bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between environmental tobacco smoke and depression among Korean women
Authors: Kim Na Hyun , Kim Hyeon Chang , Lee Joo Young , Lee Ju-Mi , Suh Il
Published: June 2015

Objective

To evaluate the association between environmental tobacco smoke (ETS) exposure and depression among Korean women.

Methods

Between 2008 and 2011, we examined 731 men and 1249 women (aged 39–85 years) for the Korean Genome and Epidemiology Study (KoGES)-Kangwha. Among 1208 never-smoking women, we excluded two women taking antidepressants and five women who did not complete the Beck Depression Inventory (BDI). Therefore, we performed a cross-sectional analysis on 1201 women. ETS exposure was assessed using a self-reported questionnaire, and was classified into three groups: no exposure, occasional exposure and regular exposure. Depression was assessed using the BDI score, which ranged from 0 to 63, and the presence of depression was defined as a BDI score ≥10.

Results

Women exposed to ETS were more likely to have depression than those without ETS exposure (p=0.019). When BDI was analysed as a continuous variable, women exposed to ETS had significantly higher BDI scores after full adjustment (overall exposure: β=1.36, p=0.013; occasional exposure: β=1.15, p=0.063; regular exposure: β=1.90, p=0.039). ETS exposure was significantly associated with depression in a dose–response manner even after adjusting for age, body mass index, menopause, socioeconomic status, lifestyle and prevalent chronic diseases. The adjusted OR for depression (95% CI) was 1.72 (1.25 to 2.37) for overall ETS exposure, 1.56 (1.09 to 2.24) for occasional exposure and 2.19 (1.30 to 3.69) for regular exposure, when compared to no exposure.

Conclusions

Exposure to ETS was associated with depression among middle aged and elderly Korean women.
Validity and reliability of chronic tic disorder and obsessive-compulsive disorder diagnoses in the Swedish National Patient Register
Authors: Rück Christian , Larsson K Johan , Lind Kristina , Perez-Vigil Ana , Isomura Kayoko , Sariaslan Amir , Lichtenstein Paul , Mataix-Cols David
Published: June 2015

Objectives

The usefulness of cases diagnosed in administrative registers for research purposes is dependent on diagnostic validity. This study aimed to investigate the validity and inter-rater reliability of recorded diagnoses of tic disorders and obsessive-compulsive disorder (OCD) in the Swedish National Patient Register (NPR).

Design

Chart review of randomly selected register cases and controls.

Method

100 tic disorder cases and 100 OCD cases were randomly selected from the NPR based on codes from the International Classification of Diseases (ICD) 8th, 9th and 10th editions, together with 50 epilepsy and 50 depression control cases. The obtained psychiatric records were blindly assessed by 2 senior psychiatrists according to the criteria of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) and ICD-10.

Primary outcome measurement

Positive predictive value (PPV; cases diagnosed correctly divided by the sum of true positives and false positives).

Results

Between 1969 and 2009, the NPR included 7286 tic disorder and 24 757 OCD cases. The vast majority (91.3% of tic cases and 80.1% of OCD cases) are coded with the most recent ICD version (ICD-10). For tic disorders, the PPV was high across all ICD versions (PPV=89% in ICD-8, 86% in ICD-9 and 97% in ICD-10). For OCD, only ICD-10 codes had high validity (PPV=91–96%). None of the epilepsy or depression control cases were wrongly diagnosed as having tic disorders or OCD, respectively. Inter-rater reliability was outstanding for both tic disorders (κ=1) and OCD (κ=0.98).

Conclusions

The validity and reliability of ICD codes for tic disorders and OCD in the Swedish NPR is generally high. We propose simple algorithms to further increase the confidence in the validity of these codes for epidemiological research.
Barriers and facilitators of access to first-trimester abortion services for women in the developed world: a systematic review
Authors: Doran Frances , Nancarrow Susan
Published: June 2015

Objectives

To identify the barriers and facilitators to accessing first-trimester abortion services for women in the developed world.

Methods

Systematic review of published literature. CINAHL, PubMed, Proquest, MEDLINE, InformIT, Scopus, PsycINFO and Academic Search Premier were searched for papers written in the English language, from the developed world, including quantitative and qualitative articles published between 1993 and 2014.

Results

The search initially yielded 2511 articles. After screening of title, abstract and removing duplicates, 38 articles were reviewed. From the provider perspective, barriers included moral opposition to abortion, lack of training, too few physicians, staff harassment, and insufficient hospital resources, particularly in rural areas. From the women's perspective, barriers included lack of access to services (including distance and lack of service availability), negative attitudes of staff, and the associated costs of the abortion procedure. Service access could be enhanced by increasing training, particularly for mid-level practitioners; by increasing the range of service options, including the use of telehealth; and by creating clear guidelines and referral procedures to alternative providers when staff have a moral opposition to abortion.

Conclusion

Despite fewer legal barriers to accessing abortion services, the evidence from this review suggests that women in developed countries still face significant inequities in terms of the level of quality and access to services as recommended by the World Health Organization.
Solitaire FR revascularization device 4×40: safety study and effectiveness in preclinical models
Authors: Wainwright John Michael , Jahan Reza
Published: June 2015

Recent randomized clinical trials have shown the benefit of stent retrievers for endovascular intervention in patients with acute ischemic stroke. The Solitaire 2 FR 4×40 device was developed to address longer clots as well as procedural difficulties. This study was undertaken to evaluate the safety of the new device in a swine model at 0, 30, and 90 days as well as its in vitro effectiveness. There were no significant differences in the overall animal health, tissue injury, hemorrhagic or thrombogenic events related to device usage. Based on the comparison at multiple time points, the Solitaire 2 4×40 device was similar in safety and usability to the Solitaire 2 4×20 device. Due to the additional length of the device, the Solitaire 2 4×40 device may in fact provide a number of additional technical benefits in the neurothrombectomy treatment of ischemic stroke.
Detection of clinically manifest and silent synovitis in the hands and wrists by fluorescence optical imaging
Authors: Kisten Yogan , Györi Noémi , af Klint Erik , Rezaei Hamed , Levitsky Adrian , Karlsson Anna , van Vollenhoven Ronald
Published: June 2015

Objectives

The correct identification of synovitis is critical for achieving optimal therapy results. Fluorescence optical imaging (FOI) is a novel modality based on the use of an intravenous fluorophore, which enables fluorescent imaging of the hands and wrists with increased focal optical signal intensities in areas of high perfusion and/or capillary leakage. The study objective was to determine the diagnostic utility of FOI in detecting apparent and clinically non-apparent active synovitis.

Methods

Bilateral hand and wrist joints (n=872) of 26 patients with inflammatory arthritis assessed by standard clinical examination, musculoskeletal ultrasound (MSUS) and FOI were studied. Synovitis was defined as tender and swollen joints on clinical examination, presence of synovial thickening and intra-articular Doppler signals on MSUS, and abnormal focal optical signal intensities on FOI, respectively. Subclinical synovitis was defined as being clinically non-apparent, but positively inflamed on MSUS.

Results

Depending on the standard used to define inflammation, FOI ranged from 73–83% sensitive and 83–95% specific for detecting manifest synovitis. For detecting clinically silent synovitis, the sensitivity, specificity and positive and negative predictive values of FOI were 80%, 96%, 77% and 97%, respectively.

Conclusions

The high degree of agreement between MSUS and FOI suggest its use in clinical practice, especially when MSUS is not available, in order to identify synovitis earlier and with greater confidence. FOI may be particularly useful in identifying patients with clinically non-apparent joint inflammation of the hands and/or wrists.
Variations in seed characteristics among and within Stipa purpurea populations on the Qinghai–Tibet Plateau
Authors: Li Xiong , Yin Xin , Yang Shihai , Yang Yunqiang , Qian Min , Zhou Yanli , Zhang Chan , Du Yan , Yang Yongping
Published: June 2015

Variation in seed size is common among plant species, populations, and individuals. On the Qinghai–Tibet Plateau, previous studies have mainly focused on interspecific variation in seed size, with little information available regarding intraspecific variation. The alpine steppe is among the most important vegetation types on the plateau, where it plays a vital role in preserving landscape heterogeneity and diversity. Stipa purpurea Griseb., endemic to the Qinghai–Tibet Plateau, is the predominant species of the alpine steppe. In the present study, we measured seed characteristics of nine S. purpurea populations and analyzed possible sources and consequences of variation in these characteristics. Seed characteristics varied greatly among and within populations. Our findings suggest that variation in seed size and awn length may affect germination and dispersal, respectively. Surprisingly, environmental factors, rather than genome size, were significantly correlated with seed size. For example, relative humidity and number of windy days were strongly correlated with seed size and awn length, respectively. We believe that variation in seed characteristics is a consequence of complex environmental conditions correlated with longitude and latitude. The results indicated that variation in seed characteristics of S. purpurea is an adaptation to environmental conditions.
Context dependence of the olfactory perceptual range in the generalist land snail Cornu aspersum
Authors: Dahirel M. , Cholé H. , Séguret A. , Madec L. , Ansart A.
Published: June 2015

Dispersal success in animals depends in part on their perceptual range, i.e., the distance from which they can acquire information about their environment. We studied how the olfactory perceptual range of a generalist species, the brown garden snail (Cornu aspersum (Müller, 1774)), varied under controlled conditions depending on the context in which stimuli were presented, whether alone or in the presence of another stimulus with opposite properties. Cornu aspersum preferentially orient themselves towards small nettle (Urtica dioica L.) patches, a highly palatable plant, and move away from repulsive plants if these stimuli are placed up to between 20 and 40 cm away from their starting point. A blend of palatable and repulsive plants, tested together, do not significantly influence the orientation of individuals in either direction. Cornu aspersum are thus capable of detecting and evaluating relatively small potential resource patches from a distance, enabling them to limit costly explorations, but this ability is context-dependent. These data could lead to a better understanding of the behaviour of C. aspersum in very heterogeneous landscapes in relation to this species’ ability to colonise a wide range of anthropised and fragmented habitats.
Synthesis and Characterization of Calcium Tartrate Dihydrate Nanoparticles
Authors: Tarpara Urvisha , Vyas Poorvesh , Joshi Mihir J.
Published: June 2015

Calcium tartrate finds various applications. In the present study, calcium tartrate nanoparticles were synthesized by wet chemical method using surfactant mediated approach. The powder XRD pattern revealed the typical broadening of peaks indicating the nanostructured nature. The average crystallite size was calculated by applying the Scherrer's formula to powder XRD pattern and was found in the range of 22.8–23.9 nm. The particle size and morphology of the synthesized nanoparticles was confirmed by using transmission electron microscopy (TEM). FTIR spectroscopy was used to confirm the presence of various functional groups. From TGA, it was found that calcium tartrate nanoparticles remained stable up to 120°C and were having two water molecules associated with them. The results are compared with the bulk crystalline materials available in the literature.
A CONTEMPORARY AND SYSTEMATIC LITERATURE REVIEW OF USER-CENTRIC INNOVATION: A CONSUMER PERSPECTIVE
Authors: GAMBLE JORDAN ROBERT , BRENNAN MICHAEL , MCADAM RODNEY
Published: June 2015

This paper aims to provide a contemporary, critical and systematic overview of user-centric innovation (UCI) from a consumer perspective. The objectives of this paper were to identify and categorise gaps in research and/or knowledge, contextually classify empirical UCI studies, critically analyse the literature in terms of coalition/fragmentation and derive practitioner implications for industry implementation. Our findings indicate that user communities should be carefully evaluated by firm management as they can represent significant risks in relation to resource requirements as well as opportunities for capitalising on new product development. Furthermore, by ascertaining which product-related resources the consumers are lacking, it may provide organisations with details of the consumers’ ahead-of-the-market needs and may be used to devise effective recognition-based proactive UCI strategies. A research framework was also formulated to help future UCI researchers navigate the complex network of previous research and to assist in developing more structured and focussed future research questions.
On the L2-Poincaré duality for incomplete Riemannian manifolds: A general construction with applications
Authors: Bei Francesco
Published: June 2015

Let [Formula: see text] be an open, oriented and incomplete Riemannian manifold of dimension [Formula: see text]. Under some general conditions we show the existence of a Hilbert complex [Formula: see text] such that its cohomology groups, labeled with [Formula: see text], satisfy the following properties:

[Formula: see text] [Formula: see text] (Poincaré duality holds) There exists a well-defined and nondegenerate pairing: [Formula: see text] If [Formula: see text] is a Fredholm complex, then every closed extension of the de Rham complex [Formula: see text] is a Fredholm complex and, for each [Formula: see text], the quotient [Formula: see text] is a finite dimensional vector space.
Tissue Pharmacology of Da-Cheng-Qi Decoction in Experimental Acute Pancreatitis in Rats
Authors: Zhao Xianlin , Zhang Yumei , Li Juan , Wan Meihua , Zhu Shifeng , Guo Hui , Xiang Jin , Thrower Edwin C. , Tang Wenfu
Published: June 2015

Objectives. The Chinese herbal medicine Da-Cheng-Qi Decoction (DCQD) can ameliorate the severity of acute pancreatitis (AP). However, the potential pharmacological mechanism remains unclear. This study explored the potential effective components and the pharmacokinetic characteristics of DCQD in target tissue in experimental acute pancreatitis in rats.Methods. Acute pancreatitis-like symptoms were first induced in rats and then they were given different doses of DCQD (6 g/kg, 12 g/kg, and 24 g/kg body weight) orally. Tissue drug concentration, tissue pathological score, and inflammatory mediators in pancreas, intestine, and lung tissues of rats were examined after 24 hours, respectively.Results. Major components of DCQD could be found in target tissues and their concentrations increased in conjunction with the intake dose of DCQD. The high-dose compounds showed maximal effect on altering levels of anti-inflammatory (interleukin-4 and interleukin-10) and proinflammatory markers (tumor necrosis factorαand interleukin-6) and ameliorating the pathological damage in target tissuesP<0.05.Conclusions. DCQD could alleviate pancreatic, intestinal, and lung injury by altering levels of inflammatory cytokines in AP rats with tissue distribution of its components.
Ship Electric Propulsion Simulation System Reliability Evaluation Based on Improved D-S Expert Weight Calculation Method
Authors: Li Bing , Gu Guoliang , Xing Bowen , Li Lihong
Published: June 2015

In order to have a better evaluation process to determine the experts weight in the evaluation process, this paper proposes a new expert weight calculation method. First of all to establish electric propulsion simulation evaluation system, use AHP method to calculate the initial weight principle of index. Then use the D-S to fuse the experts evaluation information, combined with the weight vector, structure of the expert weight objective function, and through the genetic algorithm to solve the expert weight size. According to the expert weight vector, calculate the final weight vector. Not only can it greatly make use of the experts information and analyze the similarity of information effectively but also it calculates the weight of each expert objectively. At the same time the evaluation subjective factors have been reduced by the adoption of this new method.
Fine Screening for Resistance to Cold-Induced Sweetening in Potato Hybrids ContainingSolanum raphanifoliumGermplasm
Authors: Ali Arfan , Jansky Shelley
Published: June 2015

Potato is an indispensable part of human food. Many wild and cultivated potato relatives have been screened to find the best germplasm to improve productivity and quality, but only a small sample of the available biodiversity has been exploited. Most wild relatives are self-incompatible diploids. Genetic variability exists within and among populations, even within a species. Therefore, it is necessary to carry out fine screening to identify individuals carrying traits of interest. This study was carried out to quantify phenotypic variability for resistance to cold-induced sweetening, an important processing trait. Five families were evaluated for potato chip (crisp) color following cold storage of tubers harvested from four greenhouse trials and one field trial. The families were generated by crossing a single diploid clone to five plants from one accession of the wild potato relativeSolanum raphanifolium. Analysis of variance revealed that resistance against cold-induced sweetening was dependent on family and trial. This study underscores the importance of fine screening to select individuals in potato accessions for use in potato improvement.
Fuzzy Number Addition with the Application of Horizontal Membership Functions
Authors: Piegat Andrzej , Pluciński Marcin
Published: June 2015

The paper presents addition of fuzzy numbers realised with the application of the multidimensional RDM arithmetic and horizontal membership functions (MFs). Fuzzy arithmetic (FA) is a very difficult task because operations should be performed here on multidimensional information granules. Instead, a lot of FA methods use α‐cuts in connection with 1‐dimensional classical interval arithmetic that operates not on multidimensional granules but on 1‐dimensional intervals. Such approach causes difficulties in calculations and is a reason for arithmetical paradoxes. The multidimensional approach allows for removing drawbacks and weaknesses of FA. It is possible thanks to the application of horizontal membership functions which considerably facilitate calculations because now uncertain values can be inserted directly into equations without using the extension principle. The paper shows how the addition operation can be realised on independent fuzzy numbers and on partly or fully dependent fuzzy numbers with taking into account the order relation and how to solve equations, which can be a difficult task for 1‐dimensional FAs.
An Antioxidant Dietary Supplement Improves Brain-Derived Neurotrophic Factor Levels in Serum of Aged Dogs: Preliminary Results
Authors: Sechi Sara , Chiavolelli Francesca , Spissu Nicoletta , Di Cerbo Alessandro , Canello Sergio , Guidetti Gianandrea , Fiore Filippo , Cocco Raffaella
Published: June 2015

Biological aging is characterized by a progressive accumulation of oxidative damage and decreased endogenous antioxidant defense mechanisms. The production of oxidants by normal metabolism damages proteins, lipids, and nucleotides, which may contribute to cognitive impairment. In this study 36 dogs were randomly divided into four groups and fed croquettes of different compositions for 6 months. We monitored derivatives of reactive oxygen metabolites (dROMs) and biological antioxidant potential (BAP) levels in dogs’ plasma samples as well as brain-derived neurotrophic factor (BDNF) serum levels at the beginning and at the end of the dietary regime. Our results showed that a dietary regime, enriched with antioxidants, induced a significant decrease of plasma levels of dROMs (p<0.005) and a significant increase in BDNF serum levels (p<0.005) after six months. Thus, we hypothesized a possible role of the diet in modulating pro- and antioxidant species as well as BDNF levels in plasma and serum, respectively. In conclusion the proposed diet enriched with antioxidants might be considered a valid alternative and a valuable strategy to counteract aging-related cognitive decline in elderly dogs.
Single-Stranded DNA Aptamers against Pathogens and Toxins: Identification and Biosensing Applications
Authors: Hong Ka Lok , Sooter Letha J.
Published: June 2015

Molecular recognition elements (MREs) can be short sequences of single-stranded DNA, RNA, small peptides, or antibody fragments. They can bind to user-defined targets with high affinity and specificity. There has been an increasing interest in the identification and application of nucleic acid molecular recognition elements, commonly known as aptamers, since they were first described in 1990 by the Gold and Szostak laboratories. A large number of target specific nucleic acids MREs and their applications are currently in the literature. This review first describes the general methodologies used in identifying single-stranded DNA (ssDNA) aptamers. It then summarizes advancements in the identification and biosensing application of ssDNA aptamers specific for bacteria, viruses, their associated molecules, and selected chemical toxins. Lastly, an overview of the basic principles of ssDNA aptamer-based biosensors is discussed.
Biotransformation of Indole to 3-Methylindole byLysinibacillus xylanilyticusStrain MA
Authors: Arora Pankaj Kumar , Dhar Kartik , Veloz García Rafael Alejandro , Sharma Ashutosh
Published: June 2015

An indole-biotransforming strain MA was identified asLysinibacillus xylanilyticuson the basis of the 16S rRNA gene sequencing. It transforms indole completely from the broth culture in the presence of an additional carbon source (i.e., sodium succinate). Gas-chromatography-mass spectrometry identified indole-3-acetamide, indole-3-acetic acid, and 3-methylindole as transformation products. Tryptophan-2-monooxygenase activity was detected in the crude extracts of indole-induced cells of strain MA, which confirms the formation of indole-3-acetamide from tryptophan in the degradation pathway of indole. On the basis of identified metabolites and enzyme assay, we have proposed a new transformation pathway for indole degradation. Indole was first transformed to indole-3-acetamide via tryptophan. Indole-3-acetamide was then transformed to indole-3-acetic acid that was decarboxylated to 3-methylindole. This is the first report of a 3-methylindole synthesis via the degradation pathway of indole.
Calculation of Spotting Particles Maximum Distance in Idealised Forest Fire Scenarios
Authors: Pereira José C. F. , Pereira José M. C. , Leite André L. A. , Albuquerque Duarte M. S.
Published: June 2015

Large eddy simulation of the wind surface layer above and within vegetation was conducted in the presence of an idealised forest fire by using an equivalent volumetric heat source. Firebrand’s particles are represented as spherical particles with a wide range of sizes, which were located into the combustion volume in a random fashion and are convected in the ascending plume as Lagrangian points. The thermally thin particles undergo drag relative to the flow and moisture loss as they are dried and pyrolysis, char-combustion, and mass loss as they burn. The particle momentum, heat and mass transfer, and combustion governing equations were computed along particle trajectories in the unsteady 3D wind field until their deposition on the ground. The spotting distances are compared with the maximum spotting distance obtained with Albini model for several idealised line grass or torching trees fires scenarios. The prediction of the particle maximum spotting distance for a 2000 kW/m short grass fire compared satisfactorily with results from Albini model and underpredicted by 40% the results for a high intensity 50000 kW/m fire. For the cases of single and four torching trees the model predicts the maximum distances consistently but for slightly different particle diameter.
A Low-Complexity Approach for Improving the Accuracy of Sensor Networks
Authors: Coluccia Angelo
Published: June 2015

The paper addresses the problem of improving the accuracy of the measurements collected by a sensor network, where simplicity and cost-effectiveness are of utmost importance. An adaptive Bayesian approach is proposed to this aim, which allows improving the accuracy of the delivered estimates with no significant increase in computational complexity. Remarkably, the resulting cooperative algorithm does not require prior knowledge of the (hyper)parameters and is able to provide a “denoised” version of the monitored field without losing accuracy in detecting extreme (less frequent) values, which can be very important for a number of applications. A novel performance metric is also introduced to suitably quantify the capability to both reduce the measurement error and retain highly-informative characteristics at the same time. The performance assessment shows that the proposed approach is superior to a low-complexity competitor that implements a conventional filtering approach.
The Albedo of Pervious Cement Concrete Linearly Decreases with Porosity
Authors: Zhang Rui , Jiang Guosheng , Liang Jia
Published: June 2015

Pervious pavements have been advocated as a potential countermeasure to the urban heat island effect. To understand if pervious pavements stay cooler than conventional pavements, the albedo of the pervious concrete must be understood. This study measured the albedo of pervious concrete with different porosity. Four Portland cement concrete mixes were casted, using designed amounts of sand to vary the porosity of the pervious concrete samples. The samples were sliced and the spectral reflectance and albedo of the sliced samples were measured and analyzed. It is found that the albedo of pervious concrete decreases linearly with the increase of the porosity. The albedo of a pervious Portland concrete varies from 0.25 to 0.35, which is 0.05~0.15 lower than the albedo of conventional cement concrete. Due to this lower albedo, it should be cautious to develop pervious concrete to battle with urban heat island unless the evaporation of pervious concrete is promoted to compensate the additional solar absorption caused by the low albedo.
Parallel Numerical Simulations of Three-Dimensional Electromagnetic Radiation with MPI-CUDA Paradigms
Authors: He Bing , Tang Long , Xie Jiang , Wang XiaoWei , Song AnPing
Published: June 2015

Using parallel computation can enhance the performance of numerical simulation of electromagnetic radiation and get great runtime reduction. We simulate the electromagnetic radiation calculation based on the multicore CPU and GPU Parallel Architecture Clusters by using MPI-OpenMP and MPI-CUDA hybrid parallel algorithm. This is an effective solution comparing to the traditional finite-difference time-domain method which has a shortage in the calculation of the electromagnetic radiation on the problem of inadequate large data space and time. What is more, we use regional segmentation, subregional data communications, consolidation, and other methods to improve procedures nested parallelism and finally verify the correctness of the calculation results. Studying these two hybrid models of parallel algorithms run on the high-performance cluster computer, we draw the conclusion that both models are suitable for large-scale numerical calculations, and MPI-CUDA hybrid model can achieve higher speedup.
Homozygosity for the E526V Mutation in Fibrinogen A Alpha-Chain Amyloidosis: The First Report
Authors: Tavares Isabel , Lobato Luísa , Matos Carlos , Santos Josefina , Moreira Paul , Saraiva Maria João , Castro Henriques António
Published: June 2015

Systemic hereditary amyloidoses are autosomal dominant diseases associated with mutations in genes encoding ten different proteins. The clinical phenotype has implications on therapeutic approach, but it is commonly variable and largely dependent on the type of mutation. Except for rare cases involving gelsolin or transthyretin, patients are heterozygous for the amyloidogenic variants. Here we describe the first patient identified worldwide as homozygous for a nephropathic amyloidosis, involving the fibrinogen variant associated with the fibrinogen alpha-chain E526V (p.Glu545Val) mutation. In 1989, a 44-year-old woman presented with hypertension, hepatosplenomegaly, nephrotic syndrome, and renal failure. She started hemodialysis in 1990 and 6 years later underwent isolated kidney transplantation from a deceased donor. Graft function and clinical status were unremarkable for 16 years, despite progressively increased left ventricular mass on echocardiography. In 2012, 4 months before death, she deteriorated rapidly with severe heart failure, precipitated byClostridium difficilecolitis and urosepsis. Affected family members developed nephropathy, on average, nearly three decades later, which may be explained by the gene dosage effects on the phenotype of E526V (p.Glu545Val) fibrinogen A alpha-chain amyloidosis.
Novel Cancer Therapeutics with Allosteric Modulation of the Mitochondrial C-Raf–DAPK Complex by Raf Inhibitor Combination Therapy
Authors: Tsai Yi-Ta , Chuang Mei-Jen , Tang Shou-Hung , Wu Sheng-Tang , Chen Yu-Chi , Sun Guang-Huan , Hsiao Pei-Wen , Huang Shih-Ming , Lee Hwei-Jen , Yu Cheng-Ping , Ho Jar-Yi , Lin Hui-Kuan , Chen Ming-Rong , Lin Chung-Chih , Chang Sun-Yran , Lin Victor C. , Yu Dah-Shyong , Cha Tai-Lung
Published: June 2015

Mitochondria are the powerhouses of cells. Mitochondrial C-Raf is a potential cancer therapeutic target, as it regulates mitochondrial function and is localized to the mitochondria by its N-terminal domain. However, Raf inhibitor monotherapy can induce S338 phosphorylation of C-Raf (pC-RafS338) and impede therapy. This study identified the interaction of C-Raf with S308 phosphorylated DAPK (pDAPKS308), which together became colocalized in the mitochondria to facilitate mitochondrial remodeling. Combined use of the Raf inhibitors sorafenib and GW5074 had synergistic anticancer effects in vitro and in vivo, but targeted mitochondrial function, rather than the canonical Raf signaling pathway. C-Raf depletion in knockout MEFC-Raf−/− or siRNA knockdown ACHN renal cancer cells abrogated the cytotoxicity of combination therapy. Crystal structure simulation showed that GW5074 bound to C-Raf and induced a C-Raf conformational change that enhanced sorafenib-binding affinity. In the presence of pDAPKS308, this drug–target interaction compromised the mitochondrial targeting effect of the N-terminal domain of C-Raf, which induced two-hit damages to cancer cells. First, combination therapy facilitated pC-RafS338 and pDAPKS308 translocation from mitochondria to cytoplasm, leading to mitochondrial dysfunction and reactive oxygen species (ROS) generation. Second, ROS facilitated PP2A-mediated dephosphorylation of pDAPKS308 to DAPK. PP2A then dissociated from the C-Raf–DAPK complex and induced profound cancer cell death. Increased pDAPKS308 modification was also observed in renal cancer tissues, which correlated with poor disease-free survival and poor overall survival in renal cancer patients. Besides mediating the anticancer effect, pDAPKS308 may serve as a predictive biomarker for Raf inhibitors combination therapy, suggesting an ideal preclinical model that is worthy of clinical translation. Cancer Res; 75(17); 3568–82. ©2015 AACR.
Tumor-Specific Effector CD8+ T Cells That Can Establish Immunological Memory in Humans after Adoptive Transfer Are Marked by Expression of IL7 Receptor and c-myc
Authors: Chandran Smita S. , Paria Biman C. , Srivastava Abhishek K. , Rothermel Luke D. , Stephens Daniel J. , Kammula Udai S.
Published: June 2015

The optimal T-cell attributes for adoptive cancer immunotherapy are unclear. Recent clinical trials of ex vivo–expanded tumor-infiltrating lymphocytes indicated that differentiated T effector cells can elicit durable antitumor responses in some patients with cancer, with their antitumor activity tightly correlated with their persistence in the host. Thus, there is great interest in the definition of intrinsic biomarkers that can predict the conversion of short-lived tumor antigen–specific T effector cells into long-lived T memory cells. Long-term persistence of ex vivo–expanded tumor-specific CD8+ T effector clones has been reported in refractory metastatic melanoma patients after adoptive T-cell transfer. By using highly homogeneous clone populations from these preparations, we performed a comparative transcriptional profiling to define preinfusion molecular attributes that can be ascribed to an effector-to-memory transition. Through this route, we discovered that preinfusion T-cell clones that expressed the IL7 receptor (IL7R) and c-myc were more likely to persist longer after adoptive transfer to patients. The predictive value of these two biomarkers was strengthened by using IL7R protein, IL7-induced pSTAT5, and c-myc mRNA expression to prospectively identify human tumor-specific T effector clones capable of engraftment into immunodeficient mice. Overall, our findings reveal IL7R and c-myc expression as intrinsic biomarkers that can predict the fate of CD8+ T effector cells after adoptive transfer. Cancer Res; 75(16); 3216–26. ©2015 AACR.
Impact of Short-term 1,25-Dihydroxyvitamin D3 on the Chemopreventive Efficacy of Erlotinib against Oral Cancer
Authors: Bothwell Katelyn D. , Shaurova Tatiana , Merzianu Mihai , Suresh Amritha , Kuriakose Moni A. , Johnson Candace S. , Hershberger Pamela A. , Seshadri Mukund
Published: June 2015

Activation of the epidermal growth factor receptor (EGFR) pathway is an early event in head and neck carcinogenesis. As a result, targeting EGFR for chemoprevention of head and neck squamous cell carcinomas (HNSCC) has received considerable attention. In the present study, we examined the impact of 1,25(OH)2D3, the active metabolite of the nutritional supplement vitamin D on the chemopreventive efficacy of the EGFR inhibitor, erlotinib, against HNSCC. Experimental studies were conducted in patient-derived xenografts (PDX) and the 4-nitroquinoline-1-oxide (4NQO) carcinogen-induced model of HNSCC. Short-term treatment (4 weeks) of PDX-bearing mice with 1,25(OH)2D3 and erlotinib resulted in significant inhibition of tumor growth. Noninvasive MRI enabled longitudinal monitoring of disease progression in the 4NQO model with 100% of control animals showing evidence of neoplastic lesions by 24 weeks. Among the experimental groups, animals treated with the combination regimen showed the greatest reduction in tumor incidence and volume (P < 0.05). Combination treatment was well tolerated and was not associated with any significant change in body weight. Histopathologic assessment revealed a significant reduction in the degree of dysplasia with combination treatment. Immunoblot analysis of whole tongue extracts showed downregulation of phospho-EGFR and phospho-Akt with the combination regimen. These results highlight the potential of 1,25(OH)2D3 to augment the efficacy of erlotinib against HNSCC. Further optimization of schedule and sequence of this combination regimen along with investigation into the activity of less calcemic analogues or dietary vitamin D is essential to fully realize the potential of this approach. Cancer Prev Res; 8(9); 765–76. ©2015 AACR.
Referral of Ovarian Cancer Patients for Genetic Counselling by Oncologists: Need for Improvement
Authors: Ricci Maria Teresa , Sciallero Stefania , Mammoliti Serafina , Gismondi Viviana , Franiuk Marzena , Bruzzi Paolo , Varesco Liliana
Published: June 2015

Background/Aims: Nearly 15% of all ovarian cancer patients carry a germline BRCA mutation. A pilot project was started at IRCCS AOU San Martino - IST, Genoa, to assess the feasibility and consequences of offering genetic counselling to all ovarian cancer patients during routine oncology appointments. We present early results of this project. Methods: Patients who attended an oncology visit at the Medical Oncology Unit 1 between November 2012 and December 2013 were identified. Medical records were reviewed for clinical data, genetic counselling and testing outcomes. Results: Out of 104 women diagnosed with ovarian cancer undergoing an oncology visit, 94 had not had genetic counselling in the past. Twenty-nine patients (29/94, 31%) were referred to the Unit of Hereditary Cancer; of these, 14/26 (54%) were referred at the first visit and 15/68 (22%) at the follow-up visit (p = 0.003). Most referred women attended genetic counselling (22/29, 76%) and had BRCA genetic testing (21/22, 95%). Four BRCA1 mutations were detected (4/21, 19%). Conclusions: Oncologists discuss genetic counselling with a minority of ovarian cancer patients. Mainstreaming such practice is important to optimize the management of these patients and their families. Efforts are needed to identify new models for introducing ovarian cancer genetic risk assessment in oncology practice.
Increased Umbilical Artery Pulsatility Index in Third-Trimester Fetuses with Trisomy 21
Authors: Wagner Philipp , Sonek Jiri , Hoopmann Markus , Abele Harald , Brucker Sara , Kagan Karl Oliver
Published: June 2015

Objective: To examine the umbilical arterial Doppler flow patterns in late third-trimester fetuses with trisomy 21. Methods: This is a retrospective study on fetuses with trisomy 21 that were evaluated after 33 weeks' gestation at the Department of Obstetrics and Gynaecology of the University of Tuebingen, Germany. The umbilical and the middle cerebral artery (UA and ACM) pulsatility index (PI) measurements and the abdominal circumference were transformed into z-values. Results: Forty-two fetuses met the study criteria. The mean gestational age at the time of the first and the second visit was 35.0 and 36.6 weeks, respectively. The mean UA PI was 1.31 and 1.38, which corresponds to z-values of 2.20 and 2.70. In 24 (57.1%) cases, both PI measurements were above the 95th centile. A linear regression analysis demonstrated that the mean of both UA PI was not dependent on the abdominal circumference or on any other examined maternal and pregnancy characteristics. The mean ACM PI at the first and the second visit was 1.62 and 1.48, respectively, corresponding to mean z-values of -0.59 and -0.75, and in none of the cases was it below the 5th centile. Conclusion: In half of the third-trimester fetuses with trisomy 21, the resistance in the UA is increased - even in the absence of placental insufficiency.
Pregnancy in Women With a Mechanical Heart Valve
Authors: van Hagen Iris M. , Roos-Hesselink Jolien W. , Ruys Titia P.E. , Merz Waltraut M. , Goland Sorel , Gabriel Harald , Lelonek Malgorzata , Trojnarska Olga , Al Mahmeed Wael Abdulrahman , Balint Hajnalka Olga , Ashour Zeinab , Baumgartner Helmut , Boersma Eric , Johnson Mark R. , Hall Roger
Published: June 2015

Background—

Pregnant women with a mechanical heart valve (MHV) are at a heightened risk of a thrombotic event, and their absolute need for adequate anticoagulation puts them at considerable risk of bleeding and, with some anticoagulants, fetotoxicity.

Methods and Results—

Within the prospective, observational, contemporary, worldwide Registry of Pregnancy and Cardiac disease (ROPAC), we describe the pregnancy outcome of 212 patients with an MHV. We compare them with 134 patients with a tissue heart valve and 2620 other patients without a prosthetic valve. Maternal mortality occurred in 1.4% of the patients with an MHV, in 1.5% of patients with a tissue heart valve (
P
=1.000), and in 0.2% of patients without a prosthetic valve (
P
=0.025). Mechanical valve thrombosis complicated pregnancy in 10 patients with an MHV (4.7%). In 5 of these patients, the valve thrombosis occurred in the first trimester, and all 5 patients had been switched to some form of heparin. Hemorrhagic events occurred in 23.1% of patients with an MHV, in 5.1% of patients with a tissue heart valve (
P
<0.001), and in 4.9% of patients without a prosthetic valve (
P
<0.001). Only 58% of the patients with an MHV had a pregnancy free of serious adverse events compared with 79% of patients with a tissue heart valve (
P
<0.001) and 78% of patients without a prosthetic valve (
P
<0.001). Vitamin K antagonist use in the first trimester compared with heparin was associated with a higher rate of miscarriage (28.6% versus 9.2%;
P
<0.001) and late fetal death (7.1% versus 0.7%;
P
=0.016).

Conclusions—

Women with an MHV have only a 58% chance of experiencing an uncomplicated pregnancy with a live birth. The markedly increased mortality and morbidity warrant extensive prepregnancy counseling and centralization of care.
Inducible Human Endothelin-1 Overexpression in Endothelium Raises Blood Pressure via Endothelin Type A Receptors
Authors: Rautureau Yohann , Coelho Suellen C. , Fraulob-Aquino Julio C. , Huo Ku-Geng , Rehman Asia , Offermanns Stefan , Paradis Pierre , Schiffrin Ernesto L.
Published: June 2015

The mechanisms of blood pressure regulation by endothelin-1 produced by endothelial cells are complex and still unclear. Transgenic mice with endothelium-restricted human endothelin-1 (
EDN1
) overexpression presented vascular damage but no significant change in blood pressure, which could be because of adaptation to life-long exposure to elevated endothelin-1 levels. We now generated a tamoxifen-inducible endothelium-restricted
EDN1
overexpressing transgenic mouse (ieET-1) using Cre/loxP technology. Sixteen days after tamoxifen treatment, ieET-1 mice presented ≥10-fold increase in plasma endothelin-1 (
P
<0.01) and ≥20 mm Hg elevation in systolic blood pressure (
P
<0.01), which could be reversed by atrasentan (
P
<0.05). Endothelin-1 overexpression did not cause vascular or kidney injury or changes in kidney perfusion or function. However, endothelin type A and B receptor expression was differentially regulated in the mesenteric arteries and the kidney. Our results demonstrate using this ieET-1 mouse model that 21 days of induction of endothelin-1 overexpression caused endothelin-1–dependent elevated blood pressure mediated by endothelin type A receptors.
Deletion of
Rictor
in Brain and Fat Alters Peripheral Clock Gene Expression and Increases Blood Pressure
Authors: Drägert Katja , Bhattacharya Indranil , Pellegrini Giovanni , Seebeck Petra , Azzi Abdelhalim , Brown Steven A. , Georgiopoulou Stavroula , Held Ulrike , Blyszczuk Przemyslaw , Arras Margarete , Humar Rok , Hall Michael N. , Battegay Edouard , Haas Elvira
Published: June 2015

The mammalian target of rapamycin complex 2 (mTORC2) contains the essential protein RICTOR and is activated by growth factors. mTORC2 in adipose tissue contributes to the regulation of glucose and lipid metabolism. In the perivascular adipose tissue, mTORC2 ensures normal vascular reactivity by controlling expression of inflammatory molecules. To assess whether RICTOR/mTORC2 contributes to blood pressure regulation, we applied a radiotelemetry approach in control and
Rictor
knockout (
Rictor

aP2KO

) mice generated using
adipocyte protein-2
gene promoter–driven CRE recombinase expression to delete
Rictor
. The 24-hour mean arterial pressure was increased in
Rictor

aP2KO

mice, and the physiological decline in mean arterial pressure during the dark period was impaired. In parallel, heart rate and locomotor activity were elevated during the dark period with a pattern similar to blood pressure changes. This phenotype was associated with mild cardiomyocyte hypertrophy, decreased cardiac natriuretic peptides, and their receptor expression in adipocytes. Moreover, clock gene expression was reduced or phase-shifted in perivascular adipose tissue. No differences in clock gene expression were observed in the master clock suprachiasmatic nucleus, although
Rictor
gene expression was also lower in brain of
Rictor

aP2KO

mice. Thus, this study highlights the importance of RICTOR/mTORC2 for interactions between vasculature, adipocytes, and brain to tune physiological outcomes, such as blood pressure and locomotor activity.
Dopamine and Consolidation of Episodic Memory: Timing Is Everything
Authors: Grogan John , Bogacz Rafal , Tsivos Demitra , Whone Alan , Coulthard Elizabeth
Published: June 2015

Memory consolidation underpins adaptive behavior and dopaminergic networks may be critical for prolonged, selective information storage. To understand the time course of the dopaminergic contribution to memory consolidation in humans, here we investigate the effect of dopaminergic medication on recall and recognition in the short and longer term in Parkinson disease (PD). Fifteen people with PD were each tested on or off dopaminergic medication during learning/early consolidation (Day 1) and/or late consolidation (Day 2). Fifteen age-matched healthy participants were tested only once. On Day 1 participants learned new information, and early episodic memory was tested after 30 min. Then on Day 2, recall and recognition were retested after a 24-hr delay. Participants on medication on Day 1 recalled less information at 30 min and 24 hr. In contrast, patients on medication on Day 2 (8–24 hr after learning) recalled more information at 24 hr than those off medication. Although recognition sensitivity was unaffected by medication, response bias was dependent on dopaminergic state: Medication during learning induced a more liberal bias 24 hr later, whereas patients off medication during learning were more conservative responders 24 hr later. We use computational modeling to propose possible mechanisms for this change in response bias. In summary, dopaminergic medication in PD patients during learning impairs early consolidation of episodic memory and makes delayed responses more liberal, but enhances late memory consolidation presumably through a dopamine-dependent consolidation pathway that may be active during sleep.
Helsinki+40 in the Historical Context
Authors: Nünlist Christian
Published: June 2015

The Ukraine Crisis has negatively impacted the reform process ‘Helsinki+40’ of the Organization for Security and Co-operation in Europe (osce). The idea to conclude this process by holding an osce summit in 2015, celebrating the 40th anniversary of the Helsinki Final Act, evaporated after Russia’s annexation of Crimea. To overcome the differences with Moscow, it is necessary to compare two radically different narratives on the evolution of the osce after 1990. As long as historical facts are mixed with myths, a common vision of European security between Russia and the West remains a distant dream. In the meantime, ‘common security’ might be more relevant for today’s osce than ‘common values’.