bluuebunny/crossref_metadata_2025 huggingface dataset:
Perceptions by and of lonely people in social networks
Authors: TSAI FEN‐FANG , REIS HARRY T.
Published: June 2009

Although past research has associated loneliness with negative perceptions of others, P. Christensen and D. A. Kashy (1998), using the social relations model (SRM), found that among new acquaintances, loneliness was associated with more positive other‐perceptions. SRM was used to examine loneliness and interpersonal perception within existing social networks. Seventy‐three university students in the United States rated themselves and others on 19 attributes and also judged how they thought others saw them (meta‐perceptions). Results indicated that lonely people tended to be more negative toward closer targets and somewhat positive toward less close acquaintances. Lonely people had lower self‐regard and perceived self‐regard, invariant across acquaintanceship, and were rated more negatively by others. Relationship contexts thus moderate effects of loneliness on other‐perceptions.
Attachment and dependence regulation within daily interactions with romantic partners
Authors: OVERALL NICKOLA C. , SIBLEY CHRIS G.
Published: June 2009

For 2 weeks, 74 New Zealand undergraduate students recorded their reactions to two components of situational dependence during interactions with their romantic partner: low personal control and high partner impact. Lower personal control predicted lower perceived regard and intimacy, greater partner derogation and withdrawal (self‐protective dependence regulation), and reduced attempts to improve interaction quality (relationship‐promotive dependence regulation). Participants also reported greater self‐protective dependence regulation the more their partner was impacting on their thoughts, feelings, and behaviors. As expected, more anxious individuals reported higher drops in perceived regard and greater self‐protective dependence regulation when experiencing lower control, whereas more avoidant individuals reported lower regard and reduced relationship‐promotive behavior when experiencing stronger partner impact. The links between attachment and dependence are discussed.
Dual PDE3/4 inhibitors as therapeutic agents for chronic obstructive pulmonary disease
Authors: Banner Katharine H , Press Neil J
Published: June 2009

Phosphodiesterase (PDE)4, and to a lesser extent, PDE3/4 inhibitors have attracted considerable interest as potential therapeutic agents for diseases including chronic obstructive pulmonary disease. Indeed, ibudilast and theophylline are utilized clinically, and roflumilast is in late‐stage clinical development. Unfortunately, however many PDE4 and dual PDE3/4 inhibitors have failed in early development due to low therapeutic ratios. The majority of these compounds are however orally administered and non‐selective for either PDE3(A, B) or PDE4(A, B, C, D) subtypes. Developing an inhaled dual PDE3/4 inhibitor with subtype specificity may represent one strategy to improve the therapeutic index. Indeed combined inhibition of PDE3 and PDE4 inhibitor has additive and synergistic anti‐inflammatory and bronchodilatory effects versus inhibition of either PDE3 or PDE4 alone. Given that synergy has been seen in terms of efficacy end points, an obvious concern is that synergy may also be observed in side effects. Interestingly, however, no synergy or additive effects with a combination of a PDE3 and PDE4 inhibitor in a cardiomyocyte assay were observed. This review will summarize the rationale for developing an inhaled dual PDE3/4 inhibitor, as a treatment for chronic obstructive pulmonary disease together with recent advances in trying to understand the pathogenesis of PDE inhibitor‐induced mesenteric vasculitis (a key potential dose‐limiting side effect of these agents), highlighting potential early and sensitive predictive biomarkers.
Clinical Application of the Ellipsoid Left Heart Assist Device
Authors: Wolner Ernst , Deutsch Manfred , Losert Udo , Stellwag Fritz , Thoma Herwig , Unger Felix , Polzer Kurt , Navratil Johann
Published: June 2009

The ellipsoid left heart assist device (E‐LVAD) was implanted in eight patients suffering from intra‐operative heart failure. It was not possible to remove these patients from extracorporeal circulation following an intracardiac procedure; therefore, implantation of the E‐LVAD was performed during extracorporeal circulation. The inflow connector was pushed forward from a purse‐string suture on the right superior pulmonary vein, across the mitral valve and into the left ventricle. The outflow connector was joined to the ascending aorta. In two patients, the artificial heart chamber was removed after complete recovery of the circulation; these patients, however, later died. In six other patients, untreatable right heart failure developed and these patients died with the pump in place. It is concluded, therefore, that the right heart must also be mechanically supported during postoperative heart failure.
Endothelial‐derived thrombospondin‐1 promotes macrophage recruitment and apoptotic cell clearance
Authors: Kirsch Torsten , Woywodt Alexander , Klose Johannes , Wyss Kristin , Beese Michaela , Erdbruegger Uta , Grossheim Marieke , Haller Hermann , Haubitz Marion
Published: June 2009

Rapid apoptotic cell engulfment is crucial for prevention of inflammation and autoimmune diseases and is conducted by special immunocompetent cells like macrophages or immature dendritic cells. We recently demonstrated that endothelial cells (ECs) also participate in apoptotic cell clearance. However, in contrast to conventional phagocytes they respond with an inflammatory phenotype. To further confirm these pro‐inflammatory responses human ECs were exposed to apoptotic murine ECs and changes in thrombospondin‐1 (TSP‐1) expression and in activation of intracellular signalling cascades were determined by real‐time qPCR, immunoblotting and immunocytochemistry. Human primary macrophages or monocytic lymphoma cells (U937) were incubated with conditioned supernatant of human ECs exposed to apoptotic cells and changes in activation, migration and phagocytosis were monitored. Finally, plasma levels of TSP‐1 in patients with anti‐neutrophil cytoplasmic antibody(ANCA)‐associated vasculitis (AAV) were determined by ELISA. We provided evidence that apoptotic cells induce enhanced expression of TSP‐1 in human ECs and that this increase in TSP‐1 is mediated by the mitogen‐activated protein kinases (MAPK) ERK1 and 2 and their upstream regulators MEK and B‐Raf. We also showed that plasma TSP‐1 levels are increased in patients with AAV. Finally, we showed that conditioned supernatant of ECs exposed to apoptotic cells induces pro‐inflammatory responses in monocytes or U937 cells and demonstrated that increased TSP‐1 expression enhances migration and facilitates engulfment of apoptotic cells by monocyte‐derived macrophages or U937 cells. These findings suggest that under pathological conditions with high numbers of uncleared dying cells in the circulation endothelial‐derived elevated TSP‐1 level may serve as an attraction signal for phagocytes promoting enhanced recognition and clearance of apoptotic cells.
Professional and patient‐based evaluation of oral rehabilitation in patients with tooth agenesis
Authors: Dueled Erik , Gotfredsen Klaus , Trab Damsgaard Mogens , Hede Børge
Published: June 2009

Objectives: The outcome of oral rehabilitation is usually monitored with clinical tests rather than by patient's perception of change. The aim of this study was to describe the objective measure and subjective perception of oral rehabilitation in patients with tooth agenesis.

Material and methods: The study included 129 patients with tooth agenesis rehabilitated with implant‐ or tooth‐supported reconstructions, and a control group of 58 patients. Professional assessments included biological, technical and aesthetic variables. An aesthetic index score included mucosal discoloration, crown morphology, crown color match, occlusal harmony, and papilla level. The Oral Health Impact Profile (OHIP) questionnaire was used to evaluate the patient‐based outcomes. Six OHIP questions were subtracted to evaluate the patient‐based aesthetic outcomes.

Results: Severe root resorption was observed in 36% of the patients in whom orthodontic treatment had been performed. Twelve percent of patients had implants with 5–7 mm peri‐implant bone defects. Mucosal discoloration was recorded in 57% of the patients. Twelve percent of the patients had metal visible on the buccal side. The median scores for all five aesthetic variables were acceptable in 92% of the implant reconstructions and for 83% of the tooth‐supported fixed dental prostheses (FDPs). The total OHIP score was inferior in rehabilitated patients with tooth agenesis to that of the control group without tooth agenesis. The total OHIP score after rehabilitation was <50 for 95% of the patients with tooth agenesis. The six OHIP questions concerning aesthetics demonstrated patient‐based aesthetic problems in 41% of patients treated with implant‐supported reconstructions and 47% of patients treated with tooth‐supported FDPs. Ninety‐eight percent of the group treated with implant‐supported reconstructions and 84% of the patients in the tooth‐supported FDP group were very satisfied or satisfied with the treatment outcome.

Conclusions: Patients with tooth agenesis had a high risk of severe root resorption after orthodontic treatment. A better aesthetic outcome was obtained with implant‐supported reconstructions than with tooth‐supported reconstructions. A positive but not significant correlation was observed between the professional and patient‐based evaluations of aesthetic outcomes.
Pseudoangiomatous stromal hyperplasia in a complex neoplastic lesion involving anogenital mammary‐like glands
Authors: Vazmitel Marina , Pavlovsky Michal , Kacerovska Denisa , Michal Michal , Kazakov Dmitry V.
Published: June 2009

Anogenital mammary‐like glands (AMLG) may give rise to various pathologic lesions identical to those known in mammary pathology. Pseudoangiomatous stromal hyperplasia (PASH), a relatively frequent hormonal change associated with different benign and malignant processes in the breast, was only once mentioned in the literature concerning the pathology of AMLG. We present here a new case of PASH in a lesion of AMLG. The present case of PASH is remarkable because of its occurrence within a complex lesion evidencing the changes identical to or reminiscent of blunt duct adenosis, fibroadenoma and hidradenoma papilliferum.
RAPID DETECTION OFBRUCELLA ABORTUSBY A NOVEL PROXIMITY LIGATION‐BASED LOOP‐MEDIATED ISOTHERMAL AMPLIFICATION METHOD
Authors: ZHU CHENGGANG , DENG XIAOYAN , SHI FENG
Published: June 2009

Brucellosis is one of the most common zoonotic diseases, and current methods of detecting this pathogen are quite difficult. This work combines the benefits of a proximity ligation assay with those of a loop‐mediated isothermal amplification method to develop a novel proximity ligation‐based loop‐mediated isothermal amplification method useful forBrucelladetection. The genomic DNA extraction procedure is not needed. Sensitivity of this assay for detectingBrucella abortusis 1 × 104cells/mL in buffer and 1 × 105cells/mL in milk. The time to detection is within 2 h of initiating the procedure, and no special equipment is needed. This new method is also suitable for the detection of other pathogens, and as such will be useful in the food safety industry.

PRACTICAL APPLICATIONS

Polymerase chain reaction (PCR) is a sensitivity method for microbe detection, but the complicated genomic DNA extraction procedure and costly equipment needed for this method makes the PCR method unpopular in developing countries. In this study, we present the novel proximity ligation‐based loop‐mediated isothermal amplification (P‐LAMP) method forBrucelladetection; this is the first time to combine the monoclonal antibody for identify microbe and LAMP method for high performance amplification DNA. The genomic DNA extraction procedure is not needed and a water‐bath boiler is the only equipment required to complete the detection process. The P‐LAMP method is useful for food safety pathogen detection in developing countries.
Quantification of Sensory and Food Quality: The R‐Index Analysis
Authors: Lee Hye‐Seong , Van Hout Danielle
Published: June 2009

ABSTRACT:  The accurate quantification of sensory difference/similarity between foods, as well as consumer acceptance/preference and concepts, is greatly needed to optimize and maintain food quality. The R‐Index is one class of measures of the degree of difference/similarity, and was originally developed for sensory difference tests for food quality control, product development, and so on. The index is based on signal detection theory and is free of the response bias that can invalidate difference testing protocols, including categorization and same‐different and A‐Not A tests. It is also a nonparametric analysis, making no assumptions about sensory distributions, and is simple to compute and understand. The R‐Index is also flexible in its application. Methods based on R‐Index analysis have been used as detection and sensory difference tests, as simple alternatives to hedonic scaling, and for the measurement of consumer concepts. This review indicates the various computational strategies for the R‐Index and its practical applications to consumer and sensory measurements in food science.
Amplified Trace Gas Removal in the Troposphere
Authors: Hofzumahaus Andreas , Rohrer Franz , Lu Keding , Bohn Birger , Brauers Theo , Chang Chih-Chung , Fuchs Hendrik , Holland Frank , Kita Kazuyuki , Kondo Yutaka , Li Xin , Lou Shengrong , Shao Min , Zeng Limin , Wahner Andreas , Zhang Yuanhang
Published: June 2009

Going Faster

The concentrations of most tropospheric pollutants and trace gases are kept in check by their reactions with hydroxyl radicals (OH). OH is a short-lived, highly reactive species that is produced in the atmosphere by photochemical processes, and regenerated in the chain of chemical reactions that follows the oxidative destruction of those molecules. These regeneration mechanisms were thought to be fairly well understood, but now

Hofzumahaus
et al.

(p.
1702
, published online 4 June) present evidence of a pathway not previously recognized. In a study of atmospheric composition in the Pearl River Delta, a highly polluted region of China, greatly elevated OH concentrations were observed without the correspondingly high levels of ozone expected from current models. Thus, OH concentrations may be augmented by a process that speeds the regeneration of OH without producing ozone.
Hidden Assumptions and the Placebo Effect
Authors: Campbell Anthony
Published: June 2009

Whether, or how far, acupuncture effects can be explained as due to the placebo response is clearly an important issue, but there is an underlying philosophical assumption implicit in much of the debate, which is often ignored. Much of the argument is cast in terms which suggest that there is an immaterial mind hovering above the brain and giving rise to spurious effects. This model derives from Cartesian dualism which would probably be rejected by nearly all those involved, but it is characteristic of “folk psychology” and seems to have an unconscious influence on much of the terminology that is used. The majority of philosophers today reject dualism and this is also the dominant trend in science. Placebo effects, on this view, must be brain effects. It is important for modern acupuncture practitioners to keep this in mind when reading research on the placebo question.
AN ORFOME ASSEMBLY APPROACH TO METAGENOMICS SEQUENCES ANALYSIS
Authors: YE YUZHEN , TANG HAIXU
Published: June 2009

Metagenomics is an emerging methodology for the direct genomic analysis of a mixed community of uncultured microorganisms. The current analyses of metagenomics data largely rely on the computational tools originally designed for microbial genomics projects. The challenge of assembling metagenomic sequences arises mainly from the short reads and the high species complexity of the community. Alternatively, individual (short) reads will be searched directly against databases of known genes (or proteins) to identify homologous sequences. The latter approach may have low sensitivity and specificity in identifying homologous sequences, which may further bias the subsequent diversity analysis. In this paper, we present a novel approach to metagenomic data analysis, called Metagenomic ORFome Assembly (MetaORFA). The whole computational framework consists of three steps. Each read from a metagenomics project will first be annotated with putative open reading frames (ORFs) that likely encode proteins. Next, the predicted ORFs are assembled into a collection of peptides using an EULER assembly method. Finally, the assembled peptides (i.e. ORFome) are used for database searching of homologs and subsequent diversity analysis. We applied MetaORFA approach to several metagenomics datasets with low coverage short reads. The results show that MetaORFA can produce long peptides even when the sequence coverage of reads is extremely low. Hence, the ORFome assembly significantly increases the sensitivity of homology searching, and may potentially improve the diversity analysis of the metagenomic data. This improvement is especially useful for metagenomic projects when the genome assembly does not work because of the low sequence coverage.
A FAST AND ACCURATE ALGORITHM FOR COMPARATIVE ANALYSIS OF METABOLIC PATHWAYS
Authors: AY FERHAT , KAHVECI TAMER , DE CRÉCY-LAGARD VALÉRIE
Published: June 2009

Pathways show how different biochemical entities interact with one another to perform vital functions for the survival of an organism. Comparative analysis of pathways is crucial in identifying functional similarities that are difficult to identify by comparing individual entities that build up these pathways. When interacting entities are of single type, the problem of identifying similarities by aligning the pathways can be reduced to graph isomorphism problem. For pathways with varying types of entities such as metabolic pathways, alignment problem is even more challenging. In order to simplify this problem, existing methods often reduce metabolic pathways to graphs with restricted topologies and single type of nodes. However, these abstractions reduce the relevance of the alignment significantly as they cause losses in the information content. In this paper, we describe an algorithm to solve the pairwise alignment problem for metabolic pathways. A distinguishing feature of our method is that it aligns different types of entities, such as enzymes, reactions and compounds. Also, our approach is free of any abstraction in modeling the pathways. We pursue the intuition that both pairwise similarities of entities (homology) and the organization of their interactions (topology) are important for metabolic pathway alignment. In our algorithm, we account for both by creating an eigenvalue problem for each entity type. We enforce the consistency while combining the alignments of different entity types by considering the reachability sets of entities. Our experiments show that our method finds biologically and statistically significant alignments in the order of milliseconds.

Availability: Our software and the source code in C programming language is available at .
EFFICIENT COMPUTATION OF KINSHIP AND IDENTITY COEFFICIENTS ON LARGE PEDIGREES
Authors: CHENG EN , ELLIOTT BRENDAN , ÖZSOYOǦLU Z. MERAL
Published: June 2009

With the rapidly expanding field of medical genetics and genetic counseling, genealogy information is becoming increasingly abundant. An important computation on pedigree data is the calculation of identity coefficients, which provide a complete description of the degree of relatedness of a pair of individuals. The areas of application of identity coefficients are numerous and diverse, from genetic counseling to disease tracking, and thus, the computation of identity coefficients merits special attention. However, the computation of identity coefficients is not done directly, but rather as the final step after computing a set of generalized kinship coefficients. In this paper, we first propose a novel Path-Counting Formula for calculating generalized kinship coefficients, which is motivated by Wright's path-counting method for computing inbreeding coefficient. We then present an efficient and scalable scheme for calculating generalized kinship coefficients on large pedigrees using NodeCodes, a special encoding scheme for expediting the evaluation of queries on pedigree graph structures. Furthermore, we propose an improved scheme using Family NodeCodes for the computation of generalized kinship coefficients, which is motivated by the significant improvement of using Family NodeCodes for inbreeding coefficient over the use of NodeCodes. We also perform experiments for evaluating the efficiency of our method, and compare it with the performance of the traditional recursive algorithm for three individuals. Experimental results demonstrate that the resulting scheme is more scalable and efficient than the traditional recursive methods for computing generalized kinship coefficients.
How Sweet it is! Cell Wall Biogenesis and Polysaccharide Capsule Formation in Cryptococcus neoformans
Authors: Doering Tamara Lea
Published: June 2009

Cryptococcus neoformans is a pathogenic fungus responsible for severe opportunistic infections. The most prominent feature of this yeast is its elaborate polysaccharide capsule, a complex structure that is required for virulence. The capsule is intimately associated with the cell wall, which underlies the capsule and offers the organism strength and flexibility in potentially hostile environments. Both structures are primarily composed of polysaccharides, offering a glimpse of the tremendous variation inherent in natural carbohydrate structures and their multiple biological functions. The steps in cell wall and capsule biosynthesis and assembly pose fascinating questions of metabolism, enzymology, cell biology, and regulation; the answers have potential application to treatment of a deadly infection. This article reviews current knowledge of cryptococcal cell wall and capsule biosynthesis and outstanding questions for the future.
Neutrophil chemokines and their role in IL-18-mediated increase in neutrophil O2−production and intestinal edema following alcohol intoxication and burn injury
Authors: Akhtar Suhail , Li Xiaoling , Chaudry Irshad H. , Choudhry Mashkoor A.
Published: June 2009

We examined the role of interleukin (IL)-18 and cytokine-induced neutrophil chemokines (CINC)-1 and CINC-3 in the neutrophil release of superoxide anion (O2−) and elastase following alcohol/ethanol (EtOH) and burn injury. Male rats (∼250 g) were gavaged with EtOH to achieve a blood EtOH level of ∼100 mg/dl before ∼12.5% total body surface area burn or sham injury. Immediately after injury, rats were administered with anti-rat IL-18 antibody (80 μg/kg) or isotype control. After 20 min, anti-IL-18 antibody-treated rats were given either recombinant (r) rat CINC-1 or CINC-3. On day 1 after injury, the combined insult of EtOH and burn injury caused a significant increase in neutrophil elastase and O2−production as well as an increase in neutrophil accumulation, myeloperoxidase activity, and edema in the intestine. Treatment of rats with anti-IL-18 antibody normalized the above parameters. However, administration of rCINC-1 in anti-IL-18 antibody-treated rats increased the above parameters to levels similar to those observed following EtOH and burn injury. In contrast, administration of rCINC-3 did not influence the above parameters except neutrophil elastase. These findings indicate that IL-18 and CINC-1 may independently modulate neutrophil tissue-damaging actions following EtOH and burn injury. However, the finding that the treatment of rats with anti-IL-18 antibodies inhibits CINC-1 and CINC-3 supports the notion that IL-18 plays a critical role in increased neutrophil tissue-damaging action following a combined insult of EtOH intoxication and burn injury.
Localization of TRPV1 and contractile effect of capsaicin in mouse large intestine: high abundance and sensitivity in rectum and distal colon
Authors: Matsumoto Kenjiro , Kurosawa Emi , Terui Hiroyuki , Hosoya Takuji , Tashima Kimihito , Murayama Toshihiko , Priestley John V. , Horie Syunji
Published: June 2009

We investigated immunohistochemical differences in the distribution of TRPV1 channels and the contractile effects of capsaicin on smooth muscle in the mouse rectum and distal, transverse, and proximal colon. In the immunohistochemical study, TRPV1 immunoreactivity was found in the mucosa, submucosal, and muscle layers and myenteric plexus. Large numbers of TRPV1-immunoreactive axons were observed in the rectum and distal colon. In contrast, TRPV1-positive axons were sparsely distributed in the transverse and proximal colon. The density of TRPV1-immunoreactive axons in the rectum and distal colon was much higher than those in the transverse and proximal colon. Axons double labeled with TRPV1 and protein gene product (PGP) 9.5 were detected in the myenteric plexus, but PGP 9.5-immunoreactive cell bodies did not colocalize with TRPV1. In motor function studies, capsaicin induced a fast transient contraction, followed by a large long-lasting contraction in the rectum and distal colon, whereas in the transverse and proximal colon only the transient contraction was observed. The capsaicin-induced transient contraction from the proximal colon to the rectum was moderately inhibited by an NK1or NK2receptor antagonist. The capsaicin-induced long-lasting contraction in the rectum and distal colon was markedly inhibited by an NK2antagonist, but not by an NK1antagonist. The present results suggest that TRPV1 channels located on the rectum and distal colon play a major role in the motor function in the large intestine.
Exercise capacity is related to calcium transients in ventricular cardiomyocytes
Authors: Prímola-Gomes Thales N. , Campos Lúcia A. , Lauton-Santos Sandra , Balthazar Cláudio H. , Guatimosim Silvia , Capettini Luciano S. A. , Lemos Virgínia S. , Coimbra Cândido C. , Soares Danusa D. , Carneiro-Júnior Miguel A. , Quintão-Júnior Judson F. , Souza Matheus O. , Cruz Jader S. , Natali Antonio J.
Published: June 2009

The aim of the present study was to evaluate the Ca2+handling and contractility properties of cardiomyocytes isolated from rats with high intrinsic aerobic exercise capacity. Standard-performance (SP) and high-performance (HP) rats were categorized with a treadmill progressive exercise test according to the exercise time to fatigue (TTF). The SP group included rats with TTF between 16.63 and 46.57 min, and the HP group included rats with TTF >46.57 min. Isolated ventricular cardiomyocytes were dissociated from the hearts of SP and HP rats, and intracellular global Ca2+([Ca2+]i) transients were measured. The [Ca2+]itransient peak was increased in the HP group relative to the SP group (5.54 ± 0.31 vs. 4.18 ± 0.12 F/F0; P ≤ 0.05) and was positively correlated with the TTF attained during the progressive test ( r = 0.81). We also performed contractility measurements in isolated cardiomyocytes and found higher amplitude of contraction in the HP group compared with the SP group (6.7 ± 0.2 vs. 6.0 ± 0.3% resting cell length; P ≤ 0.05). To reinforce the intrinsic differences between SP and HP rats, we performed Western blot experiments and observed increased expression of sarco(endo)plasmic reticulum Ca2+-ATPase type 2a (1.30 ± 0.07 vs. 1.74 ± 0.18 arbitrary units; P ≤ 0.05) and ryanodine receptor type 2 (1.86 ± 0.13 vs. 3.57 ± 0.12 arbitrary units; P ≤ 0.05) in HP rats. In summary, our data showed important intrinsic differences in cardiomyocyte properties that could explain some of the divergence observed in rats with high intrinsic aerobic exercise capacity.
Temporal pattern of skeletal muscle gene expression following endurance exercise in Alaskan sled dogs
Authors: Brass Eric P. , Peters Mette A. , Hinchcliff Kenneth W. , He Yudong D. , Ulrich Roger G.
Published: June 2009

Muscle responses to exercise are complex and include acute responses to exercise-induced injury, as well as longer term adaptive training responses. Using Alaskan sled dogs as an experimental model, changes in muscle gene expression were analyzed to test the hypotheses that important regulatory elements of the muscle's adaptation to exercise could be identified based on the temporal pattern of gene expression. Dogs were randomly assigned to undertake a 160-km run ( n = 9), or to remain at rest ( n = 4). Biceps femoris muscle was obtained from the unexercised dogs and two dogs at each of 2, 6, and 12 h after the exercise, and from three dogs 24 h after exercise. RNA was extracted and microarray analysis used to define gene transcriptional changes. The changes in gene expression after exercise occurred in a temporal pattern. Overall, 569, 469, 316, and 223 transcripts were differentially expressed at 2, 6, 12, and 24 h postexercise, respectively, compared with unexercised dogs (based on P ≤ 0.01 and an absolute fold change of ≥1.5). Increases in a number of known transcriptional regulators, including peroxisome proliferator-activated receptor-α, cAMP-responsive element modulator, and CCAAT enhancer binding protein-δ, and potential signaling molecules, including brain-derived neurotrophic factor, dermokine, and suprabasin, were observed 2 h after exercise. Biological functional analysis suggested changes in expression of genes with known functional relationships, including genes involved in muscle remodeling and growth, intermediary metabolism, and immune regulation. Sustained endurance exercise by Alaskan sled dogs induces coordinated changes in gene expression with a clear temporal pattern. RNA expression profiling has the potential to identify novel regulatory mechanisms and responses to exercise stimuli.
Laboratory Diagnosis of von Willebrand Disease Type 1/2E (2A Subtype IIE), Type 1 Vicenza and Mild Type 1 Caused by Mutations in the D3, D4, B1–B3 and C1–C2 Domains of the von Willebrand Factor Gene
Authors: Gadisseur Alain , Berneman Zwi , Schroyens Wilfried , Michiels Jan Jacques
Published: June 2009

Autosomal dominant von Willebrand disease (VWD) type 1/2E is a quantitative/qualitative defect in the von Willebrand factor (VWF) caused by heterozygous cysteine and non-cysteine mutations in the D3 domain of the VWF gene and results in a secretion-multimerization-clearance defect in mutant VWF with the loss of large VWF multimers not due to proteolysis. The multimers of patients with dominant VWD type 1/2E due to mutations in the D3 domain show an aberrant triplet structure with lack of outer bands but with pronounced inner bands of the triplet structure combined with a relative decrease in large multimers reflecting heterozygosity for multimerization defects. There is a good response to desmopressin (DDAVP) followed by rapid clearance of VWF:antigen (Ag), factor VIII coagulant activity (FVIII:C) and VWF:ristocetin cofactor activity (RCo) as the main cause of VWD type 1 or 2 with typical 2E multimeric pattern (VWD type 1/2E). Cysteine mutations in the D3 domains (C1130, C1149 and C1190) show pronounced features of VWD 1/2E with the relative loss of large and relative increase in small VWF multimers with abnormal triplet structure in heterozygotes. Such abnormalities are less pronounced in patients with a milder form of VWD type 1 due to non-cysteine mutations W1144G, T1156M and W1120S in the D3 domain. VWD type 1 Vicenza is caused by the R1205H mutation in the D3 domain and characterized by equally low levels of FVIII:C, VWF:Ag and VWF:RCo. The response to DDAVP in VWD Vicenza is good for FVIII:C, VWF:Ag and VWF:RCo, which is followed by a rapid clearance in less than a few hours of FVIII:C and VWF parameters. The ratios for FVIII:C/VWF:Ag, VWF:RCo/Ag and VWF:CB/Ag remain normal before and after DDAVP indicating that VWD Vicenza clearly differs from VWD type 1, 1/2E and 2M. A new set of missense mutations in D4, B1–B3 and C1–C2 domains has been discovered as the cause of a mild VWD type 1 secretion defect with normal VWF multimers or smeary VWF multimeric pattern. Cysteine mutations in exons 38, 40, 42 and 43 (D4, B1–B3 and C1 domain), show smeary patterns (either smf or sm), with the presence of large VWF multimers and a laboratory phenotype of mild VWD type 1 with variable penetrance of bleeding manifestations. Recent studies showed that the ratio of VWF propeptide (pp) to VWF:Ag can be used to predict a shorter than normal half-life for VWF:Ag. There is a strong inverse correlation between rapid clearance of VWF:Ag after DDAVP and increased VWFpp/Ag ratios >10 in VWD type 1 Vicenza, and >2 in VWD type 1/2E but normal or slightly increased (1–<2) VWFpp/Ag ratios in mild-type VWD due to nonsense or missense mutations in the D1, D2, D4, B and C domains.
Evaluation of Immediate Allergic Reactions to Cephalosporins in Non-Penicillin-Allergic Patients
Authors: Somech Raz , Weber Elizabeth A. , Lavi Sasson
Published: June 2009

Background: Cephalosporins can induce severe or life-threatening IgE-mediated reactions in some individuals. In this study, we wish to describe a group of non-penicillin-allergic patients who were evaluated for immediate allergic reactions to cephalosporins. Methods: The patients were assessed by skin tests with the culprit cephalosporin as well as with other cephalosporins and penicillins. If indicated, oral challenge testing was performed. Results: Six patients were assessed. A total of 42 skin tests and 20 oral challenges were performed. In 4 patients, skin tests included the causative drug; in 2 patients, the diagnosis of a cephalosporin allergy was made by skin test; in 4 patients, the diagnosis of a cephalosporin hypersensitivity was made by oral challenge. In 96.9% of the oral challenges, which were done using medications with no structural side chain similarities to the culprit drug, no adverse reaction occurred. Conclusion: A positive skin test to cephalosporin implies the presence of drug-specific IgE antibodies. Cephalosporins without side chain similarities are suggested to patients with cephalosporin reactions and no β-lactam reactivity.
Local Nasal Immunotherapy: Efficacy of Dermatophagoides farinae-Chitosan Vaccine in Murine Asthma
Authors: Liu Zhigang , Guo Hua , Wu Yiaojiong , Yu Haiqiong , Yang Haitao , Li Jing
Published: June 2009

Background: Local nasal immunotherapy has been reported to be effective for airway allergic diseases. A biodegradable material, chitosan (CS), has been reported to be safe and effective in allergen delivery.In this study, we tested immunotherapeutic efficiency by intranasal administration of Der f entrapped in CS microparticles to sensitized mice. Methods: BALB/c mice were sensitized intraperitoneally with Der f extract absorbed to alum, followed by intranasal treatment with PBS, CS, Der f or Der f-CS nano-vaccine for 6 weeks. The mice were subsequently challenged intranasally with Der f extract for 1 week, and we analyzed their clinical symptoms, antibody expression levels, cytokine levels, T cell proliferation and regulatory T cell numbers. Results: Mice treated with intranasal Der f-CS nano-vaccine prior to challenge displayed an alleviated spectrum of symptoms including airway hyper-reactivity, lung inflammation and mucus production and had fewer eosinophilic cells in bronchoalveolar lavage fluid (BALF). Interestingly, the cytokine levels in Der f-specific IgE were reduced, but IgA in serum and BALF was increased. We also observed that IL-4 was reduced and IFN-γ and IL-10 were increased among splenocytes and in BALF, which inhibits Der f-specific T-cell proliferation in splenocytes and increases regulatory T cells in the spleen. However, the mice challenged without intranasal Der f or Der f-CS vaccine treatment developed allergic asthma. Conclusion: Our results illustrate that intranasal administration of Der f-CS nano-vaccine plays roles in immunologic protection in murine allergic asthma by inducing regulatory T cells and Th1-type reaction.
Association between ApoE ε4 and Cognitive Impairment after Stroke
Authors: Wagle Jørgen , Farner Lasse , Flekkøy Kjell , Wyller Torgeir Bruun , Sandvik Leiv , Eiklid Kristin L. , Fure Brynjar , Stensrød Brynhild , Engedal Knut
Published: June 2009

Background and Purpose: The understanding of the contribution of genetic factors to cognitive impairment after stroke is incomplete. The aim of the study was to examine whether the apolipoprotein E ε4 allele (ApoE ε4) is a risk factor for cognitive impairment in the early phase after stroke. Methods: The sample comprised 152 Norwegian stroke rehabilitation inpatients (mean age 76.8 years, SD 10.5) examined at a mean of 18.3 days (SD 13.4) after hospital admission. Post-stroke cognitive impairment was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The following proposed risk factors were analysed: ApoE genotype, demographics (age, sex, education), pre-stroke cognitive reduction [Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)], pre-stroke vascular factors (including previous stroke), stroke characteristics (type, location), and neurological stroke-related impairment [National Institutes of Health Stroke Scale (NIHSS)]. Cognitive impairment was defined as an RBANS total index score ≤1.5 SD below the mean. Multiple logistic regression analyses were performed to find risk factors for post-stroke cognitive impairment. Results: Four variables were found to be independent risk factors for cognitive impairment after stroke: ApoE ε4 (OR = 3.7; 95% CI = 1.2–11.6), IQCODE score ≥3.44 (OR = 9.2; 95% = CI 2.3–37.2), total or partial anterior stroke syndromes (OR = 3.2; 95% CI = 1.3–8.0), and NIHSS total score >5 (OR = 7.3; 95% CI = 2.7–19.7). No association between ApoE ε4 and pre-stroke cognitive reduction (IQCODE) was found. Conclusions: The presence of one or two ApoE ε4 alleles may be a significant independent risk factor for cognitive impairment in the early phase after stroke.
Evaluation of Glucocorticoid Sensitivity and Its Potential Clinical Applicability
Authors: Longui Carlos Alberto , Faria Cláudia Dutra Costantin
Published: June 2009

Glucocorticoids (GC) play an important role in physiologic and pathophysiologic adaptive responses to stress. The majority of these effects are mediated by the GC receptors (GR). GC sensitivity largely depends of the amount of available GR, and their ability to bind the GC-responsive element and/or other nuclear transcription factors, leading to modulation of the expression of GC target genes. Clinical conditions of tissue-specific GC resistance or GC hypersensitivity have been described in several diseases, such as chronic inflammatory and autoimmune conditions, and in visceral obesity, such as metabolic syndrome. Several in vivo and in vitro methods have been described, allowing the evaluation and quantitation of GC sensitivity. The recognition of these parameters has improved our comprehension of the mechanisms involved in those diseases, with potential implications for the diagnosis and therapy of such abnormalities.
Three Common Variants of LEP, NPY1R and GPR54 Show No Association with Age at Menarche
Authors: Rothenbuhler Anya , Lotton Chantal , Fradin Delphine
Published: June 2009

Context: Twin and family studies indicate a significant heritability of pubertal timing and more specifically of age at menarche (AAM). Objective: Test the association of AAM with common variants of three candidate genes suspected to have a prominent role in reproductive physiology: leptin (LEP), neuropeptide Y receptor 1 (NPY1R) and GPR54. Design and Methods: We selected the –2459 LEP, the rs7687423 NPY1R and thers350132 GPR54 variants as the more common coding or regulatory variants (minor allelic frequency >0.10) in these gene regions. To avoid stratification problems that can impair association studies, we used the Q-TDT method based on allele transmission to evaluate the relationship of these variants with AAM in 245 healthy women from 107 families of European ancestry. Results: We found no association of AAM with any of the studied variants. Conclusions: Keeping in mind that common variants do not recapitulate the whole genetic variation in a given gene region, this study indicates that the studied LEP, NPY1R and GPR54 variants do not have a major influence upon pubertal timing in Caucasian women. Effects of these genetic loci on age at menarche can definitively be excluded only through determination of extended haplotypes in a larger cohort.
Use of Magnetic Resonance Angiography to Predict Long-Term Outcomes of Ischemic Stroke Patients with Concurrent Stenoses in Hong Kong
Authors: Man B.L. , Fu Y.P. , Chan Y.Y. , Lam W. , Hui C.F. , Leung W.H. , Wong K.S.
Published: June 2009

Purpose: To determine the long-term outcome of ischemic stroke patients with concurrent intracranial and extracranial atherosclerosis using magnetic resonance angiography. Methods: A prospective cohort of patients in Hong Kong with acute ischemic stroke was studied with magnetic resonance angiography of the brain and carotid duplex. All patients were followed up regularly for the development of recurrent stroke, cardiac events, or death. Results: Totally 343 patients with acute ischemic stroke were included, of whom 104 (30%) had concurrent intracranial and extracranial lesions. The follow-up period was up to 76 months (mean 44.5 months). Overall, 55 patients (15.5%) died of any cause and 91 patients (26.5%) suffered a further nonfatal vascular event. The overall 5-year cumulative rates of mortality, restroke and poor outcomes (combined death and further vascular events) were 18, 27 and 37%, respectively. In patients with concurrent lesions, these rates were 31, 41 and 51%, respectively. The corresponding rates were 13, 22 and 31% in patients without concurrent lesions. The risks were highest in the first year after stroke. More deaths (log rank, 16.3; p = 0.0001), restrokes (log rank, 9.71; p = 0.002) and poor outcomes (log rank, 13.87; p = 0.0001) were found among patients with concurrent lesions. The presence of concurrent vascular lesions, advanced age, smoking, hyperlipidemia and previous history of stroke were independent predictors of poor outcomes. Conclusions: The long-term prognosis of ischemic stroke patients with concurrent atherosclerosis of intracranial and extracranial vessels is poor. They are at high risk of further vascular events or death.
Dickkopf-1 Enhances Inflammatory Interaction Between Platelets and Endothelial Cells and Shows Increased Expression in Atherosclerosis
Authors: Ueland Thor , Otterdal Kari , Lekva Tove , Halvorsen Bente , Gabrielsen Anders , Sandberg Wiggo J. , Paulsson-Berne Gabrielle , Pedersen Turid M. , Folkersen Lasse , Gullestad Lars , Øie Erik , Hansson Göran K. , Aukrust Pål
Published: June 2009

Objective—

Based on the emerging importance of the wingless (Wnt) pathways in inflammation and vascular biology, we hypothesized a role for Dickkopf-1 (DKK-1), a major modulator of Wnt signaling, in atherogenesis and plaque destabilization.

Methods and Results—

We report increased levels of DKK-1 in experimental (ApoE
−/−
mice) and clinical (patients with coronary artery disease [n=80] and patients with carotid plaque [n=47]) atherosclerosis, both systemically (serum) and within the lesion, with particularly high levels in advanced and unstable disease. We identified platelets as an important cellular source of DKK-1 as shown by in vitro experiments and by immunostaining of thrombus material obtained at the site of plaque rupture in patients with acute ST-elevation myocardial infarction, with strong immunoreactivity in platelet aggregates. Our in vitro experiments identified a role for platelet- and endothelial-derived DKK-1 in platelet-dependent endothelial activation, promoting enhanced release of inflammatory cytokines. These inflammatory effects of DKK-1 involved inhibition of the Wnt/β-catenin pathway and activation of nuclear factor κB.

Conclusion—

Our findings identify DKK-1 as a novel mediator in platelet-mediated endothelial cell activation. The demonstration of enhanced DKK-1 expression within advanced carotid plaques may suggest that this DKK-1-driven inflammatory loop could be operating within the atherosclerotic lesion.
Gene Expression Profiling of the Forming Atrioventricular Node Using a Novel
Tbx3
-Based Node-Specific Transgenic Reporter
Authors: Horsthuis Thomas , Buermans Henk P.J. , Brons Janynke F. , Verkerk Arie O. , Bakker Martijn L. , Wakker Vincent , Clout Danielle E.W. , Moorman Antoon F.M. , 't Hoen Peter A.C. , Christoffels Vincent M.
Published: June 2009

The atrioventricular (AV) node is a recurrent source of potentially life-threatening arrhythmias. Nevertheless, limited data are available on its developmental control or molecular phenotype. We used a novel AV nodal myocardium–specific reporter mouse to gain insight into the gene programs determining the formation and phenotype of the developing AV node. In this reporter, green fluorescent protein (GFP) expression was driven by a 160-kbp bacterial artificial chromosome with
Tbx3
and flanking sequences. GFP was selectively active in the AV canal of embryos and AV node of adults, whereas the
Tbx3
-positive AV bundle and sinus node were devoid of GFP, demonstrating that distinct regulatory sequences and pathways control expression in the components of the conduction system. Fluorescent AV nodal and complementary
Nppa
-positive chamber myocardial cell populations of embryonic day 10.5 embryos and of embryonic day 17.5 fetuses were purified using fluorescence-activated cell sorting, and their expression profiles were assessed by genome-wide microarray analysis, providing valuable information concerning their molecular identities. We constructed a comprehensive list of sodium, calcium, and potassium channel genes specific for developing nodal or chamber myocardium. Furthermore, the data revealed that the AV node and the chamber (working) myocardium phenotypes diverge during development but that the functional gene classes characterizing both subtypes are maintained. One of the repertoires identified in the AV node–specific gene profiles consists of multiple neurotrophic factors and semaphorins, not yet appreciated to play a role in nodal development, revealing shared characteristics between nodal and nervous system development.
Number Needed to Treat to Benefit and to Harm for Intravenous Tissue Plasminogen Activator Therapy in the 3- to 4.5-Hour Window
Authors: Saver Jeffrey L. , Gornbein Jeffrey , Grotta James , Liebeskind David , Lutsep Helmi , Schwamm Lee , Scott Phillip , Starkman Sidney
Published: June 2009

Background and Purpose—

Measures of a therapy’s effect size are important guides to clinicians, patients, and policy-makers on treatment decisions in clinical practice. The ECASS 3 trial demonstrated a statistically significant benefit of intravenous tissue plasminogen activator for acute cerebral ischemia in the 3- to 4.5-hour window, but an effect size estimate incorporating benefit and harm across all levels of poststroke disability has not previously been derived.

Methods—

Joint outcome table specification was used to derive number needed to treat to benefit (NNTB) and number needed to treat to harm (NNTH) values summarizing treatment impact over the entire outcome range on the modified Rankin scale of global disability, including both expert-dependent and expert-independent (algorithmic and repeated random sampling) array generation.

Results—

For the full 7-category modified Rankin scale, algorithmic analysis demonstrated that the NNTB for 1 additional patient to have a better outcome by ≥1 grades than with placebo must lie between 4.0 and 13.0. In bootstrap simulations, the mean NNTB was 7.1. Expert joint outcome table analyses indicated that the NNTB for improved final outcome was 6.1 (95% CI, 5.6–6.7) and the NNTH 37.5 (95% CI, 34.6–40.5). Benefit per 100 patients treated was 16.3 and harm per 100 was 2.7. The likelihood of help to harm ratio was 6.0.

Conclusions—

Treatment with tissue plasminogen activator in the 3- to 4.5-hour window confers benefit on approximately half as many patients as treatment <3 hours, with no increase in the conferral of harm. Approximately 1 in 6 patients has a better and 1 in 35 has a worse outcome as a result of therapy.