bluuebunny/crossref_metadata_2025 huggingface dataset:
Serological Survey and Factors Associated withToxoplasma gondiiInfection in Domestic Goats in Myanmar
Authors: Bawm Saw , Maung Wint Yi , Win Myat Yee , Thu May June , Chel Hla Myet , Khaing Tin Aye , Wai Soe Soe , Htun Lat Lat , Myaing Tin Tin , Tiwananthagorn Saruda , Igarashi Makoto , Katakura Ken
Published: January 2016

Goat farming is important for the livelihood of millions of rural people because it contributes to food security and creation of assets. However, infection of goats withToxoplasma gondiicould be a source of parasite transmission to humans. The information onT. gondiiinfection of goat was not reported yet in Myanmar. A total of 119 goat serum samples were collected from three cities in the central region of Myanmar forT. gondiiantibody survey. With the occurrence value obtained in this first study, a second one, more complete, with larger number (162) of animals and properties, was carried out and the risk factors and prevalence were determined. In both studies the samples were analyzed by the LAT. Of these, 32 (11.4%) samples were showed to be positive. The infection was associated with the presence of cats at the farm (odds ratio [OR] = 4.66, 95% confidential interval [CI] = 1.03–21.06), farming with different animal species (sheep, cattle, and pigs) (OR = 4.33, 95% CI = 1.57–11.94), and farming without good management practices (OR = 0.23, 95% CI = 0.06–0.83). This is the firstT. gondiiprevalence study in goats in the country.
F2AC: A Lightweight, Fine-Grained, and Flexible Access Control Scheme for File Storage in Mobile Cloud Computing
Authors: Ren Wei , Zeng Lingling , Liu Ran , Cheng Chi
Published: January 2016

Current file storage service models for cloud servers assume that users either belong to single layer with different privileges or cannot authorize privileges iteratively. Thus, the access control is not fine-grained and flexible. Besides, most access control methods at cloud servers mainly rely on computationally intensive cryptographic algorithms and, especially, may not be able to support highly dynamic ad hoc groups with addition and removal of group members. In this paper, we propose a scheme called F2AC, which is a lightweight, fine-grained, and flexible access control scheme for file storage in mobile cloud computing. F2AC can not only achieve iterative authorization, authentication with tailored policies, and access control for dynamically changing accessing groups, but also provide access privilege transition and revocation. A new access control model called directed tree with linked leaf model is proposed for further implementations in data structures and algorithms. The extensive analysis is given for justifying the soundness and completeness of F2AC.
Electrophysiological and Behavioral Responses ofTheocolax elegans(Westwood) (Hymenoptera: Pteromalidae) to Cereal Grain Volatiles
Authors: Germinara Giacinto Salvatore , De Cristofaro Antonio , Rotundo Giuseppe
Published: January 2016

Volatiles emitted by the host’s food would be the first signals used by parasitoids in the host location process and are thought to play an important role in host habitat location. In this study, the olfactory responses ofTheocolax elegans(Westwood), a Pteromalid wasp that parasitizes immature stages of stored-product insect pests developing inside cereal or leguminous grains, to volatiles emitted by healthy wheat grains, their hexane extracts, and different doses of three individual compounds previously identified in cereal grain odors were investigated in Y-tube olfactometer and Petri dish arena behavioral bioassays and electroantennogram recordings. In Y-tube olfactometer bioassays, odors from healthy wheat grains and their hexane extracts were attractive to both sexes ofT. elegans. Moreover, hexane extracts elicited arresting effects in Petri dish arena. The three synthetic compounds valeraldehyde, maltol, and vanillin elicited dose-dependent responses in both male and female adult wasps confirming the capability of the peripheral olfactory systems to perceive cereal volatiles. In behavioral bioassays, different doses of vanillin were significantly attractive to both sexes.
Urinary APE1/Ref-1: A Potential Bladder Cancer Biomarker
Authors: Choi Sunga , Shin Ju Hyun , Lee Yu Ran , Joo Hee Kyoung , Song Ki Hak , Na Yong Gil , Chang Seok Jong , Lim Jae Sung , Jeon Byeong Hwa
Published: January 2016

Bladder cancer (BCa) is one of the most common urothelial cancers with still noticeable incidence rate. Early detection of BCa is highly correlated with successful therapeutic outcomes. We previously showed that apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) was expressed at an increased level in the serum of BCa patients when compared to the level in healthy controls. In this study, we investigated whether urinary APE1/Ref-1 was also elevated in patients with BCa. In this case-control study, voided urine was collected from 277 subjects including 169 BCa patients and 108 non-BCa controls. Urinary APE1/Ref-1 level was assessed by enzyme-linked immunosorbent assay (ELISA). APE1/Ref-1 levels were significantly elevated in BCa patients relative to levels in non-BCa controls and were correlated with tumor grade and stage. Urinary APE1/Ref-1 levels were also higher in patients with recurrence history of BCa. The receiver operating characteristics (ROC) curve of APE1/Ref-1 showed an area under the curve of 0.83, indicating the reliability and validity of this biomarker. The optimal combination of sensitivity and specificity was determined to be 82% and 80% at a cut-off value of 0.376 ng/100 μL for detection of APE1/Ref-1 in urine. In conclusion, urinary APE1/Ref-1 levels measured from noninvasively obtained body fluids would be clinically applicable for diagnosis of BCa.
Expressing Status and Correlation of ARID1A and Histone H2B on Breast Cancer
Authors: Wu Yan , Gu Yan , Guo Shanyu , Dai Qiancheng , Zhang Wei
Published: January 2016

ARID1A is one of the important cancer-related genes and regulates transcription of certain genes by altering chromatin structure. Inactivated mutations and decreased expression of ARID1A gene have been reported in several kinds of cancer. Histone H2B is a major component of chromatin and encoded by HIST1H2BE. The goal of the study is to evaluate expressing status of ARID1A and H2B as well as their correlation on breast cancer. Gene expression profiles of ARID1A and H2B on Oncomine database are analyzed. Tissue microarray of breast cancer was used for examination of ARID1A and H2B expression by immunohistochemistry. As a result, the disagreement of ARID1A expression was found, while HIST1H2BE expression is elevated in 4 out of 5 datasets on Oncomine database. There were 15 cases (20%) of breast cancers that were positive for ARID1A. Fifty-eight out of 75 cases of breast cancer (77.3%) were highly expressed for H2B protein and 17 cases (22.7%) were low expressed for H2B protein. All cases with ARID1A expression are overlapped with H2B high expression. Among 15 cases with ARID1A and H2B coexpression, 13 are invasive ductal carcinoma and 2 are mucinous carcinoma. Our results indicate that ARID1A gene may be involved in carcinogenesis of some subtypes of breast cancer.
Fabrication and Crystallization of ZnO-SLS Glass Derived Willemite Glass-Ceramics as a Potential Material for Optics Applications
Authors: Mohd Zaid Mohd Hafiz , Amin Matori Khamirul , Abdul Aziz Sidek Hj. , Kamari Halimah Mohamed , Mat Yunus Wan Mahmood , Abdul Wahab Zaidan , Samsudin Nur Farhana
Published: January 2016

Willemite glass-ceramics were successfully derived from conventional melt-quench ZnO-SLS precursor glass by an isothermal heat treatment process. The effect of heat treatment temperatures on the physical properties was investigated by Archimedes principle and linear shrinkage. The generation of willemite crystal phase and morphology with increase in heat treatment temperature was examined by X-ray diffraction (XRD), Fourier transform infrared (FTIR), and field emission scanning electron microscopy (FESEM) techniques. X-ray diffraction revealed that the metastableβ-Zn2SiO4and thermodynamically stable zinc orthosilicateα-Zn2SiO4phases can be observed at temperatures above 700°C. The experimental results indicated that the density and shrinkage of the glass-ceramic vary with increasing the sintering temperature. FTIR studies showed that the structure of glass-ceramic consists of SiO2and ZnO4units and exhibits the structural evolution of willemite glass-ceramics. The characteristic of strong vibrational bands can be related to theSiO44-tetrahedron corresponding to reference spectra of willemite.
Fast and Sensitive Method for Determination of Domoic Acid in Mussel Tissue
Authors: Barbaro Elena , Zangrando Roberta , Barbante Carlo , Gambaro Andrea
Published: January 2016

Domoic acid (DA), a neurotoxic amino acid produced by diatoms, is the main cause of amnesic shellfish poisoning (ASP). In this work, we propose a very simple and fast analytical method to determine DA in mussel tissue. The method consists of two consecutive extractions and requires no purification steps, due to a reduction of the extraction of the interfering species and the application of very sensitive and selective HILIC-MS/MS method. The procedural method was validated through the estimation of trueness, extract yield, precision, detection, and quantification limits of analytical method. The sample preparation was also evaluated through qualitative and quantitative evaluations of the matrix effect. These evaluations were conducted both on the DA-free matrix spiked with known DA concentration and on the reference certified material (RCM). We developed a very selective LC-MS/MS method with a very low value of method detection limit (9 ng g−1) without cleanup steps.
Ultrasound-Assisted Extraction of Total Flavonoids from Corn Silk and Their Antioxidant Activity
Authors: Zheng Ling-Li , Wen Guan , Yuan Min-Yong , Gao Feng
Published: January 2016

Object. Ultrasound-assisted extraction of total flavonoids from corn silk and their antioxidant activities were studied.Methods. Response surface methodology was adopted to optimize the extraction conditions and antioxidant activities of the extracted total flavonoids were detected through ferric reducing antioxidant power (FRAP) assay.Results. Through a three-level, three-variable Box-Behnken design of response surface methodology (RSM) adopting yield as response, the optimal conditions were determined as follows: ultrasonic power 500 W, extraction time 20 min, material solvent ratio 1 : 20, and ethanol concentration 30%. Under the optimum conditions, the extraction yield of total flavonoids was 1.13%. FRAP value of total flavonoids extracted from corn silk was 467.59 μmol/L.Conclusion. The total flavonoids of corn silk could be developed as food natural antioxidant reagents.
Bioactive Flavonoids, Antioxidant Behaviour, and Cytoprotective Effects of Dried Grapefruit Peels (Citrus paradisi Macf.)
Authors: Castro-Vazquez Lucia , Alañón María Elena , Rodríguez-Robledo Virginia , Pérez-Coello María Soledad , Hermosín-Gutierrez Isidro , Díaz-Maroto María Consuelo , Jordán Joaquín , Galindo María Francisca , Arroyo-Jiménez María del Mar
Published: January 2016

Grapefruit (Citrus paradisi Macf.) is an important cultivar of the Citrus genus which contains a number of nutrients beneficial to human health. The objective of the present study was to evaluate changes in bioactive flavonoids, antioxidant behaviour, and in vitro cytoprotective effect of processed white and pink peels after oven‐drying (45°C–60°C) and freeze‐drying treatments. Comparison with fresh grapefruit peels was also assessed. Significant increases in DPPH, FRAPS, and ABTS values were observed in dried grapefruit peel samples in comparison with fresh peels, indicating the suitability of the treatments for use as tools to greatly enhance the antioxidant potential of these natural byproducts. A total of thirteen flavonoids were quantified in grapefruit peel extracts by HPLC‐MS/MS. It was found that naringin, followed by isonaringin, was the main flavonoid occurring in fresh, oven‐dried, and freeze‐dried grapefruit peels. In vivo assay revealed that fresh and oven‐dried grapefruit peel extracts (45°C) exerted a strong cytoprotective effect on SH‐SY5Y neuroblastoma cell lines at concentrations ranging within 0.1–0.25 mg/mL. Our data suggest that grapefruit (Citrus paradisi Macf.) peel has considerable potential as a source of natural bioactive flavonoids with outstanding antioxidant activity which can be used as agents in several therapeutic strategies.
A Natural Language Interface Concordant with a Knowledge Base
Authors: Han Yong-Jin , Park Seong-Bae , Park Se-Young
Published: January 2016

The discordance between expressions interpretable by a natural language interface (NLI) system and those answerable by a knowledge base is a critical problem in the field of NLIs. In order to solve this discordance problem, this paper proposes a method to translate natural language questions into formal queries that can be generated from a graph-based knowledge base. The proposed method considers a subgraph of a knowledge base as a formal query. Thus, all formal queries corresponding to a concept or a predicate in the knowledge base can be generated prior to query time and all possible natural language expressions corresponding to each formal query can also be collected in advance. A natural language expression has a one-to-one mapping with a formal query. Hence, a natural language question is translated into a formal query by matching the question with the most appropriate natural language expression. If the confidence of this matching is not sufficiently high the proposed method rejects the question and does not answer it. Multipredicate queries are processed by regarding them as a set of collected expressions. The experimental results show that the proposed method thoroughly handles answerable questions from the knowledge base and rejects unanswerable ones effectively.
A Novel Particle Swarm Optimization Algorithm for Global Optimization
Authors: Wang Chun-Feng , Liu Kui
Published: January 2016

Particle Swarm Optimization (PSO) is a recently developed optimization method, which has attracted interest of researchers in various areas due to its simplicity and effectiveness, and many variants have been proposed. In this paper, a novel Particle Swarm Optimization algorithm is presented, in which the information of the best neighbor of each particle and the best particle of the entire population in the current iteration is considered. Meanwhile, to avoid premature, an abandoned mechanism is used. Furthermore, for improving the global convergence speed of our algorithm, a chaotic search is adopted in the best solution of the current iteration. To verify the performance of our algorithm, standard test functions have been employed. The experimental results show that the algorithm is much more robust and efficient than some existing Particle Swarm Optimization algorithms.
Study on the Control Strategy of Shifting Time Involving Multigroup Clutches
Authors: Zhu Zhen , Gao Xiang , Pan Daoyuan , Zhu Yu , Cao Leilei
Published: January 2016

This paper focuses on the control strategy of shifting time involving multigroup clutches for a hydromechanical continuously variable transmission (HMCVT). The dynamic analyses of mathematical models are presented in this paper, and the simulation models are used to study the control strategy of HMCVT. Simulations are performed in SimulationXplatform to investigate the shifting time of clutches under different operating conditions. On this basis, simulation analysis and test verification of two typical conditions, which play the decisive roles for the shifting quality, are carried out. The results show that there are differences in the shifting time of the two typical conditions. In the shifting process from the negative transmission of hydromechanical ranges to the positive transmission of hydromechanical ranges, the control strategy based on the shifting time is switching the clutches of shifting mechanism firstly and then disengaging a group of clutches of planetary gear mechanism and engaging another group of the clutches of planetary gear mechanism lastly. In the shifting process from the hydraulic range to the hydromechanical range, the control strategy based on the shifting time is switching the clutches of hydraulic shifting mechanism and planetary gear mechanism at first and then engaging the clutch of shifting mechanism.
TREC to WHERE? Transdisciplinary Research on Energetics and Cancer
Authors: Schmitz Kathryn H. , Gehlert Sarah , Patterson Ruth E. , Colditz Graham A. , Chavarro Jorge E. , Hu Frank B. , Neuhouser Marian L. , Sturgeon Kathleen M. , Thornquist Mark , Tobias Deirdre , Nebeling Linda C.
Published: January 2016

When information is exchanged across disciplinary boundaries, resources are shared, and discipline-specific approaches are altered to achieve a common scientific goal, we create a new intellectual space for transdisciplinary research. This approach, fostered heavily by multiple NCI-funded initiatives, has the potential to forge new understanding of major public health issues. By breaking down disciplinary barriers, we work toward making real, meaningful, and lasting forward motion in addressing key public health issues. One of the transdisciplinary initiatives of the NCI is TREC: Transdisciplinary Research on Energetics and Cancer. In this article, we review the goals and scope of TREC, as well as the ways in which the initiative promotes transdisciplinary science. A particular focus is on multiple examples of the most unique aspect of the initiative: the funding of developmental projects across multiple TREC centers, toward the goal of incubating high-risk science that has the potential to translate into major leaps forward in understanding energetics in cancer. As we enter an era of greater focus on investigator-initiated science, new approaches may be needed to ensure that the peer review process is not solely organized along disciplinary lines. Inclusion of expertise regarding transdisciplinarity, as well as representation from multiple scientific disciplines within a panel, may allow transdisciplinary research to receive an educated hearing. The body of researchers trained to work in a transdisciplinary research space is ideally suited to address these challenges. Clin Cancer Res; 22(7); 1565–71. ©2016 AACR.
MYD88L265P Mutations, But No Other Variants, Identify a Subpopulation of DLBCL Patients of Activated B-cell Origin, Extranodal Involvement, and Poor Outcome
Authors: Rovira Jordina , Karube Kennosuke , Valera Alexandra , Colomer Dolors , Enjuanes Anna , Colomo Lluís , Martínez-Trillos Alejandra , Giné Eva , Dlouhy Ivan , Magnano Laura , Delgado Julio , Martínez Antonio , Villamor Neus , Campo Elías , López-Guillermo Armando
Published: January 2016

Purpose: Mutations in MYD88 are found in different lymphoproliferative disorders associated with particular biologic characteristics and clinical impact. The aim of this study was to analyze the incidence of MYD88 mutations and its clinical impact in diffuse large B-cell lymphoma (DLBCL).

Experimental Design: The incidence, clinicobiological features, and outcome of 213 patients (115 M/98 F; median age, 65 years) with DLBCL treated with immunochemotherapy in a single institution according to MYD88 mutational status as assessed by an allele-specific PCR assay were analyzed. The cell of origin (COO) was determined in 129 cases by gene expression.

Results: MYD88 mutations were found in 47 cases (22%), including L265P in 39 and S219C and M232F in 4 cases, respectively. Patients with MYD88 L265P were older, presenting frequent extranodal involvement, and mostly corresponded to activated B-cell like (ABC) subtype, whereas no preference in COO was observed in patients with other MYD88 mutations. Five-year overall survival (OS) for MYD88 wild-type, MYD88 L265P, and other variants was 62%, 52%, and 75%, respectively (P = 0.05). International Prognostic Index (IPI) (HR, 2.71; P < 0.001) and MYD88 L265P (HR, 1.786; P = 0.023) were independent variables predicting OS in the multivariate analysis. However, MYD88 L265P lost its independent value when COO was included in the model.

Conclusions: Our findings indicate that MYD88 L265P mutations, but no other variants, identify a subgroup of DLBCL mainly of ABC origin, with extranodal involvement and poor outcome. Clin Cancer Res; 22(11); 2755–64. ©2016 AACR.
Questionnaire-Based Survey on Diagnostic and Therapeutic Endoscopies and H. pylori Eradication for Elderly Patients in East Asian Countries
Authors: Matsuzaki Juntaro , Hayashi Ryoma , Arakawa Tetsuo , Ueno Fumiaki , Kinoshita Yoshikazu , Joh Takashi , Takahashi Shin''ichi , Naito Yuji , Fukudo Shin , Chan Francis K.L. , Hahm Ki-Baik , Kachintorn Udom , Fock Kwong Ming , Syam Ari Fahrial , Rani Abdul Aziz , Sollano Jose D. , Zhu Qi , Fujiwara Yasuhiro , Kubota Eiji , Kataoka Hiromi , Tokunaga Kengo , Uchiyama Kazuhiko , Suzuki Hidekazu ,   IGICS (The International Gastroenterology Consensus Symposium) Study Group
Published: January 2016

Background: Gastrointestinal endoscopy and Helicobacter pylori(H. pylori) eradication therapy are commonly performed even among the elderly population. The aim of this study was to understand the way endoscopists viewed the application of endoscopy and H. pylori eradication in the elderly of East Asian countries. Methods: Self-administered questionnaires containing 13 questions on endoscopy and H. pylori eradication in the elderly were distributed to major institutions in Japan, South Korea, China, Indonesia, and the Philippines. Results: Two hundred and fifteen endoscopists (111 in Japan, 39 in China, 24 in Korea, 21 in Indonesia, and 20 in the Philippines) participated in this study. In the institutions where these endoscopists were associated, around 50% of patients undergoing endoscopy were above the age of 60 years. The participating endoscopists indicated that the necessity of screening esophagogastroduodenoscopy and colonoscopy was lower in populations aged over 81 than the other age groups. They hesitated to perform therapeutic endoscopy, such as endoscopic submucosal dissection or endoscopic retrograde cholangiopancreatography, more often in patients over 85. They also hesitated to perform H. pylori eradication in patients aged over 81, especially in Japan. Conclusion: Endoscopists had significantly different attitudes regarding the indications for screening or therapeutic endoscopy and H. pylori eradication therapy in younger and elderly populations in East Asian countries.
The House Dust Mite Major Allergen Der p 23 Displays O-Glycan-Independent IgE Reactivities but No Chitin-Binding Activity
Authors: Soh Wai Tuck , Le Mignon Maxime , Suratannon Narissara , Satitsuksanoa Pattraporn , Chatchatee Pantipa , Wongpiyaboron Jongkonnee , Vangveravong Mukda , Rerkpattanapipat Ticha , Sangasapaviliya Atik , Nony Emmanuel , Piboonpocanun Surapon , Ruxrungtham Kiat , Jacquet Alain ,   Mite Allergy Research Cohort (MARC) Study Team
Published: January 2016

Background: The in-depth characterization of the recently identified house dust mite (HDM) major allergen Der p 23 requires the production of its recombinant counterpart because the natural allergen is poorly extractable from fecal pellets. This study aimed to provide a detailed physico-chemical characterization of recombinant Der p 23 (rDer p 23) as well as to investigate its IgE reactivity in a cohort of HDM-allergic patients from Thailand. Methods: Purified rDer p 23, secreted from recombinant Pichia pastoris, was characterized by mass spectrometry and circular dichroism analyses as well as for its chitin-binding activity. The IgE-binding frequency and allergenicity of Der p 23 were determined by ELISA and RBL-SX38 degranulation assays, respectively. Results: Purified intact rDer p 23 carried O-mannosylation and mainly adopted a random coil structure. Polyclonal antibodies to rDer p 23 can detect the corresponding natural allergen (nDer p 23) in aqueous fecal pellet extracts, suggesting that both forms of Der p 23 share common B-cell epitopes. Despite its homologies with chitin-binding proteins, both natural Der p 23 and rDer p 23 were unable to interact in vitro with chitin matrices. Of 222 Thai HDM-allergic patients tested, 54% displayed Der p 23-specific IgE responses. Finally, the allergenicity of rDer p 23 was confirmed by the degranulation of rat basophil leukemia cells. Conclusion: Our findings highlighted important levels of Der p 23 sensitizations in Thailand. Our study clearly suggested that rDer p 23 is likely more appropriate for HDM allergy component-resolved diagnosis than HDM extracts.
The Problem of Borderline Hemoglobin A2 Levels in the Screening for β-Thalassemia Carriers in Sardinia
Authors: Paglietti Maria Elisabetta , Satta Stefania , Sollaino Maria Carla , Barella Susanna , Ventrella Arianna , Desogus Maria Franca , Demartis Franca Rosa , Manunza Laura , Origa Raffaella
Published: January 2016

Background: The increase in HbA2 is the most important parameter for the identification of thalassemia carriers. However, in routine screening for hemoglobinopathies, some cases are difficult to classify because the level of HbA2 is not typically elevated. In this work, we report the results of a molecular investigation on a cohort of subjects with borderline HbA2. Methods: All subjects with a β-thalassemia carrier partner and a borderline percentage level of HbA2 were investigated for the presence of a pathological mutation in the β-globin gene. All negative subjects were screened for both the KLF1 mutation and the presence of ααα/ or αααα/ alleles. The subjects with reduced MCV and/or MCH were also screened for deletional and nondeletional α-globin gene defects. Results: Various β-globin mutations and KLF1 gene defects are the most common genetic determinants responsible for this phenotype in our population. Conclusion: KLF1 mutations are important in a screening program for hemoglobinopathies. An increase in HbF in association with borderline HbA2 levels is a useful but not exclusive marker that suggests the investigation of this gene. On the basis of our findings, we are able to suggest the molecular procedure to use in a population characterized by a high prevalence of thalassemia carriers.
Effectiveness of Early Preventive Intervention with Semiannual Fluoride Varnish Application in Toddlers Living in High-Risk Areas: A Stratified Cluster-Randomized Controlled Trial
Authors: Anderson Maria , Dahllöf Göran , Twetman Svante , Jansson Leif , Bergenlid Ann-Cathrine , Grindefjord Margaret
Published: January 2016

This study evaluated whether toddlers in an extended preventive program of semiannual fluoride varnish applications from 1 year of age had a lower incidence of caries than those undergoing a standard program. A cohort of 1-year-old children (n = 3,403) living in multicultural areas of low socioeconomic standing in Stockholm participated in a cluster-randomized controlled field trial with two parallel arms. The children attended 23 dental clinics. Using the ICDAS II criteria, the examiners recorded caries at baseline and after 1 and 2 years. The children in the reference group received a standardized oral health program once yearly between 1 and 3 years of age. The children in the test group received the same standard program supplemented with topical applications of fluoride varnish every 6 months. We compared the test group and the reference group for the prevalence and increment of caries. At baseline, 5% of the children had already developed caries (ICDAS II 1-6). We reexamined the children after 1 year (n = 2,675) and after 2 years (n = 2,536). Neither prevalence nor caries increment differed between the groups. At 3 years of age, 12% of the children had developed moderate and severe carious lesions (ICDAS II 3-6), with a mean increment of 0.5 (SD 2.4) in the test group and 0.6 (SD 2.2) in the reference group. In conclusion, semiannual professional applications of fluoride varnish, as a supplement to a standard oral health program, failed to reduce caries development in toddlers from high-risk communities.
Unicystic Ameloblastomatoid Cystic Craniopharyngioma: Pathological Discussion and Clinical Significance of Cyst Formation in Adamantinomatous Craniopharyngioma
Authors: Okada Tomu , Fujitsu Kazuhiko , Ichikawa Teruo , Miyahara Kousuke , Tanino Shin , Niino Hitoshi , Yagishita Saburou
Published: January 2016

An 8-year-old boy presented complaining principally of headache and vomiting. A single large cystic lesion extending from the suprasellar region to the ventral brainstem was identified, and total extirpation was performed via a right orbitozygomatic, transtemporal transchoroidal fissure approach. The cyst contents resembled motor oil, and no strong adhesions were identified between the tumor and the surrounding tissue except at the site of origin of the tumor, allowing easy dissection. The tumor originated at the junction of the adenohypophysis and the pituitary stalk. Although the histopathological diagnosis was adamantinomatous craniopharyngioma, the cyst walls comprising the majority of the tumor were not thin, fragile tissues formed by squamous metaplasia, but were thick and robust, bearing a close resemblance to unicystic ameloblastoma mixed with solid tissue. The existence of this type of cyst wall represents corroborating evidence that craniopharyngiomas are derived from the oral primordium. The existence of such tumors that can be totally extirpated in a single procedure while preserving hypothalamo-pituitary function may be taken as a warning not to rush at random to perform treatments that might encourage recurrence or regrowth by carrying out cyst fenestration and drug injection with the addition of stereotactic radiotherapy.
Transmission Behavior of B Chromosomes in Prochilodus lineatus (Characiformes, Prochilodontidae)
Authors: Penitente Manolo , Daniel Sandro N. , Senhorini José A. , Foresti Fausto , Porto-Foresti Fábio
Published: January 2016

The population of Prochilodus lineatus found in the Mogi-Guaçu River is karyotypically polymorphic, carrying acrocentric, metacentric, and submetacentric B chromosomes. The analysis of each B chromosome frequency in this species revealed a variation in the distribution pattern, with the metacentric type having the highest frequency (73.30%), followed by submetacentric (25.22%) and acrocentric B chromosomes (1.48%). The transmission pattern of the supernumerary chromosomes was identified by controlled crosses, and it was shown that the acro- and submetacentric B chromosomes have a transmission pattern below the Mendelian rate (kB = 0.333 and kB = 0.385, respectively), but the metacentric variant has a cumulative transmission pattern (kB = 0.587). These results indicate that the acro- and submetacentric B chromosomes are undergoing an extinction process, while the metacentric B chromosomes appear to be accumulating in frequency with each generation.
Associated Aneurysms in Infratentorial Arteriovenous Malformations: Role of Aneurysm Size and Comparison with Supratentorial Lesions
Authors: Stein Klaus-Peter , Wanke Isabel , Forsting Michael , Oezkan Neriman , Huetter Bernd-Otto , Sandalcioglu Ibrahim Erol , Sure Ulrich
Published: January 2016

Background: The natural history and treatment of brain arteriovenous malformations (AVMs) is the object of ongoing debates and discussions. To capture the entirety of these complex lesions, associated vascular pathologies, such as associated aneurysms (AAs), have to be implemented in future risk stratification models, as they are believed to represent additional risk factors for intracranial hemorrhage. The present study aims to determine AA characteristics in posterior fossa AVMs and to compare with AAs accompanying supratentorial AVMs, with special focus on aneurysm size. Methods: Patients with cerebral AVMs, treated in our department between 1990 and 2013, were analyzed retrospectively. Only patients with flow-related AAs of the feeding arteries were evaluated. Thus, patients harboring intranidal, venous or remote aneurysms were excluded. Results: Of 485 patients with cerebral AVM, 76 patients harbored an AVM of the posterior fossa. Among those, 22 individuals exhibited a total of 35 AAs (n = 8 patients with multiple AAs). Most common location of AAs was the posterior inferior cerebellar artery (n = 20, 57%) and mean AA diameter was 7.9 mm (SD 5.5). In the subgroup of patients with a single AA, mean aneurysm size in posterior fossa AVMs was with 7.8 mm (SD 6.0; range 2-25 mm) significantly larger than the mean size of AAs with supratentorial AVMs (4.8 mm, SD 3.0; range 2-20 mm; p = 0.048). Intracranial hemorrhage was found in 18 of 22 patients (82%) with infratentorial AVMs, and of these, 11 patients suffered from aneurysm rupture. In 14 patients bearing a single AA, 8 (57%) had sustained hemorrhage from aneurysm rupture. The mean diameter of AAs was as supposed in the ruptured group with 9.8 mm (SD 6.9; range 4-25 mm) significantly larger than in the unruptured AA group exhibiting a mean of 5.0 mm (SD 3.3; range 2-10 mm; p = 0.038). Patients with posterior fossa AVMs and AAs were significantly older as compared to those patients with supratentorial lesions (57.1, SD 12.6 vs. 45.8 years, SD 15.9 years; p = 0.004), which was also evident in the subgroup of patients with single AAs (55.2, SD 11.7 vs. 45.8 years, SD 14.9 years; p = 0.038). Conclusions: AAs of posterior fossa AVMs are larger in diameter than aneurysms accompanying supratentorial AVMs. AA size influences risk for hemorrhage, which, together with the high number of hemorrhagic events in posterior fossa AVMs, justifies treating these pathologies. The higher age of patients with AVMs of the posterior fossa might be one reason for larger AAs in this cohort, when compared to patients with supratentorial AVMs and AAs.
Concepts of Chronic Lymphocytic Leukemia Pathogenesis: DNA Damage Response and Tumor Microenvironment
Authors: Frenzel Lukas P. , Reinhardt H. Christian , Pallasch Christian P.
Published: January 2016

Pathogenesis of chronic lymphocytic leukemia (CLL) is characterized by specific genetic aberrations and alterations of cellular signaling pathways. In particular, a disturbed DNA damage response (DDR) and an activated B-cell receptor signaling pathway play a major role in promoting CLL cell survival. External stimuli are similarly essential for CLL cell survival and lead to activation of the PI3K/AKT and MAPK pathways. Activation of nuclear factor-kappa B (NFkB) influences the disturbed anti-apoptotic balance of CLL cells. Losses or disabling mutations in TP53 and ATM are frequent events in chemotherapy-naïve patients and are further enriched in chemotherapy-resistant patients. As these lesions define key regulatory elements of the DDR pathway, they also determine treatment response to genotoxic therapy. Novel therapeutic strategies therefore try to circumvent defective DDR signaling and to suppress the pro-survival stimuli received from the tumor microenvironment. With increasing knowledge on specific genetic alterations of CLL, we may be able to target CLL cells more efficiently even in the situation of mutated DDR pathways or protection by microenvironmental stimuli.
Dok-1 negatively regulates platelet integrin αIIbβ3 outside-in signalling and inhibits thrombosis in mice
Authors: Niki Masaru , Nayak Manasa K. , Jin Hong , Bhasin Neha , Plow Edward F. , Pandolfi Pier Paolo , Rothman Paul B. , Chauhan Anil K. , Lentz Steven R.
Published: January 2016

Adaptor proteins play a critical role in the assembly of signalling complexes after engagement of platelet receptors by agonists such as collagen, ADP and thrombin. Recently, using proteomics, the Dok (downstream of tyrosine kinase) adapter proteins were identified in human and mouse platelets. In vitro studies suggest that Dok-1 binds to platelet integrin β3, but the underlying effects of Dok-1 on αIIbβ3 signalling, platelet activation and thrombosis remain to be elucidated. In the present study, using Dok-1-deficient (Dok-1-/-) mice, we determined the phenotypic role of Dok-1 in αIIbβ3 signalling. We found that platelets from Dok-1-/- mice displayed normal aggregation, activation of αIIβ3 (assessed by binding of JON/A), P-selectin surface expression (assessed by anti-CD62P), and soluble fibrinogen binding. These findings indicate that Dok-1 does not affect “inside-out” platelet signalling. Compared with platelets from wild-type (WT) mice, platelets from Dok-1-/- mice exhibited increased clot retraction (p < 0.05 vs WT), increased PLCγ2 phosphorylation, and enhanced spreading on fibrinogen after thrombin stimulation (p < 0.01 vs WT), demonstrating that Dok-1 negatively regulates αIIbβ3 “outside-in” signalling. Finally, we found that Dok-1-/- mice exhibited significantly shortened bleeding times and accelerated carotid artery thrombosis in response to photochemical injury (p < 0.05 vs WT mice). We conclude that Dok-1 modulates thrombosis and haemostasis by negatively regulating αIIbβ3 outside-in signalling.

Supplementary Material to this article is available online at www.thrombosis-online.com.
Discontinuing early prophylaxis in severe haemophilia leads to deterioration of joint status despite low bleeding rates
Authors: Nijdam Annelies , Foppen Wouter , Kleijn Piet de , Mauser-Bunschoten Evelien P. , Roosendaal Goris , van Galen Karin P. M. , Schutgens Roger E. G. , van der Schouw Yvonne T. , Fischer Kathelijn
Published: January 2016

Prophylaxis is the recommended treatment for children with severe haemophilia A, but whether prophylaxis should be continued in adulthood is still under debate. Previous studies with limited follow-up have suggested that some patients may be able to stop prophylaxis in adulthood, while maintaining good joint health. This single-centre observational cohort study examined patients with severe haemophilia A born 1970–1988 without inhibitor development, and assessed the long-term consequences of discontinuing prophylaxis. Patient-initiated changes in prophylaxis, including all switches to on-demand treatment lasting a minimum of two consecutive weeks, were recorded from the time self-infusion began until the last evaluation. Sixty-six patients were evaluated at a median age of 32.4 years: 26 of patients had stopped prophylaxis for a median of 10 years, 15 had interrupted prophylaxis and 59 had continued prophylaxis. Annual joint bleeding rate (AJBR), Haemophilia Joint Health Score (HJHS-2.1; 0–124 points), radiological Pettersson score (0–78 points) and Haemophilia Activities List score (HAL; 100–0 points) were compared between patients who stopped and patients who continued prophylaxis. Although self-reported bleeding rates and functional limitations were similar in both groups (AJBR: 1.5 vs 1.2 and HAL: 84 vs 84 for those who stopped and continued prophylaxis, respectively), objective assessment of joint status showed increased arthropathy after 10 years of on-demand treatment in patients who stopped prophylaxis compared with those who continued (HJHS: 23 vs. 14 and Pettersson: 16 vs 5, respectively; P< 0.01). These results support continuation of long-term prophylaxis in adults and demonstrate the need for objective monitoring of joint status.

Trial registration: Dutch Trial Registry number 3098; UTN U1111–1121–7069.
A novel ELISA-based diagnosis of acquired von Willebrand disease with increased VWF proteolysis
Authors: Rauch Antoine , Caron Claudine , Vincent Flavien , Jeanpierre Emmanuelle , Ternisien Catherine , Boisseau Pierre , Zawadzki Christophe , Fressinaud Edith , Borel-Derlon Annie , Hermoire Sylvie , Paris Camille , Lavenu-Bombled Cécile , Veyradier Agnès , Ung Alexandre , Vincentelli André , Van Belle Eric , Lenting Peter J. , Goudemand Jenny , Susen Sophie
Published: January 2016

Von Willebrand disease-type 2A (VWD-2A) and acquired von Willebrand syndrome (AVWS) due to aortic stenosis (AS) or left ventricular assist device (LVAD) are associated with an increased proteolysis of von Willebrand factor (VWF). Analysis of VWF multimeric profile is the most sensitive way to assess such increased VWF-proteolysis. However, several technical aspects hamper a large diffusion among routine diagnosis laboratories. This makes early diagnosis and early appropriate care of increased proteolysis challenging. In this context of unmet medical need, we developed a new ELISA aiming a quick, easy and reliable assessment of VWF-proteolysis. This ELISA was assessed successively in a LVAD-model, healthy subjects (n=39), acquired TTP-patients (n=4), VWD-patients (including VWD-2A(IIA), n=22; VWD-2B, n=26; VWD-2A(IIE), n=21; and VWD-1C, n=8) and in AVWS-patients (AS, n=9; LVAD, n=9; and MGUS, n=8). A standard of VWF-proteolysis was specifically developed. Extent of VWF-proteolysis was expressed as relative percentage and as VWF proteolysis/VWF:Ag ratio. A speeddependent increase in VWF-proteolysis was assessed in the LVAD model whereas no proteolysis was observed in TTP-patients. In VWDpatients, VWF-proteolysis was significantly increased in VWD-2A(IIA) and VWD-2B and significantly decreased in VWD-2A(IIE) versus controls (p< 0.0001). In AVWS-patients, VWF-proteolysis was significantly increased in AS- and LVAD-patients compared to controls (p< 0.0001) and not detectable in MGUS-patients. A significant increase in VWFproteolysis was detected as soon as three hours after LVAD implantation (p< 0.01). In conclusion, we describe a new ELISA allowing a rapid and accurate diagnosis of VWF-proteolysis validated in three different clinical situations. This assay represents a helpful alternative to electrophoresis-based assay in the diagnosis and management of AVWS with increased VWF-proteolysis.

Supplementary Material to this article is available online at www.thrombosis-online.com.
Practical considerations in choosing a factor VIII prophylaxis regimen: Role of clinical phenotype and trough levels
Authors: Fischer Kathelijn , Carcao Manuel , Santagostino Elena , Manco-Johnson Marilyn J. , Mathew Prasad , Ljung Rolf
Published: January 2016

Current therapy for haemophilia A is guided by severity of the disease, which in turn is best reflected in patients' endogenous factor VIII activity levels. For patients with severe haemophilia (particularly children), prophylaxis with continuous routine factor replacement has become standard of care in developed countries and is gradually becoming the standard of care in developing countries. The question arises then: what is an appropriate prophylaxis regimen to prevent bleeding events and arthropathy, while also maximizing patient quality of life and taking into consideration the costs of prophylaxis? Should all patients be treated with one standard, fixed prophylaxis regimen, or should prophylaxis be individualised for each patient? If so, what factors need to be considered in choosing the appropriate dose and frequency of factor administration? If prophylaxis is tailored to the individual patient, then patient-related factors (bleeding phenotype, activity profiles, age, joint status) and product-specific factors (half-life of the replacement factor in the individual patient) will determine the choice of regimen, whether it be a fixed-regimen prophylaxis or prophylaxis that is tailored to patient activity and bleeding risk. Regardless of the choice of prophylaxis regimen, for any regimen to be effective, adherence to therapy is key to optimising outcomes.
Cardiac Mechano-Gated Ion Channels and Arrhythmias
Authors: Peyronnet Rémi , Nerbonne Jeanne M. , Kohl Peter
Published: January 2016

Mechanical forces will have been omnipresent since the origin of life, and living organisms have evolved mechanisms to sense, interpret, and respond to mechanical stimuli. The cardiovascular system in general, and the heart in particular, is exposed to constantly changing mechanical signals, including stretch, compression, bending, and shear. The heart adjusts its performance to the mechanical environment, modifying electrical, mechanical, metabolic, and structural properties over a range of time scales. Many of the underlying regulatory processes are encoded intracardially and are, thus, maintained even in heart transplant recipients. Although mechanosensitivity of heart rhythm has been described in the medical literature for over a century, its molecular mechanisms are incompletely understood. Thanks to modern biophysical and molecular technologies, the roles of mechanical forces in cardiac biology are being explored in more detail, and detailed mechanisms of mechanotransduction have started to emerge. Mechano-gated ion channels are cardiac mechanoreceptors. They give rise to mechano-electric feedback, thought to contribute to normal function, disease development, and, potentially, therapeutic interventions. In this review, we focus on acute mechanical effects on cardiac electrophysiology, explore molecular candidates underlying observed responses, and discuss their pharmaceutical regulation. From this, we identify open research questions and highlight emerging technologies that may help in addressing them.
RhoA/Rho-Kinase in the Cardiovascular System
Authors: Shimokawa Hiroaki , Sunamura Shinichiro , Satoh Kimio
Published: January 2016

Twenty years ago, Rho-kinase was identified as an important downstream effector of the small GTP-binding protein, RhoA. Thereafter, a series of studies demonstrated the important roles of Rho-kinase in the cardiovascular system. The RhoA/Rho-kinase pathway is now widely known to play important roles in many cellular functions, including contraction, motility, proliferation, and apoptosis, and its excessive activity induces oxidative stress and promotes the development of cardiovascular diseases. Furthermore, the important role of Rho-kinase has been demonstrated in the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, and heart failure. Cyclophilin A is secreted by vascular smooth muscle cells and inflammatory cells and activated platelets in a Rho-kinase–dependent manner, playing important roles in a wide range of cardiovascular diseases. Thus, the RhoA/Rho-kinase pathway plays crucial roles under both physiological and pathological conditions and is an important therapeutic target in cardiovascular medicine. Recently, functional differences between ROCK1 and ROCK2 have been reported in vitro. ROCK1 is specifically cleaved by caspase-3, whereas granzyme B cleaves ROCK2. However, limited information is available on the functional differences and interactions between ROCK1 and ROCK2 in the cardiovascular system in vivo. Herein, we will review the recent advances about the importance of RhoA/Rho-kinase in the cardiovascular system.
Mending a Faltering Heart
Authors: Li Mo , Izpisua Belmonte Juan Carlos
Published: January 2016

More people die every year from ischemic heart disease than any other disease. Because the human heart lacks sufficient ability to replenish the damaged cardiac muscles, extensive research has been devoted toward understanding the homeostatic and regenerative potential of the heart and to develop regenerative therapies for heart disease. Here, we discuss recent advances in the understanding of mechanisms governing heart growth during homeostasis or injury, including those from observational studies in humans and experimental research in animal models of cardiac regeneration. We also discuss how progress in stem cell biology and cellular reprogramming has enabled exciting new strategies for cardiac regeneration.