bluuebunny/crossref_metadata_2025 huggingface dataset:
Is it all about price? Why requests for government subsidy of anticancer drugs were rejected in Australia
Authors: Karikios Deme J. , Chim Lesley , Martin Andrew , Nagrial Adnan , Howard Kirsten , Salkeld Glenn , Stockler Martin R.
Published: December 2016

Background

Australians access anticancer drugs predominantly through the Pharmaceutical Benefits Scheme (PBS).

Aim

To determine why the Pharmaceutical Benefits Advisory Committee (PBAC) rejects submissions to list anticancer drugs on the PBS.

Methods

We reviewed publicly available information about submissions made to the PBAC for PBS listing of anticancer drugs from 2005 to 2014. Submission characteristics, including clinical and economic evidence, PBAC recommendations, and the reasons offered for rejection were recorded. Two reviewers independently categorised the reason for rejection offered by the PBAC. Logistic regression was used to determine submission characteristics associated with rejection.

Results

We identified 213 submissions for 110 unique indications of 60 anticancer drugs. The overall rejection rate was 56% (119/213). Of the 110 indications assessed, 69% (76/110) were rejected at least once. The annual rejection rate ranged from 50 to 73% with little evidence of a trend over time (P = 0.2). Submission characteristics strongly associated with rejection in multivariable analysis included: PBAC judged the clinical evidence to be problematic or uncertain (P < 0.001); PBAC judged the economic evidence to be problematic or uncertain (P < 0.001); and, inactive comparator used (P < 0.001). The most frequent reasons for rejection offered by the PBAC was ‘inadequate cost‐effectiveness or drug price too high’ (75/109, 69%).

Conclusions

Inadequate cost‐effectiveness and PBAC uncertainty about the clinical and economic evidence were the most frequent reasons for rejection. Clarity of information about PBAC deliberations and their reasons for rejection are important for patients and doctors grappling with decisions about the use of expensive unfunded anticancer drugs.
Analyst Tipping: Additional Evidence
Authors: Markov Stanimir , Muslu Volkan , Subasi Musa
Published: December 2016

We examine whether analysts tip investors during investor conferences. We find that conference‐day abnormal returns of a presenting company are about 0.6% higher when the conference is hosted by an analyst who will initiate coverage with a Buy recommendation than when the conference is hosted by non‐initiating analysts. Furthermore, conference‐day abnormal returns of the presenting company amount to half of the price run‐up during the 20 trading days prior to the Buy initiation. Finally, there is a statistically and economically significant price run‐up prior to a Sell initiation (by about –0.7%) when the analyst who will initiate coverage with a Sell recommendation hosts a conference but does not invite the company to present. Our findings collectively suggest that analysts, rather than companies, tip select investors about upcoming initiations during conferences.
Incidence of Cardiac Perforation With Conventional and With Leadless Pacemaker Systems: A Systematic Review and Meta‐Analysis
Authors: VAMOS MATE , ERATH JULIA W. , BENZ ALEXANDER P. , BARI ZSOLT , DURAY GABOR Z. , HOHNLOSER STEFAN H.
Published: December 2016

Meta‐Analysis of Pacemaker Lead Perforation

Introduction

Two leadless pacemaker (PM) systems were recently developed to avoid pocket‐ and lead‐related complications. As leadless PMs are implanted with a large delivery catheter, cardiac perforation remains a major safety concern. We aimed to provide a literature review on incidence of cardiac perforation with conventional and with leadless PM systems.

Methods and Results

A systematic review over the last 25 years for studies reporting data on PM lead perforation was performed. Findings were synthesized descriptively. Where control groups were available, data were meta‐analyzed to identify important clinical risk factors.

A total of 28 studies comprising 60,744 patients undergoing conventional PM implantation were analyzed. The incidence of lead perforation ranged from 0% to 6.37% (mean 0.82%, weighted mean 0.31%, median of 0.40%). There was no significant difference in perforation risk between atrial and ventricular electrodes (POR 0.72, 95% confidence interval [CI], 0.28–1.87, P = 0.50) and between MRI conditional and conventional leads (POR 5.93, 95% CI, 0.72–48.76, P = 0.10). The use of active fixation leads (POR 4.25, 95% CI, 1.00–17.95, P = 0.05) and utilization of DDD versus VVI PM systems (POR 3.50, 95% CI, 1.48–8.28, P < 0.01) were associated with higher rates of perforation. In the 2 leadless PM studies, the incidence of cardiac perforation was 1.52% for each.

Conclusion

PM lead perforation rates vary in individual studies with an overall low incidence. Leadless PMs seem to be associated with a slightly higher perforation risk, most likely reflecting a learning curve effect of this novel technology.
Financial Compliance in the European Union: A Cross‐National Assessment of Financial Correction Patterns and Causes in Cohesion Policy
Authors: Mendez Carlos , Bachtler John
Published: December 2016

EU compliance scholarship has expanded rapidly over the last decade but has neglected the financial dimension of compliance in terms of Member States' conformity with EU financial rules on the regularity and legality of EU spending. This article makes the case for a multi‐dimensional approach to compliance research and provides the first cross‐national assessment of financial compliance in EU Cohesion policy, employing quantitative and qualitative methods. To account for cross‐national variations in the application of financial corrections for non‐compliant spending, several factors are explored, focusing on regional autonomy, administrative capacity and goodness‐of‐fit. The quantitative analysis finds strong support for the impact of administrative capacity on cross‐national compliance patterns and some evidence for the role of goodness‐of‐fit. Contrary to expectations, regional autonomy is not associated with compliance in this critical case of EU multi‐level governance. Qualitative analysis reinforces these findings while revealing additional factors of relevance.
Harmonizing Internationally to Harmonize Internally: Accounting for a Global Exit from the EU's Decision Trap
Authors: Kudrna Zdenek , Müller Patrick
Published: December 2016

The joint decision trap concept traditionally explains progress in EU policy‐making through dynamics located within the EU's multi‐level governance. Yet, with the expansion of global regulatory co‐ordination, the EU governance system increasingly interacts with policy‐making in international regimes, which influences the internal dynamics of the EU's decision‐making. This article seeks to refine the joint decision trap model by introducing global exit mechanisms and illustrating their empirical relevance for the case of accounting standards. The global exit builds on leveraging the outside benefits of global policy, the legitimacy of global standards, and new opportunities for locking in policy preferences through global commitments. Specifically, the accounting case demonstrates the Commission's strategy of ‘harmonizing globally to harmonize internally’ that produced an agreement after decades of stalemate. Moreover, it demonstrates how the global exit enables the Commission to protect internal harmonization despite the growing criticism and calls for the repatriation of regulatory sovereignty.
Estimating effects of craniofacial morphology on gingival recession and clinical attachment loss
Authors: Salti Loutfi , Holtfreter Birte , Pink Christiane , Habes Mohamad , Biffar Reiner , Kiliaridis Stavros , Krey Karl‐Friedrich , Bülow Robin , Völzke Henry , Kocher Thomas , Daboul Amro
Published: December 2016

Objectives

Evidence on possible associations between facial morphology, attachment loss and gingival recession is lacking. We analysed whether the facial type, which can be described by the ratio of facial width and length (facial index), is related to periodontal loss of attachment, hypothesizing that a broad face might be associated with less gingival recession (GR) and less clinical attachment loss (CAL) than a long face.

Materials and methods

Data from the 11‐year follow‐up of the population‐based Study of Health in Pomerania were used. Periodontal loss of attachment was assessed by GR and CAL. Linear regression models, adjusted for age and gender, were used to assess associations between specific landmark based distances extracted from magnetic resonance imaging head scans and clinically assessed GR or CAL (N = 556).

Results

Analysing all teeth, a higher maximum cranial width was associated with a lower mean GR (B = −0.016, 95% CI: −0.030; −0.003, p = 0.02) and a lower mean CAL (B = −0.023, 95% CI: −0.040; −0.005, p = 0.01). Moreover, a long narrow face was significantly associated with increased mean GR and CAL (facial index, P for trend = 0.02 and p = 0.01, respectively). Observed associations were more pronounced for incisors and canines than for premolars and molars.

Conclusion

This study revealed craniofacial morphology, specifically the cranial width and the facial index, as a putative risk factor for periodontal loss of attachment.
Metamorphic inheritance of Rheic passive margin evolution and its early‐Variscan overprint in the Teplá‐Barrandian Unit, Bohemian Massif
Authors: Peřestý V. , Lexa O. , Holder R. , Jeřábek P. , Racek M. , Štípská P. , Schulmann K. , Hacker B.
Published: December 2016

Rift‐related regional metamorphism of passive margins is usually difficult to observe on the surface, mainly due to its strong metamorphic overprint during the subsequent orogenic processes that cause its exposure. However, recognition of such a pre‐orogenic evolution is achievable by careful characterization of the polyphase tectono‐metamorphic record of the orogenic upper plate. A multidisciplinary approach, involving metamorphic petrology, P–T modelling, structural geology and in situ U‐Pb monazite geochronology using laser‐ablation split‐stream inductively coupled plasma mass spectrometry, was applied to unravel the polyphase tectono‐metamorphic record of metapelites at the western margin of the Teplá‐Barrandian domain in the Bohemian Massif. The study resulted in discovery of three tectono‐metamorphic events. The oldest event M1 is LP–HT regional metamorphism with a geothermal gradient between 30 and 50 °C km−1, peak temperatures up to 650 °C and of Cambro‐Ordovician age (c. 485 Ma). The M1 event was followed by M2‐D2, which is characterized by a Barrovian sequence of minerals from biotite to kyanite and a geothermal gradient of 20–25 °C km−1. D2‐M2 is associated with a vertical fabric S2 and was dated as Devonian (c. 375 Ma). Finally, the vertical fabric S2 was overprinted by a D3‐M3 event that formed sillimanite to chlorite bearing gently inclined fabric S3 also of Devonian age. The high geothermal gradient of the M1 event can be explained as the result of an extensional, rift‐related tectonic setting. In addition, restoration of the deep architecture and polarity of the extended domain before the Devonian history – together with the supracrustal sedimentary and magmatic record – lead us to propose a model for formation of an Ordovician passive continental margin. The subsequent Devonian evolution is interpreted as horizontal shortening of the passive margin at the beginning of Variscan convergence, followed by detachment‐accommodated exhumation of lower‐crustal rocks. Both Devonian shortening and detachment occurred in the upper plate of a Devonian subduction zone. The tectonic evolution presented in this article modifies previous models of the tectonic history of the western margin of the Teplá‐Barrandian domain, and also put constraints on the evolution of the southern margin of the Rheic ocean from the passive margin formation to the early phases of Variscan orogeny.
Cesarean Outcomes in US Birth Centers and Collaborating Hospitals: A Cohort Comparison
Authors: Thornton Patrick , McFarlin Barbara L. , Park Chang , Rankin Kristin , Schorn Mavis , Finnegan Lorna , Stapleton Susan
Published: December 2016

Introduction

High rates of cesarean birth are a significant health care quality issue, and birth centers have shown potential to reduce rates of cesarean birth. Measuring this potential is complicated by lack of randomized trials and limited observational comparisons. Cesarean rates vary by provider type, setting, and clinical and nonclinical characteristics of women, but our understanding of these dynamics is incomplete.

Methods

We sought to isolate labor setting from other risk factors in order to assess the effect of birth centers on the odds of cesarean birth. We generated low‐risk cohorts admitted in labor to hospitals (n = 2527) and birth centers (n = 8776) using secondary data obtained from the American Association of Birth Centers (AABC). All women received prenatal care in the birth center and midwifery care in labor, but some chose hospital admission for labor. Analysis was intent to treat according to site of admission in spontaneous labor. We used propensity score adjustment and multivariable logistic regression to control for cohort differences and measured effect sizes associated with setting.

Results

There was a 37% (adjusted odds ratio [OR], 0.63; 95% confidence interval [CI], 0.50‐0.79) to 38% (adjusted OR, 0.62; 95% CI, 0.49‐0.79) decreased odds of cesarean in the birth center cohort and a remarkably low overall cesarean rate of less than 5% in both cohorts.

Discussion

These findings suggest that low rates of cesarean in birth centers are not attributable to labor setting alone. The entire birth center care model, including prenatal preparation and relationship‐based midwifery care, should be studied, promoted, and implemented by policy makers interested in achieving appropriate cesarean rates in the United States.
Docosahexaenoic acid up‐regulates both PI3K/AKT‐dependent FABP7–PPARγ interaction and MKP3 that enhance GFAP in developing rat brain astrocytes
Authors: Tripathi Sachin , Kushwaha Rajesh , Mishra Juhi , Gupta Manoj Kumar , Kumar Harish , Sanyal Somali , Singh Dhirendra , Sanyal Sabyasachi , Sahasrabuddhe Amogh Anant , Kamthan Mohan , Mudiam Mohana Krishna Reddy , Bandyopadhyay Sanghamitra
Published: December 2016

The astrocyte marker, glial fibrillary acidic protein (GFAP), has essential functions in the brain, but may trigger astroglial scarring when expressed in excess. Docosahexaenoic acid (DHA) is an n‐3 fatty acid that is protective during brain development. However, the effect of DHA on GFAP levels of developing brain remains unexplored. Here, we detected that treating developing rats with DHA‐enriched fish‐oil caused dose‐dependent GFAP augmentation. We investigated the mechanism promoting GFAP, hypothesizing the participation of fatty acid‐binding protein‐7 (FABP7), known to bind DHA. We identified that DHA stimulated FABP7 expression in astrocytes, and FABP7‐silencing suppressed DHA‐induced GFAP, indicating FABP7‐mediated GFAP increase. Further investigation proved FABP7 expression to be phosphatidylinositide 3‐kinases (PI3K)/AKT and nuclear receptor peroxisome proliferator‐activated receptor‐gamma (PPARγ)‐dependent. We found that PI3K/AKT activated PPARγ that triggered FABP7 expression via PPARγ‐responsive elements within its gene. Towards identifying FABP7‐downstream pathways, we considered our previous report that demonstrated cyclin‐dependent kinase‐5 (CDK5)‐PPARγ‐protein–protein complex to suppress GFAP. We found that the DHA‐induced FABP7 underwent protein‐protein interaction with PPARγ, which impeded CDK5‐PPARγ formation. Hence, it appeared that enhanced FABP7‐PPARγ in lieu of CDK5‐PPARγ resulted in increased GFAP. PI3K/AKT not only stimulated formation of FABP7‐PPARγ protein‐protein complex, but also up‐regulated a FABP7‐independent MAP‐kinase‐phosphatase‐3 pathway that inactivated CDK5 and hence attenuated CDK5‐PPARγ. Overall, our data reveal that via the proximal PI3K/AKT, DHA induces FABP7‐PPARγ, through genomic and non‐genomic mechanisms, and MAP‐kinase‐phosphatase‐3 that converged at attenuated CDK5‐PPARγ and therefore, enhanced GFAP. Accordingly, our study demonstrates a DHA‐mediated astroglial hyperactivation, pointing toward a probable injurious role of DHA in brain development.

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Dopamine‐dependent effects on basal and glutamate stimulated network dynamics in cultured hippocampal neurons
Authors: Li Yan , Chen Xin , Dzakpasu Rhonda , Conant Katherine
Published: December 2016

Oscillatory activity occurs in cortical and hippocampal networks with specific frequency ranges thought to be critical to working memory, attention, differentiation of neuronal precursors, and memory trace replay. Synchronized activity within relatively large neuronal populations is influenced by firing and bursting frequency within individual cells, and the latter is modulated by changes in intrinsic membrane excitability and synaptic transmission. Published work suggests that dopamine, a potent modulator of learning and memory, acts on dopamine receptor 1‐like dopamine receptors to influence the phosphorylation and trafficking of glutamate receptor subunits, along with long‐term potentiation of excitatory synaptic transmission in striatum and prefrontal cortex. Prior studies also suggest that dopamine can influence voltage gated ion channel function and membrane excitability in these regions. Fewer studies have examined dopamine's effect on related endpoints in hippocampus, or potential consequences in terms of network burst dynamics. In this study, we record action potential activity using a microelectrode array system to examine the ability of dopamine to modulate baseline and glutamate‐stimulated bursting activity in an in vitro network of cultured murine hippocampal neurons. We show that dopamine stimulates a dopamine type‐1 receptor‐dependent increase in number of overall bursts within minutes of its application. Notably, however, at the concentration used herein, dopamine did not increase the overall synchrony of bursts between electrodes. Although the number of bursts normalizes by 40 min, bursting in response to a subsequent glutamate challenge is enhanced by dopamine pretreatment. Dopamine‐dependent potentiation of glutamate‐stimulated bursting was not observed when the two modulators were administered concurrently. In parallel, pretreatment of murine hippocampal cultures with dopamine stimulated lasting increases in the phosphorylation of the glutamate receptor subunit GluA1 at serine 845. This effect is consistent with the possibility that enhanced membrane insertion of GluAs may contribute to a more slowly evolving dopamine‐dependent potentiation of glutamate‐stimulated bursting. Together, these results are consistent with the possibility that dopamine can influence hippocampal bursting by at least two temporally distinct mechanisms, contributing to an emerging appreciation of dopamine‐dependent effects on network activity in the hippocampus.

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Efficacy of a single 40‐mg intravenous dose of parecoxib for postoperative pain control after elective cesarean delivery: A double‐blind randomized placebo‐controlled trial
Authors: Inthigood Nittaya , Lertbunnaphong Tripop , Jaishuen Atthapon
Published: December 2016

Aim

The aim of this study was to determine the efficacy of a single 40‐mg intravenous (i.v.) dose of parecoxib as an adjunctive analgesia to intrathecal morphine after elective cesarean delivery (CD).

Methods

A total of 82 low‐risk term pregnant women who were scheduled for elective CD during the June 2014–June 2015 study period were enrolled. Two hours after surgery, subjects were randomly assigned to receive either i.v. injection of 2 mL (40 mg) parecoxib (study group; n = 41) or 2 mL normal saline solution (control group; n = 41). Patient randomization into groups was determined by the hospital's central computer system. Outcome measurements included total postoperative supplemental meperidine consumption, recorded pain score by numeric pain rating scale at 6, 12, 18, and 24 h, postoperatively, and patient satisfaction.

Results

Patient characteristics and pregnancy outcomes were comparable between groups. Total postoperative meperidine consumption was not significantly different between groups (12.7 ± 18.8 mg vs 8.3 ± 16.7 mg; P > 0.05). Compared with control, the study group was significantly less likely to experience moderate to severe postoperative pain (score ≥ 4) at 6 h (0% vs 21.9%; P = 0.002). Study group patients reported higher satisfaction than control group patients (median score: 8 vs 6; P < 0.01). No patients in either group reported adverse effects from their assigned intervention.

Conclusion

Parecoxib did not demonstrate effectiveness in reducing patient requirement for supplementary meperidine after CD. However, administration of a single 40‐mg dose of i.v. parecoxib after elective CD demonstrated effectiveness in reducing pain scores, with a resulting increase in patient satisfaction.
Germination of sorghum grain results in significant changes in paste and texture properties
Authors: Yi Cuiping , Li Yan , Ping Junai
Published: December 2016

The changes in sorghum [Sorghum bicolor (L.) Moench] proteins during germination and the resultant effects on the physicochemical properties of sorghum flour were studied using non‐germinated grains as a control. Results showed that flour obtained from germinated sorghum grains had lower protein levels, higher protease levels, and higher free amino nitrogen content compared with the control. There was an increase in the albumin and globulin protein fractions and a decrease in kafirin. Sodium dodecyl sulfate‐polyacrylamide gel electrophoresis analysis indicated that this decrease was the result of a decrease in γ‐kafirins, while microscopy found that a continuous protein network was formed. Following the germination‐associated protein changes, the viscosities of sorghum paste decreased with germination from a peak viscosity value of 1,324 rapid visco units (RVU) down to 727 RVU in white sorghum (WS), and from 1,549 RVU to 1,295 RVU in red sorghum (RS). The hardness of the sorghum gels was significantly enhanced after germination, with WS increasing from 1,640 g to 5,374 g and RS from 970 g to 5,529 g. Thus, the study revealed that germination decreased the viscosity of sorghum paste and increased the strength of sorghum gel by changing the content and structure of sorghum protein, making it possible to design new foods that require thickening and gelling using germinated sorghum.

Practical applications

Germination triggers the protease system of sprouting seeds, leading to the breakdown of proteins into simpler forms that decrease the viscosity of sorghum paste and improve the strength of sorghum gel, allowing the use of germinated sorghum to design new foods that require thickening and gelling.
Effects of chicken by‐product gelatin on the physicochemical properties and texture of chocolate spread
Authors: Almeida Poliana Fernandes , Lannes Suzana Caetano da Silva
Published: December 2016

Chocolate spread has a fat‐based formulation and the application of gelatin as a fat replacement is related to the demand for healthier foods. The aim of this study was to evaluate the influence of gelatin as a by‐product from the poultry industry in the fat replacement of chocolate spread. Vegetable fat was replaced (15, 25, 50, 75, and 100%) with gelatin (0.3, 0.5, 0.8, 1.0, and 1.2%) using a central composite rotatable design and the effects were evaluated by a response surface methodology. Formulations with a greater proportion of fat were lighter, of higher volume and lower density. As expected, water activity was intensified in low‐fat formulations. The consistency was controlled mainly by the properties of the gelatin phase. The formulations with 50 and 75% fat replacement and 0.5–1.0% gelatin had satisfactory spreadability at 10C. All formulations were spreadable at 20C. Low‐fat samples with low gelatin concentrations, at 30C, had very low consistency. Statistically, the properties were significantly influenced by the factors analyzed according to the mathematical models.

Practical applications

Although several studies have been conducted on obtaining alternative gelatin sources for mammals, the extracted gelatin from poultry by‐product is still little explored and the knowledge on the application in food products, particularly in complex systems such as emulsions, has not been well established. The development of a low‐fat food should take into account the complexity of the system involved, such as the emulsion spreads. The incorporation of gelatin in aqueous solution is a challenging task because the physical properties and the rheological behavior can be strongly influenced. Given the nutritional and functional properties of the gelatin and chocolate and its wide acceptability among the consumers, the incorporation of these two ingredients in the development of a new product sets up a promising study.
Epigenetic analysis of the IFNλ3 gene identifies a novel marker for response to therapy in HCV‐infected subjects
Authors: Waring J. F. , Davis J. W. , Dumas E. , Cohen D. , Idler K. , Abel S. , Georgantas R. , Podsadecki T. , Dutta S.
Published: December 2016

Chronic hepatitis C virus (HCV) infection is characterized by high interindividual variability in response to pegylated interferon and ribavirin. A genetic polymorphism on chromosome 19 (rs12979860) upstream of interferon‐λ3 (IFNλ3) is associated with a twofold change in sustained virologic response rate after 48 weeks of treatment with pegylated interferon/ribavirin in HCV genotype 1 (GT1) treatment‐naïve patients. We conducted epigenetic analysis on the IFNλ3 promoter to investigate whether DNA methylation is associated with response to HCV therapy. DNA samples from HCV GT1‐infected subjects receiving an interferon‐free paritaprevir‐containing combination regimen (N=540) and from HCV‐uninfected, healthy controls (N=124) were analysed for IFNλ3 methylation levels. Methylation was strongly associated with rs12979860 allele status whether adjusting for HCV status (r=65.0%, 95% CI: [60.2%, 69.5%]), or not (r=64.4%), both with P<2.2×10−16. In HCV GT1‐infected subjects, C/C genotypes had significantly lower methylation levels relative to C/T or T/T genotypes (P<1×10−14), with each T allele resulting in a nine‐unit increase in mean methylation level. Methylation levels did not correlate with response in subjects treated for 12 or 24 weeks. However, non‐C/C subjects with higher methylation levels were more likely to relapse when treatment duration was 8 weeks. This analysis suggests that methylation status of the IFNλ3 promoter region may be a useful parameter that identifies patients more likely to relapse following HCV therapy; however, continuing therapy for a sufficient duration can overcome this difference. These findings may provide mechanistic insight into the role of IFNλ3 genetic variants in HCV treatment response.
Microvessels of the heart: Formation, regeneration, and dysfunction
Authors: Spyridopoulos Ioakim , Arthur Helen M.
Published: December 2016

This issue of microcirculation focusses on the special topic of “microvessels of the heart” and contains five state‐of‐the‐art reviews and one expert article that reflect current efforts to address the major gaps in our understanding of these key microvessels. In the adult heart, most attention until recently (especially among the clinical cardiology community) has been given to the main coronary arteries, which are the culprit vessels in patients with coronary artery disease, including its most serious manifestation, acute MI. However, due to major advances in efficiently reopening the acutely blocked coronary arteries, MI is no longer the killer disease it once was. In contrast, there are few treatment options for patients who develop microvascular obstruction during acute MI. Indeed, we have a very poor understanding of this disease, or even how heart vessels are initially formed in development. This is surprising in light of the essential nature of the cardiac microvessels for efficient cardiac function throughout life. The articles in this issue are from six keynote speakers at the 66th annual meeting of the BMS at Newcastle University and review our understanding of these key vessels from initial development to their role in adult heart disease.
Conventional and unconventional ubiquitination in plant immunity
Authors: Zhou Bangjun , Zeng Lirong
Published: December 2016

Ubiquitination is one of the most abundant types of protein post‐translational modification (PTM) in plant cells. The importance of ubiquitination in the regulation of many aspects of plant immunity has been increasingly appreciated in recent years. Most of the studies linking ubiquitination to the plant immune system, however, have been focused on the E3 ubiquitin ligases and the conventional ubiquitination that leads to the degradation of the substrate proteins by the 26S proteasome. By contrast, our knowledge about the role of unconventional ubiquitination that often serves as non‐degradative, regulatory signal remains a significant gap. We discuss, in this review, the recent advances in our understanding of ubiquitination in the modulation of plant immunity, with a particular focus on the E3 ubiquitin ligases. We approach the topic from a perspective of two broadly defined types of ubiquitination in an attempt to highlight the importance, yet current scarcity, in our knowledge about the regulation of plant immunity by unconventional ubiquitination.
Diabetes mellitus, superoxide dismutase and peroxisome proliferator activated receptor gamma polymorphisms modify the outcome of end‐stage renal disease patients of Han Chinese origin
Authors: Chao Chia‐Ter , Huang Jenq‐Wen , Chiang Chih‐Kang , Chen Yen‐Ching , Fang Cheng‐Chung , Hu Fu‐Chang , Chang Chen‐Chih , Yen Chung‐Jen
Published: December 2016

Aim

Increased oxidative stress significantly modifies the outcome of patients with diabetes mellitus (DM) and end‐stage renal disease (ESRD), and is counteracted by antioxidative capacity. We aimed to investigate whether antioxidant single nucleotide polymorphisms (SNPs) influence the outcome of ESRD individuals and the influences exerted by DM, which has not been tested before.

Methods

We prospectively enrolled multi‐centre ESRD patients of Han Chinese origin between 2002 and 2003, recording their antioxidant (superoxide dismutase [SOD2], glutathione peroxidase [GPX1]) and peroxisome proliferator activated receptor‐γ (PPAR‐γ) genotyping results, and stratified based on DM. They were followed up until 2008, with risk factors for mortality analyzed by Cox proportional hazard regression.

Results

We discovered that diabetic ESRD carriers of CC genotype of SOD2 exon 2 had an increased risk of mortality compared to non‐diabetic ones with other genotypes (hazard ratio [HR] 4.04, P = 0.04), while GPX1 SNPs had no influence. Interactions between SOD2 and PPAR‐γ SNPs regarding the mortality influence were also detected (for SOD2 CC genotype x PPAR‐γ exon 6 CT genotype, HR 3.19, P = 0.008), suggesting the importance of considering a combination panel of SNPs on patient survival.

Conclusion

This might be the largest study focusing on the relationship between antioxidant SNPs and the outcomes of diabetic ESRD patients of Han Chinese origin. More studies are needed to validate our findings.
Schwannoma‐like tumor in the anterior cranial fossa immunonegative for Leu7 but immunopositive for Schwann/2E
Authors: Bohoun Christian Aïssè , Terakawa Yuzo , Goto Takeo , Tanaka Sayaka , Kuwae Yuko , Ohsawa Masahiko , Morisako Hiroki , Nakajo Kosuke , Sato Hidetoshi , Ohata Kenji , Yokoo Hideaki
Published: December 2016

Schwannoma arising from the olfactory system, often called olfactory groove schwannoma (OGS), is rare, as the olfactory bulb and tract, belonging to the central nervous system, should lack Schwann cells. Another rare entity called olfactory ensheathing cell tumor (OECT) has been reported, which mimics clinical and radiological characteristics of OGS. Here, we report two rare cases of schwannoma‐like tumor in the anterior cranial fossa that showed negative staining for Leu7, but positive staining for Schwann/2E, and discuss their origin. Two cases of mass lesions in the anterior cranial fossa in a 26‐year‐old man and a 24‐year‐old woman were successfully removed. Morphological examination of these tumors was compatible with a diagnosis of schwannoma. Immunohistochemically, both cases were negative for Leu7, yielding a diagnosis of OECT, but were positive for the schwannoma‐specific marker, Schwann/2E. Immunohistochemical staining results in our two cases question the current assumption that OGS and OECT can be distinguished only by Leu7 staining pattern. In conclusion, the origins of OGS and OECT remain to be determined, and further studies in larger numbers of cases are needed to characterize these rare tumors in the anterior cranial fossa.
Leaf gas films contribute to rice (Oryza sativa) submergence tolerance during saline floods
Authors: Herzog Max , Konnerup Dennis , Pedersen Ole , Winkel Anders , Colmer Timothy David
Published: December 2016

Floods and salinization of agricultural land adversely impact global rice production. We investigated whether gas films on leaves of submerged rice delay salt entry during saline submergence. Two‐week‐old plants with leaf gas films (+GF) or with gas films experimentally removed (−GF) were submerged in artificial floodwater with 0 or 50 mm NaCl for up to 16 d. Gas films were present >9 d on GF plants after which gas films were diminished. Tissue ion analysis (Na+, Cl− and K+) showed that gas films caused some delay of Na+ entry, as leaf Na+ concentration was 36–42% higher in −GF leaves than +GF leaves on days 1–5. However, significant net uptakes of Na+ and Cl−, and K+ net loss, occurred despite the presence of gas films, indicating the likely presence of some leaf‐to‐floodwater contact, so that the gas layer must not have completely separated the leaf surfaces from the water. Natural loss and removal of gas films resulted in severe declines in growth, underwater photosynthesis, chlorophylla and tissue porosity. Submergence was more detrimental to leaf PN and growth than the additional effect of 50 mm NaCl, as salt did not significantly affect underwater PN at 200 μm CO2 nor growth.
Herbivore perception decreases photosynthetic carbon assimilation and reduces stomatal conductance by engaging 12‐oxo‐phytodienoic acid, mitogen‐activated protein kinase 4 and cytokinin perception
Authors: Meza‐Canales Ivan D. , Meldau Stefan , Zavala Jorge A. , Baldwin Ian T.
Published: December 2016

Herbivory‐induced changes in photosynthesis have been documented in many plant species; however, the complexity of photosynthetic regulation and analysis has thwarted progress in understanding the mechanism involved, particularly those elicited by herbivore‐specific elicitors. Here, we analysed the early photosynthetic gas exchange responses in Nicotiana attenuata plants after wounding and elicitation with Manduca sexta oral secretions and the pathways regulating these responses. Elicitation with M. sexta oral secretions rapidly decreased photosynthetic carbon assimilation (AC) in treated and systemic (untreated, vascularly connected) leaves, which were associated with changes in stomatal conductance, rather than with changes in Rubisco activity and 1‐5 ribulose‐1,5‐bisphosphate turnover. Phytohormone profiling and gas exchange analysis of oral secretion‐elicited transgenic plants altered in phytohormone regulation, biosynthesis and perception, combined with micrografting techniques, revealed that the local photosynthetic responses were mediated by 12‐oxo‐phytodienoic acid, while the systemic responses involved interactions among jasmonates, cytokinins and abscisic acid signalling mediated by mitogen‐activated protein kinase 4. The analysis also revealed a role for cytokinins interacting with mitogen‐activated protein kinase 4 in CO2‐mediated stomatal regulation. Hence, oral secretions, while eliciting jasmonic acid‐mediated defence responses, also elicit 12‐oxo‐phytodienoic acid‐mediated changes in stomatal conductance and AC, an observation illustrating the complexity and economy of the signalling that regulates defence and carbon assimilation pathways in response to herbivore attack.
Insights into Light‐driven DNA Repair by Photolyases: Challenges and Opportunities for Electronic Structure Theory
Authors: Faraji Shirin , Dreuw Andreas
Published: December 2016

Ultraviolet radiation causes two of the most abundant mutagenic and cytotoxic DNA lesions: cyclobutane pyrimidine dimers and 6‐4 photoproducts. (6‐4) Photolyases are light‐activated enzymes that selectively bind to DNA and trigger repair of mutagenic 6‐4 photoproducts via photoinduced electron transfer from flavin adenine dinucleotide anion (FADH−) to the lesion triggering repair. This review provides an overview of the sequential steps of the repair process, that is light absorption and resonance energy transfer, photoinduced electron transfer and electron‐induced splitting mechanisms, with an emphasis on the role of theory and computation. In addition, theoretical calculations and physical properties that can be used to classify specific mechanism are discussed in an effort to trace the fundamental aspects of each individual step and assist the interpretation of experimental data. The current challenges and suggested future directions are outlined for each step, concluding with a view on the future.
Conformational and Intermolecular Interaction Dynamics of Photolyase/Cryptochrome Proteins Monitored by the Time‐Resolved Diffusion Technique
Authors: Kondoh Masato , Terazima Masahide
Published: December 2016

Cryptochrome (CRY), a blue light sensor protein, possesses a similar domain structure to photolyase (PHR) that, upon absorption of light, repairs DNA damage. In this review, we compare the reaction dynamics of these systems by monitoring the reaction kinetics of conformational change and intermolecular interaction change based on time‐dependent diffusion coefficient measurements obtained by using the pulsed laser‐induced transient grating technique. Using this method, time‐dependent biomolecular interactions, such as transient dissociation reactions in solution, have been successfully detected in real time. Conformational change in (6‐4) PHR has not been detected after the photoexcitation by monitoring the diffusion coefficient. However, the repaired DNA dissociates from PHR with a time constant of 50 μs, which must relate to a minor conformational change. However, CRY exhibits a considerable diffusion change with a time constant of 400 ms, which indicates that the protein–solvent interaction is changed by the conformational change. The C‐terminal domain of CRY is shown to be responsible for this change.
A new device to inseminate cows at the base of the uterine horns
Authors: García‐Peña O , Rangel‐Santos R , Rodríguez‐De Lara R , Apodaca‐Sarabia CA , Maldonado‐Simán E
Published: December 2016

Content

A new device (Chapingo device) to deposit semen at the base of the uterine horns of cattle was developed at Universidad Autonoma Chapingo, Mexico. Nine Holstein heifers were inseminated by transvaginal laparoscopy, using a laparoscope for cattle and the Chapingo device. A dose of sexed semen (2.1 × 106 spermatozoa) was deposited at the base of the uterine horn ipsilateral to the ovary where the preovulatory follicle was identified. Insemination was achieved in all the heifers, taking on average 13.7 ± 3.1 min per animal. In all cases, it was possible to see both ovaries, the base of the uterine horns and the oviducts. After the procedure, none of the heifers showed any type of complications such as haemorrhage, adhesions or trauma. On days 21 and 22 after insemination, four of the nine heifers (44.4%) returned into oestrus; on day 30 after insemination, one heifer was found to be pregnant by ultrasound. The results show the feasibility of generating pregnancies by transvaginal laparoscopy in heifers inseminated with sexed semen.
Isolation, proliferation and characterization of endometrial canine stem cells
Authors: De Cesaris V , Grolli S , Bresciani C , Conti V , Basini G , Parmigiani E , Bigliardi E
Published: December 2016

Contents

In the last decade, progenitor cells isolated from dissociated endometrial tissue have been the subject of many studies in several animal species. Recently, endometrial cells showing characteristics of mesenchymal stem cells (MSC) have been demonstrated in human, pig and cow uterine tissue samples. The aim of this study was the isolation and characterization of stromal cells from the endometrium of healthy bitches, a tissue that after elective surgery is routinely discarded. Multipotent stromal cells could be isolated from all bitches enrolled in the study (n = 7). The multipotency of cells was demonstrated by their capacity to differentiate into adipocytic, osteocytic and chondrocytic lineages. Clonogenicity and cell proliferation ability were also tested. Furthermore, gene expression analysis by RT‐PCR was used to compare the expression of a set of genes (CD44, CD29, CD34, CD45, CD90, CD13, CD133, CD73, CD31 CD105, Oct4) with adipose tissue‐derived MSC. Stromal cells isolated from uterine endometrium showed similar morphology, ability of subculture and plasticity, and also expressed a panel of genes comparable with adipose tissue‐derived MSC. These data suggest that endometrial stromal cells fulfil the basic criteria proposed by the “Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy” for the identification of mesenchymal stem cells. Although endometrial mesenchymal stem cells (EnMSC) showed a lower replicative ability in comparison with adipose tissue‐derived MSC, they could be considered a cell therapeutic agent alternative to adipose tissue or bone marrow‐derived MSC in dog.
Evaluation of epididymis storage temperature and cryopreservation conditions for improved mitochondrial membrane potential, membrane integrity, sperm motility and in vitro fertilization in bovine epididymal sperm
Authors: Nichi M , Rijsselaere T , Losano JDA , Angrimani DSR , Kawai GKV , Goovaerts IGF , Van Soom A , Barnabe VH , De Clercq JBP , Bols PEJ
Published: December 2016

Contents

The maintaining of the epididymis at lower temperatures during storage and transport improves sperm quality. Our study aimed to test whether epididymis storage temperature (post‐mortem) and sperm cryopreservation affect sperm kinetics, membrane integrity, mitochondrial potential and fertility capacity. Thirty‐six epididymides were collected from 18 bulls after slaughter and divided into two groups: at 4 or 34°C for 2–3 hr. The sperm was collected from the epididymis cauda. The evaluation consisted of computer‐assisted sperm analysis (CASA), SYBR14/PI/JC1 to evaluate membrane integrity, mitochondrial membrane potential (MMP) and measurement of lipid peroxidation (TBARS). The sperm was then frozen using an automatic device. After thawing, sperm samples were evaluated by the same variables and further in vitro fertilization rates. Cryopreservation negatively affected sperm motility in samples stored at 4 and 34°C. Nevertheless, the 4°C samples yielded higher rates of blastocyst formation. Pre‐freeze sperm motility, progressive motility and velocity were higher in sperm from epididymis stored at 4°C while post‐thaw sperm motility, progressive motility and velocity remained the same among samples from epididymis stored at 4 or 34°C. However, with regard to the kinetic patterns, samples collected from epididymis stored at 34°C had lower values when compared to those stored at 4°C prior the cryopreservation process. Our results indicate that epididymis handling conditions after cryopreservation may affect sperm quality after thawing, especially due to compromised MMP in sperm collected from epididymis stored at higher temperatures.
A novel HLA allele, HLA‐B*50:48, identified by sequencing‐based typing
Authors: Gama T. F. K. , Fabreti‐Oliveira R. A. , Souza P. A M. , Nascimento E.
Published: December 2016

The HLA‐B*50:48 allele differs from HLA‐B*50:01:01 by one nucleotide substitution at position 130.
A kidney transplant recipient with renal medullary viral cytopathic changes
Authors: Ramanan Poornima , Timmerman Elizabeth A. , Fidler Mary E. , Amer Hatem , Pritt Bobbi S. , Schwab Dale A. , Batterman Hollis J. , Binnicker Matthew J.
Published: December 2016

We present a case of JC polyomavirus (JCV)‐associated nephropathy (PyVAN) in an asymptomatic deceased‐donor kidney transplant recipient. Despite the presence of viral cytopathic effect in the kidney biopsy and positive BK polyomavirus (BKV) in situ hybridization (ISH), BKV real‐time polymerase chain reaction (PCR) results of plasma and urine were negative. JCV ISH was performed and was found to be positive. JCV real‐time PCR on urine, plasma, and the kidney biopsy tissue was positive. Reduction in immunosuppression resulted in resolution of JCV viremia. This case highlights that JC‐PyVAN is a distinct clinical entity and is likely to have a better clinical outcome than BK‐PyVAN. Concurrent infection with BKV and JCV may occur, but may be difficult to confirm due to the potential for cross‐reactivity between BKV and JCV ISH stains.
Domesticating transnational education: discourses of social value, self‐worth and the institutionalisation of failure in ‘meritocratic’ Hong Kong
Authors: Waters Johanna L , Leung Maggi W H
Published: December 2016

This paper explores the changing spatialities of education in response to processes of internationalisation, through the lens of transnational education (TNE). It argues that rather than producing outward‐looking education, international credentials are becoming ‘domesticated’ – that is, they form an indistinguishable feature of existing local education systems. The paper explores the importance of discourses of meritocracy and the production of value (suzhi) in East Asian societies and how TNE fits into a wider ideological system of biopolitical governance, for which examinations represent a key technology. It demonstrates, through data collected from interviews with students in Hong Kong, the ways in which young people have internalised their own identities as failures and argues that studying for a transnational qualification serves only to accentuate this subject positioning. We also uncover some counter‐narratives to dominant discourses, or examples of ‘biopolitics from below’, where nascent political identities were expressed by some individuals. These exceptions offered some exciting possibilities for an alternative existence – such that the majority of young people, as well as a more privileged minority, are able to escape the damaging classification imposed by the pathologising of educational failure. The paper concludes with some reflections on why a more expansive definition of international education is now required, one that not only takes account of the spatial extension that occurs through internationalisation, but is also sensitive to domestication, and the profound ways in which foreign credentials are being enlisted in wider governance projects within their host communities.