bluuebunny/crossref_metadata_2025 huggingface dataset:
High Risk Strawberry Viruses by Region in the United States and Canada: Implications for Certification, Nurseries, and Fruit Production
Authors: Martin Robert R. , Tzanetakis Ioannis E.
Published: April 2013

There is limited information about the distribution of strawberry viruses in North America and around the world. Since the turn of the century, there has been a concerted effort to develop sensitive tests for many of the previously uncharacterized, graft-transmissible agents infecting strawberry. These tests were employed to determine the presence of strawberry viruses in major strawberry production and nursery areas of North America. The viruses evaluated in this study were Apple mosaic, Beet pseudo-yellows, Fragaria chiloensis latent, Strawberry chlorotic fleck, Strawberry crinkle, Strawberry latent ring spot, Strawberry mild yellow edge, Strawberry mottle, Strawberry necrotic shock, Strawberry pallidosis, Strawberry vein banding, and Tobacco streak. The aphid-borne viruses were predominant in the Pacific Northwest whereas the whitefly-borne viruses were prevalent in California, the Midwest, and the Southeast. In the Northeast, the aphid-transmitted Strawberry mottle and Strawberry mild yellow edge viruses along with the whitefly-transmitted viruses were most common. The incidence of pollen-borne viruses was low in most areas, with Strawberry necrotic shock being the most prevalent virus of this group. These results indicate that there are hotspots for individual virus groups that normally coincide with the presence of the vectors. The information presented highlights the high-risk viruses for nursery production, where efforts are made to control all viruses, and fruit production, where efforts are made to control virus diseases.
Rapid diagnosis of Mycobacterium abscessus endophthalmitis
Authors: Rolfe Nancy E. , Garcia Catherine , Widen Raymond H. , Taylor Stephanie P.
Published: April 2013

Nontuberculous mycobacteria are widely distributed in the environment and have the potential to cause a wide spectrum of infections including pulmonary, bone, soft tissue or ocular infections. They are a rare cause of endophthalmitis, a potentially devastating condition, which may be acquired through contamination of water or antiseptic solutions. Diagnosis is often delayed due to low clinical suspicion, resulting in poor clinical outcomes. Newer laboratory techniques such as real-time PCR can be used for rapid detection, identification and speciation of mycobacteria and allow for initiation of focused antibiotic therapy. We describe a case of Mycobacterium abscessus endophthalmitis that developed 30 years after traumatic loss of cornea in a patient with diabetes mellitus.
Upregulation of Nrf2 expression by human cytomegalovirus infection protects host cells from oxidative stress
Authors: Lee Junsub , Koh Kyungmi , Kim Young-Eui , Ahn Jin-Hyun , Kim Sunyoung
Published: April 2013

NF-E2 related factor 2 (Nrf2) is a transcription factor that plays a key role(s) in cellular defence against oxidative stress. In this study, we showed that the expression of Nrf2 was upregulated in primary human foreskin fibroblasts (HFFs), following human cytomegalovirus (HCMV/HHV-5) infection. The expression of haem oxygenase-1, a downstream target of Nrf2, was also increased by HCMV infection, and this induction was suppressed in HFFs expressing a small hairpin RNA (shRNA) against Nrf2. The HCMV-mediated increase in Nrf2 expression was abolished when UV-irradiated virus was used or when the activity of casein kinase 2 was inhibited. Host cells infected by HCMV had higher survival rates following oxidative stress induced by buthionine sulfoximine compared with uninfected control cells, but this cell-protective effect was abolished by the use of Nrf2 shRNA. Our results suggest that HCMV-mediated activation of Nrf2 might be beneficial to the virus by increasing the host cell’s ability to cope with oxidative stress resulting from viral infection and/or inflammation.
Inhibition of indoleamine 2,3-dioxygenase enhances the T-cell response to influenza virus infection
Authors: Fox Julie M. , Sage Leo K. , Huang Lei , Barber James , Klonowski Kimberly D. , Mellor Andrew L. , Tompkins S. Mark , Tripp Ralph A.
Published: April 2013

Influenza infection induces an increase in the level of indoleamine 2,3-dioxygenase (IDO) activity in the lung parenchyma. IDO is the first and rate-limiting step in the kynurenine pathway where tryptophan is reduced to kynurenine and other metabolites. The depletion of tryptophan, and production of associated metabolites, attenuates the immune response to infection. The impact of IDO on the primary immune response to influenza virus infection was determined using the IDO inhibitor 1-methyl-d,l-tryptophan (1MT). C57BL/6 mice treated with 1MT and infected with A/HKx31 influenza virus had increased numbers of activated and functional CD4+T-cells, influenza-specific CD8+T-cells and effector memory cells in the lung. Inhibition of IDO increased the Th1 response in CD4+T-cells as well as enhanced the Th17 response. These studies show that inhibition of IDO engenders a more robust T-cell response to influenza virus, and suggests an approach for enhancing the immune response to influenza vaccination by facilitating increased influenza-specific T-cell response.
Roles for transcript leaders in translation and mRNA decay revealed by transcript leader sequencing
Authors: Arribere Joshua A. , Gilbert Wendy V.
Published: April 2013

Transcript leaders (TLs) can have profound effects on mRNA translation and stability. To map TL boundaries genome-wide, we developed TL-sequencing (TL-seq), a technique combining enzymatic capture of m7G-capped mRNA 5′ ends with high-throughput sequencing. TL-seq identified mRNA start sites for the majority of yeast genes and revealed many examples of intragenic TL heterogeneity. Surprisingly, TL-seq identified transcription initiation sites within 6% of protein-coding regions, and these sites were concentrated near the 5′ ends of ORFs. Furthermore, ribosome density analysis showed these truncated mRNAs are translated. Translation-associated TL-seq (TATL-seq), which combines TL-seq with polysome fractionation, enabled annotation of TLs, and simultaneously assayed their function in translation. Using TATL-seq to address relationships between TL features and translation of the downstream ORF, we observed that upstream AUGs (uAUGs), and no other upstream codons, were associated with poor translation and nonsense-mediated mRNA decay (NMD). We also identified hundreds of genes with very short TLs, and demonstrated that short TLs were associated with poor translation initiation at the annotated start codon and increased initiation at downstream AUGs. This frequently resulted in out-of-frame translation and subsequent termination at premature termination codons, culminating in NMD of the transcript. Unlike previous approaches, our technique enabled observation of alternative TL variants for hundreds of genes and revealed significant differences in translation in genes with distinct TL isoforms. TL-seq and TATL-seq are useful tools for annotation and functional characterization of TLs, and can be applied to any eukaryotic system to investigate TL-mediated regulation of gene expression.
Genetic Factors in Nonsmokers with Age‐Related Macular Degeneration Revealed Through Genome‐Wide Gene‐Environment Interaction Analysis
Authors: Naj Adam C. , Scott William K. , Courtenay Monique D. , Cade William H. , Schwartz Stephen G. , Kovach Jaclyn L. , Agarwal Anita , Wang Gaofeng , Haines Jonathan L. , Pericak‐Vance Margaret A.
Published: April 2013

Relatively little is known about the interaction between genes and environment in the complex etiology of age‐related macular degeneration (AMD). This study aimed to identify novel factors associated with AMD by analyzing gene‐smoking interactions in a genome‐wide association study of 1207 AMD cases and 686 controls of Caucasian background with genotype data on 668,238 single nucleotide polymorphisms (SNPs) after quality control. Participants’ history of smoking at least 100 cigarettes lifetime was determined by a self‐administered questionnaire. SNP associations modeled the effect of the minor allele additively on AMD using logistic regression, with adjustment for age, sex, and ever/never smoking. Joint effects of SNPs and smoking were examined comparing a null model containing only age, sex, and smoking against an extended model including genotypic and interaction terms. Genome‐wide significant main effects were detected at three known AMD loci: CFH (P = 7.51×10−30), ARMS2 (P = 1.94×10−23), and RDBP/CFB/C2 (P = 4.37×10−10), while joint effects analysis revealed three genomic regions with P < 10−5. Analyses stratified by smoking found genetic associations largely restricted to nonsmokers, with one notable exception: the chromosome 18q22.1 intergenic SNP rs17073641 (between SERPINB8 and CDH7), more strongly associated in nonsmokers (OR = 0.57, P = 2.73 × 10−5), with an inverse association among smokers (OR = 1.42, P = 0.00228), suggesting that smoking modifies the effect of some genetic polymorphisms on AMD risk.
Caprine sex affects skeletal muscle profile and MRFs expression during postnatal development
Authors: Zhong Tao , Jin Peng‐Fei , Dong En‐Ni , Li Li , Wang Lin‐Jie , Zhang Hong‐Ping
Published: April 2013

The important roles of myogenic regulatory factors (MRFs) have been well addressed in the process of mammalian skeletal myogenesis, while limited research has been performed in small ruminants. Furthermore, the effects of gender on the development of skeletal muscle and MRFs expression remain unknown. In this study, we identified the caprine Myf5, Myf6, MyoD and myogenin genes and quantified their expressions at six different postnatal time points by real‐time RT‐PCR. The sex has a marked effect on the expression differences of Myf5, MyoD and myogenin in the five investigated skeletal muscles, while minor influence on the expression difference of Myf6 except for Semitendinosus and Quadriceps femoris tissues (P < 0.001). The histological sections of muscles revealed a constant increase of muscle fiber diameter with aging but non‐significant differences between genders. We provide novel evidence for MRFs expression in age‐ and gender‐dependent manners, which will contribute to prioritizing these genes as potential candidate genes for trait‐associated study and provide a foundation for understanding the molecular control of skeletal muscle growth in goat species.
Role of Immunotherapy in Castration‐Resistant Prostate Cancer (CRPC)
Authors: Suárez Cristina , Morales‐Barrera Rafael , Ramos Victor , Núñez Isaac , Valverde Claudia , Planas Jacques , Morote Juan , Maldonado Xavier , Carles Joan
Published: April 2013

Initial therapy for metastatic prostate cancer consists of androgenic suppression. However, this is only a palliative treatment with an effective duration that usually lasts 12–24 months. Historically, castration‐resistant prostate cancer (CRPC) had been considered a chemoresistant tumour.

In 2004, docetaxel received USA Food and Drug Administration approval as a first‐line treatment for metastatic prostate cancer, after two independent phase III trials showed an increased survival benefit. Recently, five new drugs have shown increased survival in CRPC: sipuleucel‐T (assymptomatic or minimally symptomatic), abiraterone acetate (before and after docetaxel), cabazitaxel (after docetaxel), MDV3100 (after docetaxel) and radium‐223 (not suitable for docetaxel or after docetaxel).

The identification of antigens in normal prostate tissue or prostate cancer that are recognised by immune effectors cells has resulted in several new studies based on immunotherapy.

Prostate cancer disease provides a test system to determine the efficacy of vaccines for different reasons. This cancer is a tumour that grows relatively slowly. Recurrence is often diagnosed early (with many patients presenting only with biochemical progression), there is a biological marker that can predict prognosis and outcome (PSA doubling time), various specific antigens have been identified and characterised, and vaccines can be used with a good safety profile combined with anti‐androgen therapy, chemotherapy, or radiotherapy.

Here we provide a review of the main important immune treatments in CRPC.
Tree‐ring‐based annual precipitation reconstruction for the Hexi Corridor, NW China: consequences for climate history on and beyond the mid‐latitude Asian continent
Authors: Chen Feng , Yuan Yujiang , Wei Wenshou , Zhang Ruibo , Yu Shulong , Shang Huaming , Zhang Tongwen , Qin Li , Wang Huiqing , Chen Fahu
Published: April 2013

An annual (July to June) precipitation reconstruction for the period AD 1760–2010 was developed from a Picea crassifolia regional tree‐ring chronology from two sites in the northern mountainous region of the Hexi Corridor, NW China. This reconstruction explains 52.1% of the actual precipitation variance during the period 1951 to 2010. Spatial correlations with gridded land‐surface data reveal that our reconstruction contains a strong regional precipitation signal for the Hexi Corridor and for the southern margin of the Badain Jaran Desert. Significant spectral peaks were identified at 31.9, 11.1, 8.0, 7.0, 3.2, 2.6 and 2.2 years. A large‐scale comparison indicates that our reconstruction is more consistent with climate records of a Westerly‐dominated Central Asia, and that the Westerlies have a greater impact on the precipitation in this region than the Asian summer monsoon. Our reconstructed precipitation series is significantly correlated with sea‐surface temperature (SST) in the tropical Atlantic Ocean (positive), the tropical Indian Ocean (positive), the western tropical Pacific Ocean (positive), and the western North Pacific Ocean (negative). The spatial correlation patterns between our precipitation reconstruction and SSTs of the Atlantic and Pacific Oceans suggest a connection between regional precipitation variations and the high‐mid‐latitude northern atmospheric circulations (Westerlies and Asian summer monsoon).
Ethnic Identity in Everyday Life: The Influence of Identity Development Status
Authors: Yip Tiffany
Published: April 2013

The current study explores the intersection of ethnic identity development and significance in a sample of 354 diverse adolescents (mean age 14). Adolescents completed surveys five times a day for 1 week. Cluster analyses revealed four identity clusters: diffused, foreclosed, moratorium, and achieved. Achieved adolescents reported the highest levels of identity salience across situations, followed by moratorium adolescents. Achieved and moratorium adolescents also reported a positive association between identity salience and private regard. For foreclosed and achieved adolescents reporting low levels of centrality, identity salience was associated with lower private regard. For foreclosed and achieved adolescents reporting high levels of centrality, identity salience was associated with higher private regard.
Achieving Lean Objectives through RFID: A Simulation‐Based Assessment*
Authors: Chongwatpol Jongsawas , Sharda Ramesh
Published: April 2013

Lean concepts in manufacturing have focused on elimination of wastes within the business processes. This study investigates whether addition of radio frequency identification (RFID) technologies in the manufacturing process can complement Lean manufacturing. Specifically, will more accurate information from RFID‐based solutions help achieve the goals of Lean initiatives in manufacturing plant performance and, if yes, in what specific ways? The analysis is based on a comparison of the following three automatic identification technologies: existing (one‐dimensional) 1D barcode, 2D barcode, and the use of RFID in a real job‐shop environment where items are manufactured for meeting actual demand and also future forecast demand. We analyze the effect of information visibility in these settings by examining the various types of wastes that are typically addressed in Lean initiatives. The results of a discrete‐event simulation suggest that employing RFID in Lean manufacturing initiatives can reduce some wastes but not necessarily all types of waste. We observe an increase in overproduction waste in our setting, although other wastes are reduced with improved information visibility. Overall, our results indicate that manufacturing organizations should explore information visibility through RFID to enhance their Lean initiatives.
Heifer‐in‐trust, Social Protection and Graduation: Conceptual Issues and Empirical Questions
Authors: Sumberg James , Lankoandé Gountiéni Damien
Published: April 2013

This article examines the ‘heifer‐in‐trust’ or ‘livestock‐in‐kind credit’ model through a social‐protection lens. Specifically it seeks to engage with debates about the use of asset‐based strategies to support graduation from social protection. Drawing on project experience with dairy goats in Ethiopia and dairy cattle in Tanzania, the article concludes that while the asset‐ness of livestock may in principle allow them to make a unique contribution to livelihood transformation and thus graduation, the most obvious target group is least likely to be able to handle the demands and risks associated with livestock assets.
Inter‐subject synchronization of brain responses during natural music listening
Authors: Abrams Daniel A. , Ryali Srikanth , Chen Tianwen , Chordia Parag , Khouzam Amirah , Levitin Daniel J. , Menon Vinod
Published: April 2013

Music is a cultural universal and a rich part of the human experience. However, little is known about common brain systems that support the processing and integration of extended, naturalistic ‘real‐world’ music stimuli. We examined this question by presenting extended excerpts of symphonic music, and two pseudomusical stimuli in which the temporal and spectral structure of the Natural Music condition were disrupted, to non‐musician participants undergoing functional brain imaging and analysing synchronized spatiotemporal activity patterns between listeners. We found that music synchronizes brain responses across listeners in bilateral auditory midbrain and thalamus, primary auditory and auditory association cortex, right‐lateralized structures in frontal and parietal cortex, and motor planning regions of the brain. These effects were greater for natural music compared to the pseudo‐musical control conditions. Remarkably, inter‐subject synchronization in the inferior colliculus and medial geniculate nucleus was also greater for the natural music condition, indicating that synchronization at these early stages of auditory processing is not simply driven by spectro‐temporal features of the stimulus. Increased synchronization during music listening was also evident in a right‐hemisphere fronto‐parietal attention network and bilateral cortical regions involved in motor planning. While these brain structures have previously been implicated in various aspects of musical processing, our results are the first to show that these regions track structural elements of a musical stimulus over extended time periods lasting minutes. Our results show that a hierarchical distributed network is synchronized between individuals during the processing of extended musical sequences, and provide new insight into the temporal integration of complex and biologically salient auditory sequences.
Juridification: Disrupting the Relationship between Law and Politics?
Authors: Magnussen Anne‐Mette , Banasiak Anna
Published: April 2013

The article addresses some possible implications of juridification in the society. The concept of juridification is unclear, and the empirical knowledge of the social implications of various processes of juridification is weak. We argue that clear‐cut conclusions about the implications of such processes cannot be drawn. To address questions of implications of juridification processes, we focus on the relationship between law and politics. An analytical framework for the analysis of juridification processes is introduced to manage the vast implications of these processes. The discussion indicates complexity and contradictory outcomes of juridification processes. We conclude that to understand the vast complexity of the different kinds of juridification processes, we need more empirical studies from a range of academic fields, including law, economics and political sciences, and that researchers in these fields need to take a step back to get a more satisfactory analytical point of departure for such studies.
European Legal Method in Denmark and Sweden—Using Social Science Theory and Methodology to Describe the Implementation of EU Law
Authors: Edwardsson Eva , Wockelberg Helena
Published: April 2013

This article presents data from a study in which national bureaucrats working in the fields of taxation and food law in Sweden and Denmark are asked which legal sources and methods of interpretation they use when implementing EU law. The purpose is to contribute to the discussion about European legal method by using social science methodology. National agencies and authorities in the fields of taxation and food law face a ‘multilayered’ or ‘multiprincipal’ reality in which there is room for policy choices. The answers given by the interviewees speak of a plurality of legal sources, a situation where bureaucrats are becoming reluctant lawmakers instructing others on how EU law is to be applied and where bureaucrats find it necessary to found their decisions on what colleagues within the authority or from other Member States have said about how EU law should be applied.
Biomass production assessment from Populus spp. short‐rotation irrigated crops in Spain
Authors: Pérez‐Cruzado César , Sanchez‐Ron David , Rodríguez‐Soalleiro Roque , Hernández Maria José , Mario Sánchez‐Martín M. , Cañellas Isabel , Sixto Hortensia
Published: April 2013

The aim of this study was to evaluate the biomass production potential for the Spanish Iberian Peninsula using the Populus spp. ‘I‐214’ clone under several management regimes and land availability scenarios, and to determine its future contribution to Spanish energy demands.

Empirical models were fitted to the data from a network of 144 plots located at 12 sites in the continental Mediterranean climatic regions of the Iberian Peninsula, in which yield was related to climate and soil, as well as to plantation management variables. Four models were developed considering average maximum temperature of the hottest month (TMAXH, °C), length of drought (A, months), intensity of drought (K, unitless) and soil pH. Predictions were made for the irrigated agricultural land (IAL), where the value of the independent variables were within the validity range, and for two management scenarios. Energy production capacity was evaluated by considering the alternatives for transforming poplar SRC biomass: heat, bio‐ethanol and electricity.

The results indicated a mean productivity for the Spanish Iberian peninsula of between 15.3 and 10.9 Mg ha−1 yr−1 for the standard management scenario and the poorly irrigated and weeded management scenario respectively. Two IAL scenarios were considered for the calculation of biomass production potential: all IAL for which it was possible to make predictions is made available for poplar SRC (TP, maximum hypothetical production capacity), and another in which only unproductive IAL is available for poplar SRC (RP, production capacity without constricting agricultural production). The TP scenario contributes up to 6.8–9.6% of total energy demands, and the RP scenario 0.7–0.9%, depending on plantation management.
Assessing preregistration nursing students' clinical competence: A systematic review of objective measures
Authors: Cant Robyn , McKenna Lisa , Cooper Simon
Published: April 2013

Nursing students are required to develop clinical knowledge, skills and attitudes for professional practice. However, objectivity and parity of students' clinical assessments has been questioned. In the last decade, more objective techniques have been developed, with increased use of Objective Structured Clinical Examinations. We reviewed objective clinical assessment measures used in preregistration nursing courses to determine utilization and the validity and reliability of assessment techniques. A systematic search was made of quantitative research publications between 2000 and May 2011, identifying 16 studies that were subsequently reviewed. The validity and reliability of studies varied, with six studies judged as high quality, using various methodologies. This paper describes methods of instrument development and reports on their application in preregistration nursing programs.
Factors affecting the compliance of Israeli women with screening for intimate partner violence
Authors: Ben Natan Merav , Abramov Luda , Dhokarker Avigail , Israelov Etery
Published: April 2013

Violence against women has become a frequent occurrence. In Israel, some 200 000 women are subjected to various types of violence by their intimate partners annually. Routine screening for intimate partner violence is endorsed by the Ministry of Health in Israel; however, screening rates in health‐care settings remain problematic. This study aimed to examine whether the model based on the Theory of Reasoned Action (TRA) succeeds in predicting women's intention to comply with screening for intimate partner violence.

A questionnaire based on the literature review and research model was administered to a convenience sample of 200 married women. Although only 4.5% (n = 9) of respondents were screened for violence at various health‐care institutions over the past year, 75% (n = 150) of women declared that they intend to cooperate with screening. A positive correlation was found between women's marriage duration, beliefs concerning violence, attitudes towards screening, family member support for compliance with screening—and women's intention to comply with screening. The TRA succeeds in partially predicting women's intention to comply with screening.
New insights into osteoporosis: the bone–fat connection
Authors: Kawai M. , de Paula F. J. A. , Rosen C. J.
Published: April 2013

Kawai M, de Paula FJA, Rosen CJ (Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan; University of São Paulo, Ribeirão Preto, SP, Brazil; and Maine Medical Center Research Institute, Scarborough, ME, USA). New insights into osteoporosis: the bone–fat connection (Review). J Intern Med 2012; 272: 317–329.

Abstract.  Osteoporosis and obesity are chronic disorders that are both increasing in prevalence. The pathophysiology of these conditions is multifactorial and includes genetic, environmental and hormonal determinants. Although it has long been considered that these are distinct disorders rarely found in the same individual, emerging evidence from basic and clinical studies support an important interaction between adipose tissue and the skeleton. It is proposed that adiposity may influence bone remodelling through three mechanisms: (i) secretion of cytokines that directly target bone, (ii) production of adipokines that influence the central nervous system thereby changing sympathetic impulses to bone and (iii) paracrine influences on adjacent skeletal cells. Here we focus on the current understanding of bone–fat interactions and the clinical implications of recent studies linking obesity to osteoporosis.
Targeting T‐cell migration in inflammatory bowel disease
Authors: Marsal J. , Agace W. W.
Published: April 2013

Crohn's disease and ulcerative colitis are chronic inflammatory disorders of the gastrointestinal tract and are collectively referred to as inflammatory bowel disease (IBD). IBD is a major cause of lifetime morbidity, has a severe impact on quality of life of patients (equivalent to that of rheumatoid arthritis, asthma, migraine or diabetes) and constitutes a substantial economic burden to the healthcare system. The introduction of anti‐tumour necrosis factor (TNF) antibodies has dramatically improved the treatment of IBD, but approximately one‐third of patients are nonresponders and another 30–50% will eventually lose the therapeutic effect or become intolerant to these antibodies. Thus, there is an urgent and unmet need for new therapies. The aetiologies of the different forms of IBD have not been fully elucidated but there is strong evidence implicating T cells and T‐cell migration to the gut in initiating and perpetuating the intestinal inflammatory process and tissue destruction. In recent years, progress in basic science has shed light on the mechanisms regulating T‐cell migration to the gut and new therapeutics targeting these pathways have been developed. It is interesting that some of the factors directing the localization of T cells to the gut have been shown to be relatively organ specific, potentially enabling new T‐cell‐targeted treatments to demonstrate improved safety whilst preserving therapeutic efficacy. Here, fundamental aspects of the gut immune system, the generation of tissue‐tropic effector T cells and the mechanisms of T‐cell trafficking to the gut mucosa will be reviewed. In addition, the role of these processes in IBD and how they have been exploited for the development of novel therapies for IBD will be discussed.
Lipoprotein(a): resurrected by genetics
Authors: Kronenberg F. , Utermann G.
Published: April 2013

Plasma lipoprotein(a) [Lp(a)] is a quantitative genetic trait with a very broad and skewed distribution, which is largely controlled by genetic variants at the LPA locus on chromosome 6q27. Based on genetic evidence provided by studies conducted over the last two decades, Lp(a) is currently considered to be the strongest genetic risk factor for coronary heart disease (CHD). The copy number variation of kringle IV in the LPA gene has been strongly associated with both Lp(a) levels in plasma and risk of CHD, thereby fulfilling the main criterion for causality in a Mendelian randomization approach. Alleles with a low kringle IV copy number that together have a population frequency of 25–35% are associated with a doubling of the relative risk for outcomes, which is exceptional in the field of complex genetic phenotypes. The recently identified binding of oxidized phospholipids to Lp(a) is considered as one of the possible mechanisms that may explain the pathogenicity of Lp(a). Drugs that have been shown to lower Lp(a) have pleiotropic effects on other CHD risk factors, and an improvement of cardiovascular endpoints is up to now lacking. However, it has been established in a proof of principle study that lowering of very high Lp(a) by apheresis in high‐risk patients with already maximally reduced low‐density lipoprotein cholesterol levels can dramatically reduce major coronary events.
Severity of overactive bladder symptoms and response to dose escalation in a randomized, double‐blind trial of solifenacin (SUNRISE)
Authors: Cardozo Linda , Amarenco Gerard , Pushkar Dmitry , Mikulas Jura , Drogendijk Ted , Wright Mark , Compion Gerhard ,   SUNRISE Study Group
Published: April 2013

What's known on the subject? and What does the study add?

Antimuscarinics are effective and well tolerated for treatment of OAB. Studies have found that a flexible dosing strategy can be effective in improving OAB symptoms with minimal impact on tolerability.

This study confirms these findings with two doses of solifenacin, and shows that improved outcomes can be achieved by increasing solifenacin dose (from 5 to 10 mg) in patients with more severe symptoms.

Objective

To determine the relationship between severity of baseline overactive bladder (OAB) symptoms and requests for solifenacin dose increases, and the efficacy of 5 and 10 mg solifenacin doses in relieving OAB symptoms in patients who requested a dose increase.

Patients and Methods

In a 16‐week clinical study, patients with OAB were randomized to double‐blind treatment with solifenacin or placebo once daily.

At week 8, all patients could request a dose increase; these patients entered a second phase of 8 weeks in which those in the solifenacin group were randomized to either 5 or 10 mg doses.

The primary efficacy variable was mean change in the number of urgency episodes with or without incontinence per 24 h, measured using the Patient Perception of Intensity of Urgency Scale (PPIUS; grades 3 and 4).

Results

Of 591 patients receiving solifenacin at 8 weeks, 275 (46.5%) requested a dose increase to 10 mg, and were further randomized to receive 10 mg (n = 140) or to remain on 5 mg (n = 135).

Patients who requested a dose increase at week 8 generally had more severe OAB symptoms at baseline and a smaller response at week 8 to the initial solifenacin 5 mg dosage than those who did not.

Greater reductions in the mean number of severe urgency episodes (PPIUS grades 3 and 4) were observed from week 8 to the end of treatment for patients requesting a dose increase and randomized to 10 mg solifenacin compared with those randomized to remain on 5 mg (mean reductions –0.9 vs –0.4, respectively), although these did not reach statistical significance.

Statistically significant reductions were observed in mean total urgency score (TUS; –2.7 vs –0.6; P = 0.010), mean maximum PPIUS urgency rating (–0.3 vs –0.1; P = 0.034) and mean micturition frequency (–0.8 vs –0.1; P = 0.037). For all other OAB variables, greater changes were observed in the solifenacin 10 mg group but these did not reach statistical significance.

Of those who requested a dose increase, eight (5.7%) patients randomized to receive 10 mg and one (0.7%) patient randomized to remain on 5 mg reported new or worsening cases of dry mouth.

Conclusions

Increasing the solifenacin dose to 10 mg further improved OAB symptoms in patients who requested a dose increase after 8 weeks' treatment with 5 mg solifenacin.

The present study supports the view that patients with severe OAB symptoms benefit from a higher antimuscarinic dose.
Combined Dominant Frequency and Complex Fractionated Atrial Electrogram Ablation After Circumferential Pulmonary Vein Isolation of Atrial Fibrillation
Authors: KUMAGAI KOJI , SAKAMOTO TAMOTSU , NAKAMURA KEIJIRO , NISHIUCHI SUGURU , HAYANO MAMORU , HAYASHI TATSUYA , SASAKI TAKEHITO , AONUMA KAZUTAKA , OSHIMA SHIGERU
Published: April 2013

Dominant Frequency‐Based Ablation of Atrial Fibrillation

Introduction

Atrial substrates with high‐dominant frequency (DF) and complex fractionated atrial electrogram (CFAE) sites have sources maintaining atrial fibrillation (AF) and are potential AF ablation targets. This study aimed to evaluate an approach of circumferential pulmonary vein isolation (PVI) followed by a DF and CFAE site ablation.

Methods and Results

Fifty consecutive AF patients (23 paroxysmal, 9 persistent, and 18 longstanding persistent) underwent ablation, using NavX. When AF continued after circumferential PVI, high‐DF sites of ≥8 Hz and then continuous left atrial (LA) CFAE sites defined by fractionated intervals (FI) of ≤50 milliseconds including the coronary sinus and right atrium were targeted. A total of 45.1% of high‐DF and 48.1% of continuous CFAE sites significantly decreased after PVI (P < 0.001). The mean LA DF and FI significantly decreased and prolonged, respectively, after PVI (P < 0.001). Only 14.1% of all high‐DF sites after PVI overlapped with continuous CFAE sites. AF terminated at high‐DF sites in 11 (22%) patients and continuous CFAE sites in 1 (2%). AF could be induced in only 8% of patients after the procedure. The mean LA DF value before ablation was significantly lower in those without recurrence (P = 0.003). AF freedom on antiarrhythmic drugs was 96% and 59%, respectively, in the paroxysmal and nonparoxysmal AF patients (89% persistent and 44% longstanding persistent) after 1 procedure over a 12‐month follow‐up.

Conclusions

A combined high‐DF and continuous CFAE site ablation in all chambers after circumferential PVI may be effective in the paroxysmal and persistent AF patients.
Effects of Electrical Stimulation of Carotid Baroreflex and Renal Denervation on Atrial Electrophysiology
Authors: LINZ DOMINIK , MAHFOUD FELIX , SCHOTTEN ULRICH , UKENA CHRISTIAN , NEUBERGER HANS‐RUPRECHT , WIRTH KLAUS , BÖHM MICHAEL
Published: April 2013

Renal Denervation and Baroreflex Stimulation

Introduction

This study was designed to compare the effect of electrical baroreflex stimulation (BRS) at an intensity used in hypertensive patients and renal denervation (RDN) on atrial electrophysiology. BRS and RDN reduce blood pressure and global sympathetic drive in patients with resistant hypertension. Whereas RDN decreases sympathetic renal afferent nerve activity, leading to decreased central sympathetic drive, BRS modulates autonomic balance by activation of the baroreflex, resulting in both reduced sympathetic drive and increased vagal activation. Increased vagal tone potentially shortens atrial refractoriness resulting in a stabilization of reentry circuits perpetuating atrial fibrillation (AF).

Methods and Results

In normotensive anesthetized pigs (n = 12), we compared the acute effect of BRS and RDN on blood pressure, atrial effective refractory period (AERP), and inducibility of AF. Electrical BRS was titrated to result in comparable heart rate and blood pressure reduction compared to irreversible RDN. BRS resulted in a rapid and pronounced shortening of AERP (from 162 ± 8 milliseconds to 117 ± 16 milliseconds, P = 0.001) associated with increased AF‐inducibility from 0% to 82%. This shortening in AERP was completely reversible after stopping BRS. After administration of atropine, AF‐inducibility during BRS was attenuated. Ventricular repolarization was not modulated by BRS. In RDN, AF was not inducible; however, it did not prevent BRS‐induced shortening of AERP.

Conclusion

RDN and BRS resulting in comparable blood pressure and heart rate reductions differently influence atrial electrophysiology. Vagally mediated shortening of AERP, resulting in increased AF‐inducibility, was observed with BRS but not with RDN.
Akt‐mediated anti‐apoptotic effects of substance P in Anti‐Fas‐induced apoptosis of human tenocytes
Authors: Backman Ludvig J. , Danielson Patrik
Published: April 2013

Substance P (SP) and its receptor, the neurokinin‐1 receptor (NK‐1 R), are expressed by human tenocytes, and they are both up‐regulated in cases of tendinosis, a condition associated with excessive apoptosis. It is known that SP can phosphorylate/activate the protein kinase Akt, which has anti‐apoptotic effects. This mechanism has not been studied for tenocytes. The aims of this study were to investigate if Anti‐Fas treatment is a good apoptosis model for human tenocytes in vitro, if SP protects from Anti‐Fas‐induced apoptosis, and by which mechanisms SP mediates an anti‐apoptotic response. Anti‐Fas treatment resulted in a time‐ and dose‐dependent release of lactate dehydrogenase (LDH), i.e. induction of cell death, and SP dose‐dependently reduced the Anti‐Fas‐induced cell death through a NK‐1 R specific pathway. The same trend was seen for the TUNEL assay, i.e. SP reduced Anti‐Fas‐induced apoptosis via NK‐1 R. In addition, it was shown that SP reduces Anti‐Fas‐induced decrease in cell viability as shown with crystal violet assay. Protein analysis using Western blot confirmed that Anti‐Fas induces cleavage/activation of caspase‐3 and cleavage of PARP; both of which were inhibited by SP via NK‐1 R. Finally, SP treatment resulted in phosphorylation/activation of Akt as shown with Western blot, and it was confirmed that the anti‐apoptotic effect of SP was, at least partly, induced through the Akt‐dependent pathway. In conclusion, we show that SP reduces Anti‐Fas‐induced apoptosis in human tenocytes and that this anti‐apoptotic effect of SP is mediated through NK‐1 R and Akt‐specific pathways.
Spatial population structure of the Neotropical tiger catfish Pseudoplatystoma metaense: skull and otolith shape variation
Authors: Pérez A. , Fabré N. N.
Published: April 2013

Using geometric morphometrics, the skull and otolith of tiger catfish Pseudoplatystoma metaense were analysed to identify population structure in tributaries of the Apure River (i.e. the Sarare, Caparo, Guanare, Portuguesa and San Carlos Rivers) in the Orinoco basin, Venezuela. The analyses show uniformity in skull and otolith shapes of P. metaense within and among four tributaries, with only the Caparo River showing significant differences. Within the Apure basin, the stock of P. metaense was differentiated through spawning, refuge and nursery areas. This study concludes that populations of P. metaense from each major tributary in the Orinoco basin should be considered as part of a metapopulation system for management purposes. Human disturbances in the catchment have directly reduced the spawning areas available to this species, decreased the total biomass and changed the spatial distribution of spawning areas.
Imaging haematopoietic cells recruitment to an acute wound in vivo identifies a role for c‐Met signalling
Authors: FALENTA K. , RODAWAY A. , JONES G.E. , WELLS C.M.
Published: April 2013

We have used a direct in vivo imaging strategy to investigate the role of c‐Met signalling and kinase activity during the immune response to wounding. Our assay utilizes the optical translucent properties of the zebrafish embryo and demonstrates the versatility of microscopy‐based approach to the screening of compounds for inhibition of the wounding response. We have focussed on the c‐Met pathway as little is known about the influence of c‐Met signalling in immune responses, although it has been suggested that the c‐Met tyrosine kinase receptor signalling pathway may be involved in cytokine secretion and directional migration in immune cells. Using both imaging of fixed zebrafish embryos in combination with digital time lapse microscopy of neutrophils recruited to a wound site, we find that pharmacological inhibition of c‐Met, using a specific inhibitor, modulates the immune response in zebrafish embryos. We have found that inhibition of c‐Met does not prevent the inflammatory response but does appear to limit recruitment and retention of immune cells at the wound site. This work demonstrates the versatility of using direct imaging assays for inhibitor studies and suggests that the HGF/c‐Met signalling cascade plays an important role in the migration of haematopoietic cells in vivo.
Hypoglycaemic episodes and risk of dementia in diabetes mellitus: 7‐year follow‐up study
Authors: Lin C.‐H. , Sheu W. H.‐H.
Published: April 2013

Objective

We investigated the risk of dementia in patients with type 2 diabetes with or without prior hypoglycaemic episodes.

Subjects and Setting

One million subjects randomly selected from the National Health Insurance Research Database, Taiwan.

Results

A total of 15 404 diabetic subjects without prior dementia and a mean age of 64.2 years were enrolled in the study. About 2% (n = 289) of participants had at least one episode of hypoglycaemia in a 3‐year period; these subjects were older and more likely to be women and also had higher rates of insulin use and comorbidities compared to those without hypoglycaemia. During a total of 7 years of follow‐up (mean and median follow‐up, 3.8 and 4.8 years, respectively), 1106 patients with diabetes (7.2%) developed dementia. The incidence rate of dementia was higher in diabetic subjects with [29.9 per 1000 person‐years (95% CI 22.1–39.2)] compared to those without [11.1 per 1000 person‐years (95% CI 10.3–11.8)] hypoglycaemic episodes. The crude rate ratio (RR) and age‐ and gender‐adjusted RR values for dementia were 2.76 (95% CI 2.06–3.70, P < 0.001) and 1.60 (95% CI 1.19–2.14, P = 0.002), respectively, in diabetic subjects with hypoglycaemia compared to those without hypoglycaemia. Results of Cox proportional hazards analysis revealed that hypoglycaemia, older age, female gender and insulin use were independent predictors of dementia.

Conclusion

Adult diabetic patients with prior hypoglycaemia had a significantly increased risk of dementia. The influence of hypoglycaemic episodes on brain function warrants further investigation.
Prevalence and extent of subclinical atherosclerosis in patients with psoriasis
Authors: Yiu K.‐H. , Yeung C.‐K. , Zhao C.‐T. , Chan J. C. , Siu C.‐W. , Tam S. , Wong C.‐S. , Yan G. H. , Yue W. S. , Khong P.‐L. , Chan H. H. , Tse H.‐F.
Published: April 2013

Objective

Patients with psoriasis are prone to premature atherosclerosis and increased risk of cardiovascular disease events. However, the prevalence and extent of atherosclerosis in patients with psoriasis are unknown.

Design

A cross‐sectional study.

Setting and subjects

The prevalence and extent of coronary and carotid atherosclerosis were compared in 70 patients with psoriasis (46 ± 9 years, 71% male) without known cardiovascular disease or joint involvement and 51 age‐ and gender‐matched healthy control subjects (45 ± 7 years, 71% male). Systemic inflammation was assessed by the level of high‐sensitivity C‐reactive protein (hs‐CRP). Coronary atherosclerosis was determined by the coronary calcification score (CCS) measured by multi‐detector computed tomography. Carotid atherosclerosis was assessed by high‐resolution ultrasound‐derived carotid intima–media thickness (cIMT).

Results

Patients with psoriasis had a higher prevalence of coronary atherosclerosis (CCS > 0; 28.6% vs. 3.9%, P < 0.01), and a higher degree of coronary atherosclerosis estimated by the mean CCS (67.4 ± 349.2 vs. 0.5 ± 3.0, P < 0.05) compared with controls. Similarly, cIMT was significantly greater in patients with psoriasis than in control subjects (0.73 ± 0.11 mm vs. 0.67 ± 0.08 mm, P < 0.01). Multiple logistic regression revealed that psoriasis [odd ratio (OR): 10.54, 95% confidence interval (CI) 1.89–58.67, P < 0.01] and serum total cholesterol level (OR 2.10, 95% CI 1.01–4.37) were associated with the presence of coronary atherosclerosis (CCS > 0). By contrast, only age was independently associated with increased cIMT. Amongst participants with no traditional cardiovascular disease risk factors, hs‐CRP level was higher in patients with psoriasis than in controls.

Conclusion

The present results demonstrate early‐onset, diffuse arterial atherosclerosis in coronary and carotid arteries in patients with psoriasis, but not in age‐ and gender‐matched control subjects. Low‐grade inflammation could explain the presence of premature atherosclerosis in patients with psoriasis.
Biofilm infections, their resilience to therapy and innovative treatment strategies
Authors: Römling U. , Balsalobre C.
Published: April 2013

Biofilm formation of microorganisms causes persistent tissue and foreign body infections resistant to treatment with antimicrobial agents. Up to 80% of human bacterial infections are biofilm associated; such infections are most frequently caused byStaphylococcus epidermidis,Pseudomonas aeruginosa,Staphylococcus aureusandEnterobacteria such asEscherichia coli. The accurate diagnosis of biofilm infections is often difficult, which prevents the appropriate choice of treatment. As biofilm infections significantly contribute to patient morbidity and substantial healthcare costs, novel strategies to treat these infections are urgently required. Nucleotide second messengers, c‐di‐GMP, (p)ppGpp and potentially c‐di‐AMP, are major regulators of biofilm formation and associated antibiotic tolerance. Consequently, different components of these signalling networks might be appropriate targets for antibiofilm therapy in combination with antibiotic treatment strategies. In addition, cyclic di‐nucleotides are microbial‐associated molecular patterns with an almost universal presence. Their conserved structures sensed by the eukaryotic host have a widespread effect on the immune system. Thus, cyclic di‐nucleotides are also potential immunotherapeutic agents to treat antibiotic‐resistant bacterial infections.