EOI)—parabens, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol and benzalkonium chloride—to hospitalised neonates in Europe and to identify risk factors for exposure.

Methods

All medicines administered to neonates during 1 day with individual prescription and demographic data were registered in a web-based point prevalence study. Excipients were identified from the Summaries of Product Characteristics. Determinants of EOI administration (geographical region, gestational age (GA), active pharmaceutical ingredient, unit level and hospital teaching status) were identified using multivariable logistical regression analysis.

Results

Overall 89 neonatal units from 21 countries participated. Altogether 2095 prescriptions for 530 products administered to 726 neonates were recorded. EOI were found in 638 (31%) prescriptions and were administered to 456 (63%) neonates through a relatively small number of products (n=142; 27%). Parabens, found in 71 (13%) products administered to 313 (43%) neonates, were used most frequently. EOI administration varied by geographical region, GA and route of administration. Geographical region remained a significant determinant of the use of parabens, polysorbate 80, propylene glycol and saccharin sodium after adjustment for the potential covariates including anatomical therapeutic chemical class of the active ingredient.

Conclusions

European neonates receive a number of potentially harmful pharmaceutical excipients. Regional differences in EOI administration suggest that EOI-free products are available and provide the potential for substitution to avoid side effects of some excipients.
Autoimmune pancreatitis mimicking Klatskin tumour on radiology
Authors: Hadi Yousaf Bashir , Sohail Abdul Malik Amir Humza , Haider Zishan
Published: April 2015

Autoimmune pancreatitis (AIP) is categorised into two distinct types, AIP type 1 and 2. Although there can be multisystem involvement, rarely, the cholangitis associated with AIP can present radiologically in a manner similar to that of Klatskin tumour. We present the case of a 65-year-old man who was almost misdiagnosed with a Klatskin tumour because of the similarity in radiological features of the two aforementioned clinical entities. The patient presented with a history of jaundice, pruritus and abdominal pain, and work up showed deranged liver function tests, elevated cancer antigen 19-9 levels and positive antinuclear antibodies. CT scan of the abdomen showed findings suggestive of Klatskin tumour but due to diffuse enlargement of the pancreas and surrounding low-attenuation halo found on a closer review, a diagnosis of AIP was performed. The patient was started on standard corticosteroid therapy and responded well, with complete resolution of the radiological findings.
Complicated septic arthritis after knee arthroscopy in a 75-year-old man with osteoarthritis and a popliteal cyst
Authors: Papadopoulos Antonios , Karachalios Theofilos S , Malizos Constantinos N , Varitimidis Sokratis
Published: April 2015

A 75-year-old man presented in shock secondary to septic arthritis of the knee. The patient, with a known history of knee osteoarthritis, was treated elsewhere for mechanical locking symptoms and effusion with arthroscopic debridement, and developed septic arthritis, which disseminated to the leg and foot after a tear in the capsule, and a ruptured pyogenic popliteal cyst. Open debridement of the knee joint, and drainage of the abscesses of the leg and foot, were performed. Antibiotic-loaded cement beads were left in the residual space. Debridement was repeated and cement beads removed after 4 days, and finally the infection was eradicated without any serious consequences for the patient. There is debate over arthroscopic intervention for osteoarthritic knees. The presence of a popliteal cyst, which is a rather common finding in the latter, could be related to a significant number of complications, such as septic arthritis.
Treasure in the chest
Authors: Blake Lucinda Katharine McCowan , Silverstone Elizabeth , Yates Deborah Helwen
Published: April 2015

A 41-year-old woman with a background of asthma was preparing for a party on New Year's Eve when she developed a mild wheeze. Concerned her symptoms would develop and impact on festivities, she located her uncapped salbutamol inhaler in her handbag. Ignoring the coarse rattle as she shook it, she proceeded to take a deep inspiration. Instantly, she felt a painful scratch in her pharynx followed by a harsh cough, which persisted over the next few minutes and became associated with haemoptysis. She was taken to the accident and emergency department. Chest X-ray revealed a radiodense foreign body in the distal right main bronchus. During endoscopy, an earring, causing subtotal occlusion in the right lower lobe bronchus was found and extracted. Her observations remained within normal limits throughout. The importance of replacing caps on inhalers when not in use is illustrated and should be encouraged when inhaler technique is taught or reviewed.
Unusual presentation of uterine leiomyoma
Authors: Al Hadidi Samer , Shaik Mohammed Tabrez , Bachuwa Ghassan
Published: April 2015

Uterine leiomyoma is the most common pelvic tumour in women. The presentation of uterine leiomyoma varies. Symptoms may include abnormal uterine bleeding or abdominal pressure and heaviness; however, most cases are asymptomatic. We report a case with renal impairment as the first presentation of uterine leiomyoma in a patient who presented with extensive bilateral lower limb oedema and no menstrual symptoms. Imaging studies, a subsequent Papanicolaou test and uterine biopsy were suggestive of uterine leiomyoma, which was confirmed by pathological examination after hysterectomy. The patient's kidney impairment resolved completely after the procedure.
Primary clear cell carcinoma of the rete testis: 1st report
Authors: Thomas Arun Zachariah , McDermott Thomas Eugene Dermot , Crowther Stephen , Thornhill John Alan
Published: April 2015

Primary tumours of the rete testis, either benign or malignant, are very rare. Such lesions require careful scrutiny including immunohistochemical analysis to exclude malignant lesions such as mesothelioma or papillary serous carcinoma. To the best of our knowledge this is the first report of a primary clear cell carcinoma of the rete testis. The possibility of a primary renal cell carcinoma or other primary site with metastatic spread to rete testis was excluded by thorough clinical and radiological work-up.
Associations between pentraxin 3 and severity of coronary artery disease
Authors: Liu Hua , Guan Shaofeng , Fang Weiyi , Yuan Fang , Zhang Min , Qu Xinkai
Published: April 2015

Objective

To investigate the associations between plasma levels of pentraxins 3 (PTX3) and C reactive protein (CRP) and the severity of coronary artery lesions.

Design and methods

60 patients with coronary heart disease (CHD) who underwent coronary angiography (CAG) in our hospital were included. Plasma was collected during CAG. The coronary Gensini score was used to evaluate the severity of coronary artery lesions. Associations between Gensini scores and plasma levels of PTX3 and CRP were analysed. Patients with estimated glomerular filtration rate <60 mL/min/1.73 m2were included in the chronic renal dysfunction subgroup.

Results

A linear correlation was observed between PTX3 and the Gensini score (r=0.513, p<0.001). One-way analysis of variance showed that PTX3 levels were significantly higher in patients with Gensini scores >90 compared with patients with scores of 46–90 or <45 (0–45:4.8±0.8, 46–90:6.7±1.2, >90:7.7±2.0, p<0.001). Stepwise multiple linear regression showed that PTX3 levels were significantly associated with Gensini score in patients with chronic renal dysfunction (p=0.012), while no significant association was found for CRP.

Conclusions

PTX3 levers were positively associated with the severity of coronary artery lesions. PTX3 is closely associated with the severity of coronary artery stenosis in patients with chronic renal dysfunction.
Description and preliminary results from a structured specialist behavioural weight management group intervention: Specialist Lifestyle Management (SLiM) programme
Authors: Brown Adrian , Gouldstone Amy , Fox Emily , Field Annmarie , Todd Wendy , Shakher Jayadave , Bellary Srikanth , Teh Ming Ming , Azam Muhammad , John Reggie , Jagielski Alison , Arora Teresa , Thomas G Neil , Taheri Shahrad
Published: April 2015

Background

Specialist Lifestyle Management (SLiM) is a structured patient education and self-management group weight management programme. Each session is run monthly over a 6-month period providing a less intensive long-term approach. The groups are patient-centred incorporating educational, motivational, behavioural and cognitive elements. The theoretical background, programme structure and preliminary results of SLiM are presented.

Subjects/methods

The study was a pragmatic service evaluation of obese patients with a body mass index (BMI) ≥35 kg/m2with comorbidity or ≥40 kg/m2without comorbidity referred to a specialist weight management service in the West Midlands, UK. 828 patients were enrolled within SLiM over a 48-month period. Trained facilitators delivered the programme. Preliminary anonymised data were analysed using the intention-to-treat principle. The primary outcome measure was weight loss at 3 and 6 months with comparisons between completers and non-completers performed. The last observation carried forward was used for missing data.

Results

Of the 828 enrolled within SLiM, 464 completed the programme (56%). The mean baseline weight was 135 kg (BMI=49.1 kg/m2) with 87.2% of patients having a BMI≥40 kg/m2and 12.4% with BMI≥60 kg/m2. The mean weight change of all patients enrolled was −4.1 kg (95% CI −3.6 to −4.6 kg, p=0.0001) at the end of SLiM, with completers (n=464) achieving −5.5 kg (95% CI −4.2 to −6.2 kg, p=0.0001) and non-completers achieving −2.3 kg (p=0.0001). The majority (78.6%) who attended the 6-month programme achieved weight loss with 32.3% achieving a ≥5% weight loss.

Conclusions

The SLiM programme is an effective group intervention for the management of severe and complex obesity.
What matters to patients? A systematic review of preferences for medication-associated outcomes in mental disorders
Authors: Eiring Øystein , Landmark Brynjar Fowels , Aas Endre , Salkeld Glenn , Nylenna Magne , Nytrøen Kari
Published: April 2015

Objective

To investigate patients’ preferences for outcomes associated with psychoactive medications.

Setting/design

Systematic review of stated preference studies. No settings restrictions were applied.

Participants/eligibility criteria

We included studies containing quantitative data regarding the relative value adults with mental disorders place on treatment outcomes. Studies with high risk of bias were excluded.

Primary and secondary outcome measures

We restricted the scope of our review to preferences for outcomes, including the consequences from, attributes of, and health states associated with particular medications or medication classes, and process outcomes.

Results

After reviewing 11 215 citations, 16 studies were included in the systematic review. These studies reported the stated preferences from patients with schizophrenia (n=9), depression (n=4), bipolar disorder (n=2) and attention deficit hyperactive disorder (n=1). The median sample size was 81. Side effects and symptom outcomes outnumbered functioning and process outcomes. Severe disease and hospitalisation were reported to be least desirable. Patients with schizophrenia tended to value disease states as higher and side effects as lower, compared to other stakeholder groups. In depression, the ability to cope with activities was found to be more important than a depressed mood, per se. Patient preferences could not consistently be predicted from demographic or disease variables. Only a limited number of potentially important outcomes had been investigated. Benefits to patients were not part of the purpose in 9 of the 16 studies, and in 10 studies patients were not involved when the outcomes to present were selected.

Conclusions

Insufficient evidence exists on the relative value patients with mental disorders place on medication-associated outcomes. To increase patient-centredness in decisions involving psychoactive drugs, further research—with outcomes elicited from patients, and for a larger number of conditions—should be undertaken.

Trial registration number

PROSPERO CRD42013005685.