bluuebunny/crossref_metadata_2025 huggingface dataset:
Debtholders’ Demand for Conservatism: Evidence from Changes in Directors’ Fiduciary Duties
Authors: AIER JAGADISON K. , CHEN LONG , PEVZNER MIKHAIL
Published: September 2014

Debtholders’ demand has been widely discussed as a key determinant of conservatism but clear causal evidence is not yet established. Using a natural experiment setting, wherein a Delaware court ruled that the fiduciary duties of directors in near insolvent Delaware companies extend to creditors, we predict and find that firms subject to the ruling significantly increased their accounting conservatism. In addition, our results suggest that the increase in conservatism is more pronounced in near insolvent Delaware firms with stronger boards, confirming that the court ruling takes effect through the channel of the board of directors. Our results are robust to using alternative measures of conservatism and near insolvency status, and controlling for potential confounding factors and other stakeholders’ demand for conservatism. Overall, our study provides empirical evidence to support the causal relation between debtholders’ demand and accounting conservatism previously suggested in the literature, and offers some insights into the role of the board of directors in financial reporting.
New dual therapy for primary treatment of Helicobacter pylori infection: A prospective randomized study in Shanghai, China
Authors: Ren Ling , Lu Hong , Li Hai Yan , Zhu Ling Yin , Xu Xiao Qing , Gu Li Yang , Ge Zhi Zheng , Li Xiao Bo
Published: September 2014

Objective

To evaluate the eradication rates, side effects and the patient compliance of a dual therapy with rabeprazole and amoxicillin as the first‐line therapy in patients with Helicobacter pylori (H. pylori) infection.

Methods

A total of 120 patients diagnosed endoscopically with non‐ulcer dyspepsia with H. pylori infection were randomly assigned into two groups, one treated with amoxicillin 1 g thrice daily plus rabeprazole 10 mg twice daily (R10A group) or 20 mg twice daily (R20A group) for 14 days. H. pylori eradication was evaluated by 13C‐urea breath test (UBT) at 4–6 weeks after the completion of treatment. H. pylori eradication rate was analyzed by per‐protocol (PP) and intention‐to‐treat (ITT) analyses together with 95% confidence interval (CI). Side effects and patients' compliance were also recorded.

Results

Overall, 117 patients (58 in the R10A group and 59 in the R20A group) completed the study, among whom five did not undertake the UBT. H. pylori eradication was achieved in 89.8% of patients in the R20A group by ITT analysis and 93.0% by PP analysis, which was significantly higher than those in the R10A group (75.9% and 80.0%, respectively, P < 0.05). Side effects, including skin rash, abdominal discomfort, headache, insomnia and nausea, were all mild and were treated symptomatically without the need to discontinue the treatment.

Conclusion

The modified dual therapy with high doses of rabeprazole and amoxicillin is considered an effective and safe primary therapy for H. pylori eradication and could be recommended as the first‐line eradication regimen for certain patients.
Influence of different image‐guided tracking methods upon the local efficacy of CyberKnife treatment in lung tumors
Authors: Guo Yihang , Zhuang Hongqing , Zhao Lujun , Yuan Zhiyong , Wang Ping
Published: September 2014

Background

The aim of this study was to explore the influence of image‐guided tumor localization modality (Synchrony tracking vs. Xsight spine‐based localization) on the local efficacy of CyberKnife treatment in lung cancer and lung metastases.

Methods

Retrospective analysis of 64 patients with pulmonary metastases and primary tumor cases (72 targets) treated with stereotactic body radiotherapy using CyberKnife was conducted. Synchrony respiratory tracking was used to treat 45 targets, and the remaining 27 targets were treated using Xsight spine (with an extended margin to account for positional uncertainty). The median (80%) isodose line (70–94%) covered the planning target volume at a total dose of 6000 cGy delivered in three fractions. Local efficacy was evaluated by Response Evaluation Criteria in Solid Tumors, accompanied by the follow‐up of local recurrence cases and analysis of tracking methods.

Results

Short‐term local control was superior for targets tracked with Synchrony than for targets localized with Xsight spine. There was no statistical difference for targets in the upper lung, but for targets in the lower lung Synchrony tracking was better. Small targets (less than 15 mL) were better controlled when Synchrony was used, but there was no difference for treatment volumes larger than 15 mL. Treatment failures were more likely in the lower lung and for small tumors localized with Xsight spine.

Conclusions

The local efficacy of CyberKnife treatment in lung cancer and lung metastases was influenced by image‐guided localization method, target location within the lung, and tumor volume.
Edge effects across boundaries between natural and restored jarrah (Eucalyptus marginata) forests in south‐western Australia
Authors: Craig Michael D. , Stokes Vicki L. , Hardy Giles E. StJ. , Hobbs Richard J.
Published: September 2014

Edge effects are a widespread and ubiquitous ecological phenomenon, yet they remain poorly studied across edges between restored and natural forests. To address this lack of knowledge, we studied vertebrate communities across edges between 3‐year old restored mine‐pits and adjacent unmined forest in the jarrah (Eucalyptus marginata) forest of south‐western Australia. We found that mammal communities showed no edge response but reptile communities did. Overall reptile abundance and Morethia obscura abundance were higher in unmined forest along edges, Egernia napoleonis abundance was lower in unmined forest along edges, while Pogona minor abundance was lower in restored mine‐pits along edges. Predictive models were unable to predict species edge responses, due to the lack of knowledge of the ecology of jarrah forest reptiles, but proved useful in identifying potential ecological mechanisms behind observed edge responses and suggested that potential mechanisms were likely different for each species. Our study is the first to show edge responses in both habitats forming the edge between restored and natural forests, emphasizing the importance of studying both habitats forming the edge. Our results also suggest that, despite being poorly studied, edge responses are common across edges between restored and natural forest and result from a variety of ecological mechanisms. An increased understanding of the ecological mechanisms driving edge responses across edges between restored and natural forests will improve our ability to integrate restored areas into cross‐landscape management and, ultimately, improve our ability to manage landscapes for biodiversity conservation.
Stable isotopes reveal regional movement patterns in an endangered bustard
Authors: Shaw Jessica M. , Ryan Peter G.
Published: September 2014

Stable isotope analysis is a valuable technique to infer animal movement between isotopically distinct landscapes. For birds in terrestrial systems, it is usually only applied at continental scales, often relying on global isotopic patterns. In contrast, we used this technique to investigate movement patterns of Ludwig's bustard (Neotis ludwigii) at a regional scale, where such information is needed to improve the conservation status of this species. We analysed carbon and nitrogen isotopic compositions of feathers from bustards across two biomes of the semi‐arid rangelands of the Karoo, South Africa, to investigate movement and explore sex and age movement strategy differences. We used a linear discriminant function analysis based on growing feathers to classify fully grown feathers to a Succulent or Nama Karoo biome origin. Six of 12 birds for which all primary feathers were analysed had at least one feather classified as having grown in the Succulent Karoo, supporting the theory that these birds are partial migrants. Feathers from two satellite‐tracked bustards broadly supported the conclusions of the analysis, although food base differences resulting from local rainfall variation probably obscured geographic signals at finer scales. There was no apparent difference in movement strategies between the sexes, but juvenile feathers were almost exclusively assigned to the Nama Karoo, suggesting that most breeding occurs in this biome. Adult and juvenile feathers also had significantly different isotope ratios, which could relate to diet or to differing metabolic processes. This study demonstrates that with a good understanding of the system, carbon and nitrogen stable isotopes can be useful to infer general movement patterns of birds at a regional level.
Y chromosome haplotype diversity of domestic sheep (Ovis aries) in northern Eurasia
Authors: Zhang Min , Peng Wei‐Feng , Yang Guang‐Li , Lv Feng‐Hua , Liu Ming‐Jun , Li Wen‐Rong , Liu Yong‐Gang , Li Jin‐Quan , Wang Feng , Shen Zhi‐Qiang , Zhao Sheng‐Guo , Hehua EEr , Marzanov Nurbiy , Murawski Maziek , Kantanen Juha , Li Meng‐Hua
Published: September 2014

Variation in two SNPs and one microsatellite on the Y chromosome was analyzed in a total of 663 rams representing 59 breeds from a large geographic range in northern Eurasia. SNPA‐oY1 showed the highest allele frequency (91.55%) across the breeds, whereas SNPG‐oY1 was present in only 56 samples. Combined genotypes established seven haplotypes (H4, H5, H6, H7, H8, H12 and H19). H6 dominated in northern Eurasia, and H8 showed the second‐highest frequency. H4, which had been earlier reported to be absent in European breeds, was detected in one European breed (Swiniarka), whereas H7, which had been previously identified to be unique to European breeds, was present in two Chinese breeds (Ninglang Black and Large‐tailed Han), one Buryatian (Transbaikal Finewool) and two Russian breeds (North Caucasus Mutton‐Wool and Kuibyshev). H12, which had been detected only in Turkish breeds, was also found in Chinese breeds in this work. An overall low level of haplotype diversity (median h = 0.1288) was observed across the breeds with relatively higher median values in breeds from the regions neighboring the Near Eastern domestication center of sheep. H6 is the dominant haplotype in northwestern and eastern China, in which the haplotype distribution could be explained by the historical translocations of the H4 and H8 Y chromosomes to China via the Mongol invasions followed by expansions to northwestern and eastern China. Our findings extend previous results of sheep Y chromosomal genetic variability and indicate probably recent paternal gene flows between sheep breeds from distinct major geographic regions.
The burden of adverse drug events
Authors: Breckenridge Alasdair
Published: September 2014

Drug safety should be considered as part of the balance between benefit and risk, and represents a burden to the patient, the healthcare professional, the regulator and industry. Each of these has a different view on adverse drug reactions and these are discussed in this article.
CENTRAL PLANNING LEGACIES: THE LINGERING EFFECTS OF THE GREAT LEAP FORWARD IN CHINA
Authors: He Qichun , Sun Meng
Published: September 2014

The Great Leap Forward (GLF) (1958–61) in China was a natural experiment that removed private property rights to achieve rapid growth via central planning, producing immediate famine and death. Using three measures for the GLF, we find that it still exerts a significant negative effect on output per worker in 2004 across Chinese provinces. This result is robust to the use of political factors from the GLF period as instruments. The causal relationship persists after controlling for climate conditions and initial output per capita. Moreover, the causal relationship exists when we change the dependent variable to output per worker in 1978, which refutes the notion that market‐oriented reforms alone explain the difference in income in 2004. Therefore, the GLF has had a lasting, negative effect on output.
The role of hexokinase in cardioprotection – mechanism and potential for translation
Authors: Halestrap Andrew P , Pereira Gonçalo C , Pasdois Philippe
Published: September 2014

Mitochondrial permeability transition pore (mPTP) opening plays a critical role in cardiac reperfusion injury and its prevention is cardioprotective. Tumour cell mitochondria usually have high levels of hexokinase isoform 2 (HK2) bound to their outer mitochondrial membranes (OMM) and HK2 binding to heart mitochondria has also been implicated in resistance to reperfusion injury. HK2 dissociates from heart mitochondria during ischaemia, and the extent of this correlates with the infarct size on reperfusion. Here we review the mechanisms and regulations of HK2 binding to mitochondria and how this inhibits mPTP opening and consequent reperfusion injury. Major determinants of HK2 dissociation are the elevated glucose‐6‐phosphate concentrations and decreased pH in ischaemia. These are modulated by the myriad of signalling pathways implicated in preconditioning protocols as a result of a decrease in pre‐ischaemic glycogen content. Loss of mitochondrial HK2 during ischaemia is associated with permeabilization of the OMM to cytochrome c, which leads to greater reactive oxygen species production and mPTP opening during reperfusion. Potential interactions between HK2 and OMM proteins associated with mitochondrial fission (e.g. Drp1) and apoptosis (B‐cell lymphoma 2 family members) in these processes are examined. Also considered is the role of HK2 binding in stabilizing contact sites between the OMM and the inner membrane. Breakage of these during ischaemia is proposed to facilitate cytochrome c loss during ischaemia while increasing mPTP opening and compromising cellular bioenergetics during reperfusion. We end by highlighting the many unanswered questions and discussing the potential of modulating mitochondrial HK2 binding as a pharmacological target.

Linked Articles

This article is part of a themed section on Conditioning the Heart – Pathways to Translation. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue‐8
Emerging role of hydrogen sulfide in hypertension and related cardiovascular diseases
Authors: Meng Guoliang , Ma Yan , Xie Liping , Ferro Albert , Ji Yong
Published: September 2014

Hydrogen sulfide (H2S) has traditionally been viewed as a highly toxic gas; however, recent studies have implicatedH2Sas a third member of the gasotransmitter family, exhibiting properties similar toNOand carbon monoxide. Accumulating evidence has suggested thatH2Sinfluences a wide range of physiological and pathological processes, among which blood vessel relaxation, cardioprotection and atherosclerosis have been particularly studied. In the cardiovascular system,H2Sproduction is predominantly catalyzed by cystathionine γ‐lyase (CSE). Decreased endogenousH2Slevels have been found in hypertensive patients and animals, andCSE−/−mice develop hypertension with age, suggesting that a deficiency inH2Scontributes importantly toBPregulation.H2Ssupplementation attenuates hypertension in different hypertensive animal models. The mechanism by whichH2Swas originally proposed to attenuate hypertension was by virtue of its action on vascular tone, which may be related to effects on different ion channels. BothH2SandNOcause vasodilatation and there is cross‐talk between these two molecules to regulateBP. Suppression of oxidative stress may also contribute to antihypertensive effects ofH2S. This review also summarizes the state of research onH2Sand hypertension inChina. A better understanding of the role ofH2Sin hypertension and related cardiovascular diseases will allow novel strategies to be devised for their treatment.

Linked Articles

This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visithttp://dx.doi.org/10.1111/bph.2015.172.issue-23
Extracellular signalling molecules in the ischaemic/reperfused heart – druggable and translatable for cardioprotection?
Authors: Kleinbongard P , Heusch G
Published: September 2014

In patients with acute myocardial infarction, timely reperfusion is essential to limit infarct size. However, reperfusion also adds to myocardial injury. Brief episodes of ischaemia/reperfusion in the myocardium or on organ remote from the heart, before or shortly after sustained myocardial ischaemia effectively reduce infarct size, provided there is eventual reperfusion. Such conditioning phenomena have been established in many experimental studies and also translated to humans. The underlying signal transduction, that is the molecular identity of triggers, mediators and effectors, is not clear yet in detail, but several extracellular signalling molecules, such as adenosine, bradykinin and opioids, have been identified to contribute to cardioprotection by conditioning manoeuvres. Several trials have attempted the translation of cardioprotection by such autacoids into a clinical scenario of myocardial ischaemia and reperfusion. Adenosine and its selective agonists reduced infarct size in a few studies, but this benefit was not translated into improved clinical outcome. All studies with bradykinin or drugs which increase bradykinin's bioavailability reported reduced infarct size and some of them also improved clinical outcome. Synthetic opioid agonists did not result in a robust infarct size reduction, but this failure of translation may relate to the cardioprotective properties of the underlying anaesthesia per se or of the comparator drugs. The translation of findings in healthy, young animals with acute coronary occlusion/reperfusion to patients of older age, with a variety of co‐morbidities and co‐medications, suffering from different scenarios of myocardial ischaemia/reperfusion remains a challenge.

Linked Articles

This article is part of a themed section on Conditioning the Heart – Pathways to Translation. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue‐8
Signalling pathways and mechanisms of protection in pre‐ and postconditioning: historical perspective and lessons for the future
Authors: Cohen Michael V , Downey James M
Published: September 2014

Ischaemic pre‐ and postconditioning are potent cardioprotective interventions that spare ischaemic myocardium and decrease infarct size after periods of myocardial ischaemia/reperfusion. They are dependent on complex signalling pathways involving ligands released from ischaemic myocardium, G‐protein‐linked receptors, membrane growth factor receptors, phospholipids, signalling kinases, NO, PKC and PKG, mitochondrial ATP‐sensitive potassium channels, reactive oxygen species, TNF‐α and sphingosine‐1‐phosphate. The final effector is probably the mitochondrial permeability transition pore and the signalling produces protection by preventing pore formation. Many investigators have worked to produce a roadmap of this signalling with the hope that it would reveal where one could intervene to therapeutically protect patients with acute myocardial infarction whose hearts are being reperfused. However, attempts to date to show efficacy of such an intervention in large clinical trials have been unsuccessful. Reasons for this inability to translate successes in the experimental laboratory to the clinical arena are evaluated in this review. It is suggested that all patients with acute coronary syndromes currently presenting to the hospital and being treated with platelet P2Y12 receptor antagonists, the current standard of care, are indeed already benefiting from protection from the conditioning pathways outlined earlier. If that proves to be the case, then future attempts to further decrease infarction will have to rely on interventions which protect by a different mechanism.

Linked Articles

This article is part of a themed section on Conditioning the Heart – Pathways to Translation. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue‐8
Preclinical development ofAMG139, a human antibody specifically targetingIL‐23
Authors: Köck K , Pan W J , Gow J M , Horner M J , Gibbs J P , Colbert A , Goletz T J , Newhall K J , Rees W A , Sun Y , Zhang Y , O'Neill J C , Umble‐Romero A N , Prokop S P , Krill C D , Som L , Buntich S A , Trimble M W , Tsuji W H , Towne J E
Published: September 2014

Background and Purpose

AMG139 is a human anti‐IL‐23 antibody currently in a phaseIItrial for treatingCrohn's disease. To support its clinical development in humans,in vitroassays andin vivostudies were conducted in cynomolgus monkeys to determine the pharmacology, preclinical characteristics and safety of this monoclonal antibody.

Experimental Approach

Thein vitropharmacology, pharmacokinetics (PK), pharmacodynamics and toxicology ofAMG139, after single or weekly i.v. or s.c. administration for up to 26 weeks, were evaluated in cynomolgus monkeys.

Key Results

AMG139 bound with high affinity to both human and cynomolgus monkeyIL‐23 and specifically neutralized the biological activity ofIL‐23 without binding or blockingIL‐12. After a single dose, linearPKwith s.c. bioavailability of 81% and mean half‐life of 8.4–13 days were observed. After weekly s.c. dosing for 3 or 6 months,AMG139 exposure increased approximately dose‐proportionally from 30 to 300 mg·kg−1and mean accumulation between the first and last dose ranged from 2‐ to 3.5‐fold. Peripheral blood immunophenotyping, T‐cell‐dependent antigen responses and bone formation markers were not different betweenAMG139 and vehicle treatment. No adverse clinical signs, effects on body weight, vital signs, ophthalmic parameters, clinical pathology,ECG, organ weights or histopathology were observed in the monkeys with the highest dose ofAMG139 tested (300 mg·kg−1s.c. or i.v.).

Conclusions and Implications

Thein vitropharmacology,PK, immunogenicity and safety characteristics ofAMG139 in cynomolgus monkeys support its continued clinical development for the treatment of various inflammatory diseases.
Antecedents of Maternal Sensitivity During Distressing Tasks: Integrating Attachment, Social Information Processing, and Psychobiological Perspectives
Authors: Leerkes Esther M. , Supple Andrew J. , O'Brien Marion , Calkins Susan D. , Haltigan John D. , Wong Maria S. , Fortuna Keren
Published: September 2014

Predictors of maternal sensitivity to infant distress were examined among 259 primiparous mothers. The Adult Attachment Interview, self‐reports of personality and emotional functioning, and measures of physiological, emotional, and cognitive responses to videotapes of crying infants were administered prenatally. Maternal sensitivity was observed during three distress‐eliciting tasks when infants were 6 months old. Coherence of mind was directly associated with higher maternal sensitivity to distress. Mothers' heightened emotional risk was indirectly associated with lower sensitivity via mothers' self‐focused and negative processing of infant cry cues. Likewise, high physiological arousal accompanied by poor physiological regulation in response to infant crying was indirectly associated with lower maternal sensitivity to distress through mothers' self‐focused and negative processing of infant cry cues.
Is Helicobacter Pylori infection inversely associated with atopy? A systematic review and meta‐analysis
Authors: Taye B. , Enquselassie F. , Tsegaye A. , Medhin G. , Davey G. , Venn A.
Published: September 2014

Background

The role Helicobacter Pylori (H. pylori) infection plays in the aetiology of atopy remains unclear, although a possible protective role has been hypothesized.

Objective

The aim of this study was to undertake a systematic review and meta‐analysis of epidemiological studies to quantify the association between H. pylori infection and atopy.

Methods

A comprehensive literature search in MEDLINE/PUBMED and EMBASE (up to August 2013) was carried out to identify all observational epidemiological studies (cross‐sectional, cohort and case–control) published in English that evaluated the association between H. pylori infection and objectively measured atopy (measured by allergen skin tests or specific IgE). The quality of included studies was assessed by the Newcastle–Ottawa scale. Random‐effects meta‐analyses were performed to obtain pooled estimates of effect.

Results

Twenty‐two observational studies involving 21 348 participants were identified as eligible for inclusion in the review, of which 16 were included in the meta‐analysis. H. pylori infection was associated with a significantly reduced odds of atopy (pooled odds ratio (OR) 0.82; 95% confidence interval (CI) 0.73 – 0.91; P < 0.01). Subgroup analysis according to atopy definition revealed a slightly greater protective effect for atopy defined as raised allergen‐specific IgE (OR 0.75; 95% CI 0.62 – 0.92; P < 0.01; seven studies). Findings did not differ according to the population age (adult or children), methodological quality or study design.

Conclusion and Clinical Relevance

Evidence from epidemiological studies suggests that H. pylori infection is associated with an estimated 18% reduction in odds of atopy. If the observed association is causal, more insights into the underlying mechanisms could provide clues to possible therapeutic opportunities in allergic disease.
Neonatal brain injury and systemic inflammation: modulation by activated protein C ex vivo
Authors: Eliwan H O , Watson R W G , Aslam S , Regan I , Philbin B , O'Hare F M , O'Neill A , Preston R , Blanco A , Grant T , Nolan B , Smith O , Molloy E J
Published: September 2014

Infection and inflammation can be antecedents of neonatal encephalopathy (NE) and increase the risk of neurological sequelae. Activated protein C (APC) has anti-coagulant and anti-inflammatory effects and provides neuroprotection in brain and spinal cord injury. We examined neutrophil and monocyte responses to lipopolysaccharide (LPS) in infants with NE compared with healthy adult and neonatal controls, and also studied the effect of APC. Whole blood was incubated with LPS and APC and Toll-like receptor (TLR)-4 (LPS recognition), CD11b expression (activation) and intracellular reactive oxygen intermediate (ROI; function) release from neutrophils and monocytes was examined by flow cytometry serially from days 1 to 7. We found a significant increase in neutrophil ROI in infants with NE on day 3 following LPS compared to neonatal controls and this augmented response was reduced significantly by APC. Neutrophil and monocyte CD11b expression was increased significantly on day 1 in infants with NE compared to neonatal controls. LPS-induced neutrophil TLR-4 expression was increased significantly in infants with NE on days 3 and 7 and was reduced by APC. LPS-induced monocyte TLR-4 was increased significantly in infants with NE on day 7. Neutrophil and monocyte activation and production of ROIs may mediate tissue damage in infants with NE. APC modified LPS responses in infants with NE. APC may reduce the inflammatory responses in NE and may ameliorate multi-organ dysfunction. Further study of the immunomodulatory effects of protein C may be warranted using mutant forms with decreased bleeding potential.
“Overlapping Memberships”: Interactive Multicultural Theory Meets Chalcedonian Christology
Authors: Hesslein Kayko Driedger
Published: September 2014

Chalcedonian Christology defines the relationship between the two natures of Christ as “truly God and truly human” but does not explain how the radically different natures interact with one another. Multicultural theory's model of interactive pluralism proposes that differences engage through “overlapping memberships.” Applying this model to the incarnation pushes beyond the limits of Chalcedon to suggest a Christology in which both immanence and transcendence mutually and equally constitute the one person of Christ.
Solus Christus within Empire: Christology in the Face of Violence against Women
Authors: Streufert Mary J.
Published: September 2014

When seen as the theocentric political confession it is, the confession “only Christ” is possible and meaningful for victim/survivors of violence against women. To confess only Christ undoes what is “required” in an empire of violence against women and is the recognition that Jesus Christ embraces our bodies, all of them. Moreover, this confession changes the body's response—individual and communal—to violence in an empire of violence against women.
Not so sweet: autoimmune diabetes mellitus on triple therapy for chronic hepatitis C infection
Authors: Blanchard E. , Vickers C. R. , Samaras K.
Published: September 2014

Background

Triple therapy with pegylated interferon, ribavirin and a protease inhibitor has proven efficacy in hepatitis C infection and is currently the standard of care. Interferon‐based therapies have been, rarely, associated with the development of Type 1 diabetes mellitus, but few cases have yet been reported in triple therapy for hepatitis C.

Case report

We describe a case of autoimmune Type 1 diabetes developing in a 23‐year‐old woman after initiation of triple therapy for chronic hepatitis C virus infection. The patient had the IL‐28B gene polymorphism rs12979860 CT genotype, which is associated not only with antiviral therapy response but also with diabetes risk after liver transplantation for hepatitis C.

Conclusion

Further studies are required to determine which individual characteristics may identify patients who are at risk of developing Type 1 diabetes when treated with interferon‐based regimens for hepatitis C infection.
Factors that drive insulin‐dosing decisions of diabetes care providers: a vignette‐based study in the Netherlands
Authors: Simon A. C. R. , Schopman J. E. , Hoekstra J. B. L. , Abu‐Hanna A. , Gerdes V. E. A. , Peek N. , Holleman F.
Published: September 2014

Aim

To test how certain patient factors would influence the decision of Dutch care providers regarding insulin dose adjustments. We hypothesize that some of these decisions would diverge from recent evidence and consensus statements.

Methods

We developed narrative vignettes describing clinical scenarios of patients receiving basal insulin therapy. For each vignette, the respondents were asked to indicate whether they would advise a change in insulin dose. A total of 520 paper questionnaires were distributed among physicians and nurses in primary and secondary care in the Netherlands. Multivariate linear and logistic regression analyses were performed to identify factors associated with dosing decisions.

Results

A total of 190 (37%) questionnaires were returned. In cases of a severe rather than mild hypoglycaemic event, care providers were nearly five times more likely to decrease the dose (odds ratio 4.77, 95% CI 1.65–13.75). Care providers were six times more likely to increase the dose when the patient's current dose was low (30 units) rather than high (90 units) (odds ratio 6.38, 95% CI 3.04–13.37). The plasma glucose concentration during a hypoglycaemic event and a known history of cardiovascular disease did not influence the care providers' dosing decisions.

Conclusion

Evidence regarding the optimum insulin titration is not always translated into clinical practice. When formulating guidelines, misconceptions should be identified and addressed.
HIF‐1α and HIF‐2α induce angiogenesis and improve muscle energy recovery
Authors: Niemi Henna , Honkonen Krista , Korpisalo Petra , Huusko Jenni , Kansanen Emilia , Merentie Mari , Rissanen Tuomas T. , André Helder , Pereira Teresa , Poellinger Lorenz , Alitalo Kari , Ylä‐Herttuala Seppo
Published: September 2014

Background

Cardiovascular patients suffer from reduced blood flow leading to ischaemia and impaired tissue metabolism. Unfortunately, an increasing group of elderly patients cannot be treated with current revascularization methods. Thus, new treatment strategies are urgently needed. Hypoxia‐inducible factors (HIFs) upregulate the expression of angiogenic mediators together with genes involved in energy metabolism and recovery of ischaemic tissues. Especially, HIF‐2α is a novel factor, and only limited information is available about its therapeutic potential.

Methods

Gene transfers with adenoviral HIF‐1α and HIF‐2α were performed into the mouse heart and rabbit ischaemic hindlimbs. Angiogenesis was evaluated by histology. Left ventricle function was analysed with echocardiography. Perfusion in rabbit skeletal muscles and energy recovery after electrical stimulation‐induced exercise were measured with ultrasound and 31P‐magnetic resonance spectroscopy (31P‐MRS), respectively.

Results

HIF‐1α and HIF‐2α gene transfers increased capillary size up to fivefold in myocardium and ischaemic skeletal muscles. Perfusion in skeletal muscles was increased by fourfold without oedema. Especially, AdHIF‐1α enhanced the recovery of ischaemic muscles from electrical stimulation‐induced energy depletion. Special characteristic of HIF‐2α gene transfer was a strong capillary growth in muscle connective tissue and that HIF‐2α gene transfer maintained left ventricle function.

Conclusions

We conclude that both AdHIF‐1α and AdHIF‐2α gene transfers induced beneficial angiogenesis in vivo. Transient moderate increases in angiogenesis improved energy recovery after exercise in ischaemic muscles. This study shows for the first time that a moderate increase in angiogenesis is enough to improve tissue energy metabolism, which is potentially a very useful feature for cardiovascular gene therapy.
Transition for patients with epilepsy due to metabolic and mitochondrial disorders
Authors: Kossoff Eric H. , Veggiotti Pierangelo , Genton Pierre , Desguerre Isabelle
Published: September 2014

The transition of adolescents with refractory epilepsy to the care of adult neurologists can be challenging. For those patients with epilepsy due to mitochondrial disorders, Lafora disease, Unverricht‐Lundborg disease, and GLUT1 deficiency syndrome, a successful transition can be even more problematic for both caregivers and neurologists. Many of these patients require dietary treatments (ketogenic and modified Atkins diets) for long‐term management of their epilepsy. For these patients, coordinating transfer of their dietary management is necessary.
Transition in adulthood: The challenge of epilepsies
Authors: Nabbout Rima , Camfield Peter
Published: September 2014

Transfer and transition for children with epilepsy to adult care is challenging because of the variety of epilepsies and of multiple comorbidities. We held an international closed symposium with 48 experts and initiated an international effort to improve transition and offer to our patients with lifelong disease a successful transfer of care.
Psychosocial long‐term outcome in juvenile myoclonic epilepsy
Authors: Holtkamp Martin , Senf Philine , Kirschbaum Andrea , Janz Dieter
Published: September 2014

Purpose

Juvenile myoclonic epilepsy (JME) is a well‐defined subsyndrome of idiopathic generalized/genetic epilepsy. It is allegedly related to specific personality characteristics and has been associated with unfavorable social outcome. We aimed to analyze psychosocial outcome in patients with JME. To delineate consequences of the chronic seizure disorder from possible neurobiologic contributions being inherent to the condition itself, we compared social outcome in JME subjects with that of age‐ and sex‐matched control patients with absence epilepsy (AE).

Methods

Patients with an epilepsy course of at least 20 years were included. All JME and AE patients (n = 41 in each group) answered a structured questionnaire asking about seizures, treatment, and psychosocial variables. In addition, patients with JME were assessed with the Quality of Life in Epilepsy Inventory 31 (QOLIE‐31).

Results

In JME, 46.3 years (20–69) after onset of epilepsy, the overall psychosocial long‐term outcome was favorable (80.5% of patients had never been unemployed for more than 1 year, 90.2% were well integrated into social context). Quality of life in all inquired subdomains revealed high scores. Compared with AE controls, JME patients did not perform worse regarding psychosocial outcome; rate of university access and degrees in JME patients was even higher (70% vs. 34%, p = 0.001). JME patients showed a high level of quality of life, and current or previous psychiatric comorbidity was associated significantly with lower overall quality of life scores (p = 0.02).

Significance

Our long‐term study on JME patients demonstrated favorable psychosocial outcome that contrasted previous findings. This is the first study to compare social outcome in JME with another genetically determined form of epilepsy. Similar outcomes in JME and AE patients argue against specific neurobiologic alterations in JME that may predispose to social deficits. In JME, reduced quality of life seems to be associated with psychiatric comorbidity.
Insertion of a 59 amino acid peptide in Salmonella Typhimurium membrane results in loss of virulence in mice
Authors: Porta Amalia , Morello Silvana , Granata Ilaria , Iannone Raffaella , Maresca Bruno
Published: September 2014

We demonstrated previously that expression of a single trans‐membrane region of the Δ12‐desaturase gene of Synechocystis sp. PCC 6803 in Salmonella enterica serovar Typhimurium (Salmonella Typhimurium) altered the membrane physical state of this pathogen, induced a significant change in the pattern of mRNA transcription of major heat shock genes, and inhibited pathogen growth inside murine macrophages. In this study, we demonstrate that injection of the modified Salmonella strain [Stm(pBAD200)] into C57Bl6j mice is safe. Survival of mice was associated with bacterial clearance, an increased number of splenic leukocytes, and high levels of interleukin–12, interferon γ and tumor necrosis factor α in spleens as well as in sera. Furthermore, Stm(pBAD200)‐injected mice developed a Salmonella‐specific antibody and Th1‐like responses. Mice challenged with Stm(pBAD200) are protected from systemic infection with Salmonella wild‐type. Similarly, mice infected with Stm(pBAD200) by the oral route survived when challenged with an oral lethal dose of Salmonella wild‐type. The avirulent Stm(pBAD200) phenotype is associated with a remarkable change in the expression of the hilC, hilD, hilA, invF and phoP genes, among others, whose products are required for invasion and replication of Salmonella inside phagocytic cells. These data demonstrate the use of trans‐membrane peptides to generate attenuated strains, providing a potential novel strategy to develop vaccines for both animal and human use.
A review of global potentially available cropland estimates and their consequences for model‐based assessments
Authors: Eitelberg David A. , van Vliet Jasper , Verburg Peter H.
Published: September 2014

The world's population is growing and demand for food, feed, fiber, and fuel is increasing, placing greater demand on land and its resources for crop production. We review previously published estimates of global scale cropland availability, discuss the underlying assumptions that lead to differences between estimates, and illustrate the consequences of applying different estimates in model‐based assessments of land‐use change. The review estimates a range from 1552 to 5131 Mha, which includes 1550 Mha that is already cropland. Hence, the lowest estimates indicate that there is almost no room for cropland expansion, while the highest estimates indicate that cropland could potentially expand to over three times its current area. Differences can largely be attributed to institutional assumptions, i.e. which land covers/uses (e.g. forests or grasslands) are societally or governmentally allowed to convert to cropland, while there was little variation in biophysical assumptions. Estimates based on comparable assumptions showed a variation of up to 84%, which originated mainly from different underlying data sources. On the basis of this synthesis of the assumptions underlying these estimates, we constructed a high, a medium, and a low estimate of cropland availability that are representative of the range of estimates in the reviewed studies. We apply these estimates in a land‐change model to illustrate the consequences on cropland expansion and intensification as well as deforestation. While uncertainty in cropland availability is hardly addressed in global land‐use change assessments, the results indicate a large range of estimates with important consequences for model‐based assessments.
Failure of productive infection of Mallards (Anas platyrhynchos) with H16 subtype of avian influenza viruses
Authors: Fereidouni Sasan R. , Harder Timm C. , Globig Anja , Starick Elke
Published: September 2014

Background

Mallard ducks and other waterfowl represent the most important reservoirs of low pathogenic avian influenza viruses (LPAIV). In addition, mallards are the most abundant duck species in Eurasia that migrate over long distances. Despite extended wild bird monitoring studies over the past decade in many Eurasian countries and investigating hundreds of thousands of wild bird samples, no mallard duck was found to be positive for avian influenza virus of subtype H16 in faecal, cloacal or oropharyngeal samples. Just three cases of H16 infections in Anseriformes species were described worldwide. In contrast, H16 viruses have been repeatedly isolated from birds of the Laridae family.

Objective

Here, we tested the hypothesis that mallards are less permissive to infection with H16 viruses.

Methods

Groups of mallard ducks of different age were inoculated via the oculo‐nasal‐oral route with different infectious doses of an H16N3 AIV.

Results

The ducks did not show any clinical symptoms, and no virus shedding was evident from cloacal and respiratory routes after experimental infection as shown by negative RT‐qPCR results. In addition, all serum samples taken on days 8, 21 and 24 post‐inoculation were negative by competitive NP‐ELISA.

Conclusions

This study provided evidence that mallards are resistant to infection with H16N3 LPAIV.
Cloning and characterization of a serotonin N‐acetyltransferase from a gymnosperm, loblolly pine (Pinus taeda)
Authors: Park Sangkyu , Byeon Yeong , Lee Hyoung Yool , Kim Young‐Soon , Ahn Taeho , Back Kyoungwhan
Published: September 2014

Serotonin N‐acetyltransferase (SNAT) is the penultimate enzyme in melatonin biosynthesis in both animals and plants. SNAT catalyzes serotonin into N‐acetylserotonin, an immediate precursor for melatonin biosynthesis by N‐acetylserotonin methyltransferase (ASMT). We cloned the SNAT gene from a gymnosperm loblolly pine (Pinus teada). The loblolly pine SNAT (PtSNAT) gene encodes 255 amino acids harboring a transit sequence with 67 amino acids and shows 67% amino acid identity with rice SNAT when comparing the mature polypeptide regions. Purified recombinant PtSNAT showed peak activity at 55°C with the Km (428 μm) and Vmax (3.9 nmol/min/mg protein) values. As predicted, PtSNAT localized to chloroplasts. The SNAT mRNA was constitutively expressed in all tissues, including leaf, bud, flower, and pinecone, whereas the corresponding protein was detected only in leaf. In accordance with the exclusive SNAT protein expression in leaf, melatonin was detected only in leaf at 0.45 ng per gram fresh weight. Sequence and phylogenetic analysis indicated that the gymnosperm PtSNAT had high homology with SNATs from all plant phyla (even with cyanobacteria), and formed a clade separated from the angiosperm SNATs, suggestive of direct gene transfer from cyanobacteria via endosymbiosis.
Genetic uniformity and long‐distance clonal dispersal in the invasive androgeneticCorbiculaclams
Authors: Pigneur Lise‐Marie , Etoundi Emilie , Aldridge David C. , Marescaux Jonathan , Yasuda Nina , Van Doninck Karine
Published: September 2014

The clam genusCorbiculais an interesting model system to study the evolution of reproductive modes as it includes both sexual and asexual (androgenetic) lineages. While the sexual populations are restricted to the native Asian areas, the androgenetic lineages are widely distributed being also found in America and Europe where they form a major aquatic invasive pest. We investigated the genetic diversity of native and invasiveCorbiculapopulations through a worldwide sampling. The use of mitochondrial and nuclear (microsatellite) markers revealed an extremely low diversity in the invasive populations with only four, undiversified, genetic lineages distributed across Europe and America. On the contrary, in the native populations, both sexual and androgenetic lineages exhibited much higher genetic diversity. Remarkably, the most abundant and widely distributed invasive forms, the so‐called form A and form R found in America and Europe respectively, are fixed for the same singleCOI(cytochrome c oxydase subunit I) haplotype and same multilocus genotype. This suggests that form R, observed in Europe since the 1980s, derived directly from form A found in America since the 1920s. In addition, this form shares alleles with some Japanese populations, indicating a Japanese origin for this invasive lineage. Finally, our study suggests that few androgeneticCorbiculaindividuals successfully invaded the non‐native range and then dispersed clonally. This is one striking case of genetic paradox raising the issue of invasive and evolutionary success of genetically undiversified populations.
Probabilistic Assessment of Civil Infrastructure Resilience to Earthquakes
Authors: Franchin Paolo , Cavalieri Francesco
Published: September 2014

The large losses occurred in the past due to earthquakes, even in highly developed countries, as well as the ensuing prolonged inactivity of the stricken societies, imparted momentum to research into regional seismic impact and community resilience to earthquakes. Need for comprehensive and consistent modeling is apparent, and this work presents a contribution in this direction. The extension of a recently developed civil infrastructure simulation framework to the evaluation of resilience, as well as the introduction of a new infrastructure network‐based resilience metric represent the novelties of the article and allow one to explore the effect that sources of uncertainty and key vulnerability factors have on the probability distribution of resilience.
A 2‐year mean follow‐up of oral appliance therapy for severe obstructive sleep apnea: a cohort study
Authors: Haviv Y , Bachar G , Aframian DJ , Almoznino G , Michaeli E , Benoliel R
Published: September 2014

Objective

Oral appliances for treating severe obstructive sleep apnea (OSA) are recommended for patients who failed to comply with continuous positive airway pressure (CPAP) treatment. The objective of this study was to evaluate medium long‐term outcome and success rates of oral appliances in patients with severe OSA.

Methods

In a retrospective study, 52 OSA patients with an apnea–hypopnea index (AHI) ≥40, who did not tolerate CPAP treatment, were enrolled and fitted with a modified Herbst oral appliance. A 2‐year mean follow‐up including a second somnography was conducted in 36 of the patients.

Results

A significant reduction (P < 0.0001) in the AHI was demonstrated between the initial somnography (55.25 ± 10.79,) and the followed one (17.74 ± 11.0, n = 36). Overall, 57.7% of total study subjects (n = 52) and 63.9% (n = 36) that had sequential sonmogarphy continued using the device. The reduction in AHI in the user group was 42.4 ± 3.1 (n = 23), which was significantly higher (P = 0.013) than in the non‐user group (28.9 ± 17.2; n = 13). Moreover, 53% (n = 19) reached AHI of <15.

Conclusions

Oral appliances were found to be successful for treating for severe OSA after first‐line treatment had failed.