bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of the HLA‐A2, CW2, B27, S31, DR2 Haplotype with Ankylosing Spondylitis. A Possible Role of NON‐B27 Factors in the Disease
Authors: La Nasa Giorgio , Mathleu Alessandro , Mulargia Marina , Carcassi Carlo , Vacca Adriana , Ledda Antonio , Contu Licinio
Published: September 2014

With the aim of searching for HLA haplotypes and non‐B27 allele frequency variations in Sardinian AS patients, HLA‐A, B, Cw, DR, DQ and Bf, C4A and C4B typing and haplotype assignment was carried out in the families of 25 AS patients and in 44 healthy individuals, all B27 heterozygotes. In the AS patients a significant increase of the A2, Cw2, B27, DR2, DQ1 haplotype was found. This depends only partially on the linkage disequilibrium existing in the Sardinian population between B27 and the other alleles of this haplotype, and rather seems to be due to a primary association of Cw2 and DR2 alleles with AS. Preliminary data seem to show that this haplotype bears the S3l complotype and the ORB1 * 1601 allele both in the AS patients and in the healthy controls. The pathogenetic implications of these findings are discussed.
Increased Frequency of the Uncommon Allele of a Tumour Necrosis Factor Alpha Gene Polymorphism in Rheumatoid Arthritis and Systemic Lupus Erythematosus
Authors: Danis Victor A. , Millington Michelle , Hyland Valentine , Lawford Ron , Huang Qirong , Grennan David
Published: September 2014

The frequency of the uncommon allele (TNF2) of a polymorphism in the promoter region of the tumour necrosis factor alpha (TN Fα) gene in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) was found to be 3 times that of the normal anglo‐saxon population. In SLE patients, this allele was strongly associated with HLA‐DR3 expression and was also more frequent in patients who did not have malar rash. Functional studies of normal monocyte cytokine production in vitro showed that this genotype was associated with increased IL‐1α protein production but there were no differences in the production of TNFα protein.
Integral Eigen-Pair Balanced Classes of Graphs with Their Ratio, Asymptote, Area, and Involution-Complementary Aspects
Authors: Winter Paul August , Jessop Carol Lynne
Published: September 2014

The association of integers, conjugate pairs, and robustness with the eigenvalues of graphs provides the motivation for the following definitions. A class of graphs, with the property that, for each graph (member) of the class, there exists a pair a,b of nonzero, distinct eigenvalues, whose sum and product are integral, is said to be eigen-bibalanced. If the ratio (a+b)/(a·b) is a function f(n), of the order n of the graphs in this class, then we investigate its asymptotic properties. Attaching the average degree to the Riemann integral of this ratio allowed for the evaluation of eigen-balanced areas of classes of graphs. Complete graphs on n vertices are eigen-bibalanced with the eigen-balanced ratio (n-2)/(1-n)=f(n) which is asymptotic to the constant value of −1. Its eigen-balanced area is (n-1)(n-ln⁡⁡(n-1))—we show that this is the maximum area for most known classes of eigen-bibalanced graphs. We also investigate the class of eigen-bibalanced graphs, whose class of complements gives rise to an eigen-balanced asymptote that is an involution and the effect of the asymptotic ratio on the energy of the graph theoretical representation of molecules.
Hybrid Recentering Energy Dissipative Device for Seismic Protection
Authors: Tang Wenke , Lui Eric M.
Published: September 2014

A hybrid recentering energy dissipative device that has both recentering and energy dissipation capabilities is proposed and studied in this paper. The proposed hybrid device, referred to as the hybrid shape memory alloy (SMA) recentering viscous fluid (RCVF) energy dissipation device, connects the apex of a chevron brace to an adjoining beam using two sets of SMA wires arranged in series on either side of the brace and a viscous fluid damper arranged in parallel with the SMA wires. The viscous damper is used because being a velocity-dependent device it does not exert any force that counteracts the recentering force from the SMA wires after the vibration of the frame ceases. In the numerical study, the Wilde’s SMA constitutive model is used to model the SMA wires, and the Maxwell model is used to simulate the viscous fluid damper. To demonstrate the viability and effectiveness of the proposed hybrid device, comparative studies are performed on several single-story shear frames and a series of four-story steel frames. The results show that the frames equipped with the hybrid device have noticeably smaller peak top story displacements and residual story drifts when subjected to ground motions at three different intensity levels.
Sugar Mill Effluent Utilization in the Cultivation of Maize (Zea mays L.) in Two Seasons
Authors: Kumar Vinod
Published: September 2014

The aim of present investigation is to study the effects of sugar mill effluent fertigation on soil properties and agronomical characteristics of Maize (Zea mays L. cv. NMH 589) in two seasons. Six treatments of sugar mill effluent, namely, 0% (control), 20%, 40%, 60%, 80%, and 100%, were used for the cultivation of Z. mays. Fertigation with different concentrations of sugar mill effluent resulted in significant (P<0.01) changes in EC, pH, OC, Na+, K+, Ca2+, Mg2+, TKN, PO43-, SO42-, Fe3+, Zn2+, Cd2+, Cu2+, Mn2+, and Cr3+ of the soil in both seasons. The maximum agronomic performance of Z. mays was noted with 40% concentration of sugar mill effluent. Biochemical components like crude proteins, crude fiber, and total carbohydrates were recorded highest with 40% concentration of sugar mill effluent in both seasons. The contamination factor (Cf) of various heavy metals was observed in order of Mn2+>Zn2+>Cu2+>Cd2+>Cr3+ for soil and Mn2+>Zn2+>Cu2+>Cr3+>Cd2+ for Z. mays in both seasons after fertigation with sugar mill effluent. It appears that sugar mill effluent can be used as a biofertigant after appropriate dilution to improve the yield.
A Parametric Learning and Identification Based Robust Iterative Learning Control for Time Varying Delay Systems
Authors: Zhai Lun , Tian Guohui , Li Yan
Published: September 2014

A parametric learning based robust iterative learning control (ILC) scheme is applied to the time varying delay multiple-input and multiple-output (MIMO) linear systems. The convergence conditions are derived by using theH∞and linear matrix inequality (LMI) approaches, and the convergence speed is analyzed as well. A practical identification strategy is applied to optimize the learning laws and to improve the robustness and performance of the control system. Numerical simulations are illustrated to validate the above concepts.
Modelling Agro-Met Station Observations Using Genetic Algorithm
Authors: Kumar Prashant , Bhattacharya Bimal K. , Kishtawal C. M. , Basu Sujit
Published: September 2014

The present work discusses the development of a nonlinear data-fitting technique based on genetic algorithm (GA) for the prediction of routine weather parameters using observations from Agro-Met Stations (AMS). The algorithm produces the equations that best describe the temporal evolutions of daily minimum and maximum near-surface (at 2.5-meter height) air temperature and relative humidity and daily averaged wind speed (at 10-meter height) at selected AMS locations. These enable the forecasts of these weather parameters, which could have possible use in crop forecast models. The forecast equations developed in the present study use only the past observations of the above-mentioned parameters. This approach, unlike other prediction methods, provides explicit analytical forecast equation for each parameter. The predictions up to 3 days in advance have been validated using independent datasets, unknown to the training algorithm, with impressive results. The power of the algorithm has also been demonstrated by its superiority over persistence forecast used as a benchmark.
Zingiber officinale(Ginger): A Future Outlook on Its Potential in Prevention and Treatment of Diabetes and Prediabetic States
Authors: Roufogalis Basil D.
Published: September 2014

Diabetes is reaching pandemic levels in both developing and developed countries and requires safe, affordable, and effective therapies. This report summarises work in our laboratory on the effects ofZingiber officinale(ginger) and its components in diabetes models and provides a future outlook on the potential for their use in type 2 diabetes. A high fat diet rat model showed modulation of body weight gain and normalisation of glucose and lipid metabolic disturbances, with reduction of insulin resistance in a high fat-high carbohydrate diet model. Ginger extract inhibits enhanced NF-κB in liver of high fat-fed rats through inhibition of the IKK/IκBα/NF-κB classical pathway. The major active component(S)-[6]-gingerol inhibited elevated cytokines in inflamed HuH7 cells through suppression of COX2 expression and protection against the ROS pathway. Ginger extract and gingerols enhanced glucose uptake in L6 myotubes, by enhancing translocation of GLUT4 to the surface membrane and activation of AMPKα1 through a Ca2+/calmodulin-dependent protein kinase kinase pathway.(S)-[6]-Gingerol also enhanced energy metabolism through marked increment of peroxisome proliferator-activated receptor-γcoactivator-1α(PGC-1α) gene expression and mitochondrial content in L6 skeletal muscle cells. Future studies will require well designed clinical trials on ginger preparations of defined chemical composition.
Transorbital Stab Injury with Retained Knife: A Narrow Escape
Authors: Rana Muhammad Asim , Alharthy Abdulrehman , Aletreby Waleed Tharwat , Huwait Basim , Kulshrestha Akhilesh
Published: September 2014

Transorbital penetrating injuries are unusual but may cause severe brain damage if cranium is entered. These kinds of injuries are dangerous as the walls of orbit are very thin, hence easily broken by the otherwise innocent objects. Because of the very critical anatomical area involved, these injuries pose a serious challenge to the physicians who first receive them as well as the treating team. These may present as trivial trauma or may be occult and are often associated with serious complications and delayed sequel. Prompt evaluation by utilizing best diagnostic modality available and timely interference to remove them are the key aspects to avoid damage to vital organs surrounding the injury and to minimize the late complications. We report a case of transorbital assault with a 13 centimeter long knife which got broken from the handle and the blade was retained. The interesting aspect is that there was no neurological deficit on presentation or after removal.
Icatibant in the Treatment of Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema
Authors: Crooks Neil H. , Patel Jaimin , Diwakar Lavanya , Smith Fang Gao
Published: September 2014

We describe the case of a 75-year-old woman who presented with massive tongue and lip swelling secondary to angiotensin-converting enzyme inhibitor-induced angioedema. An awake fibre-optic intubation was performed because of impending airway obstruction. As there was no improvement in symptoms after 72 hours, the selective bradykinin B2 receptor antagonist icatibant (Firazyr) was administered and the patient’s trachea was successfully extubated 36 hours later. To our knowledge this is the first documented case of icatibant being used for the treatment of angiotensin-converting enzyme inhibitor-induced angioedema in the United Kingdom and represents a novel therapeutic option in its management.
Role of Indium Alloying with Lead as a Means to Reduce the Passivation Phenomena in Lead/Acid Batteries
Authors: El-Sayed Abdel-Rahman , Mohran Hossnia S. , Shilkamy Hoda Abdel Shafy
Published: September 2014

The influence of indium content on the anodic behaviour of Pb-In alloys in 4 M H2SO4solution is investigated by potentiodynamic, potentiostatic, chronopotentiometric, and cyclic voltammetric techniques. The composition and microstructure of the corrosion layer on Pb-In alloys are characterized by X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy analysis (EDX), and scanning electron microscopy (SEM). The potentiodynamic and chronopotentiometric curves show that the anodic behavior of all investigated electrodes exhibits active/passive transition. The active dissolution (except for alloy I) and passive currents increase with increasing both In content and temperature. This indicates that the conductivity of the anodic film on Pb-In alloy is enhanced. This study exhibits that indium catalyses the oxidation of Pb (II) to Pb (IV) and facilitates the formation of a more highly conductive corrosion layer on lead. Alloy I (0.5% In) exhibits that the corrosion rate is lower, while the passive current is higher than that of Pb. XRD, EDX, and SEM results reveal that the formation of both PbSO4and PbO on the surface decreases gradually with increasing In level in the alloy and completely disappear at higher In content (15% In). Therefore, recharge of the battery will be improved due to indium addition to Pb.
Development of a Novel Switched-Mode 2.45 GHz Microwave Multiapplicator Ablation System
Authors: Biffi Gentili Guido , Ignesti Cosimo , Tesi Vasco
Published: September 2014

The development of a novel switched-mode 2.45 GHz microwave (MW) multiapplicator system intended for laparoscopic and open surgical thermoablative treatments is presented. The system differs from the other synchronous and asynchronous commercially available equipments because it employs a fast sequential switching (FSS) technique for feeding an array of up to four high efficiency MW applicators. FSS technology, if properly engineered, allows improving system compactness, modularity, overall efficiency, and operational flexibility. Full-wave electromagnetic (EM) and thermal (TH) simulations have been made to confirm the expected performances of the FSS technology. Here we provide an overview of technical details and early ex-vivo experiments carried out with a full functional β-prototype of the system.
Oncogene Pathway Activation in Mammary Tumors Dictates FDG-PET Uptake
Authors: Alvarez James V. , Belka George K. , Pan Tien-Chi , Chen Chien-Chung , Blankemeyer Eric , Alavi Abass , Karp Joel S. , Chodosh Lewis A.
Published: September 2014

Increased glucose utilization is a hallmark of human cancer that is used to image tumors clinically. In this widely used application, glucose uptake by tumors is monitored by positron emission tomography of the labeled glucose analogue 2[18F]fluoro-2-deoxy-d-glucose (FDG). Despite its widespread clinical use, the cellular and molecular mechanisms that determine FDG uptake—and that underlie the heterogeneity observed across cancers—remain poorly understood. In this study, we compared FDG uptake in mammary tumors driven by the Akt1, c-MYC, HER2/neu, Wnt1, or H-Ras oncogenes in genetically engineered mice, correlating it to tumor growth, cell proliferation, and expression levels of gene involved in key steps of glycolytic metabolism. We found that FDG uptake by tumors was dictated principally by the driver oncogene and was not independently associated with tumor growth or cellular proliferation. Oncogene downregulation resulted in a rapid decrease in FDG uptake, preceding effects on tumor regression, irrespective of the baseline level of uptake. FDG uptake correlated positively with expression of hexokinase-2 (HK2) and hypoxia-inducible factor-1α (HIF1α) and associated negatively with PFK-2b expression and p-AMPK. The correlation between HK2 and FDG uptake was independent of all variables tested, including the initiating oncogene, suggesting that HK2 is an independent predictor of FDG uptake. In contrast, expression of Glut1 was correlated with FDG uptake only in tumors driven by Akt or HER2/neu. Together, these results demonstrate that the oncogenic pathway activated within a tumor is a primary determinant of its FDG uptake, mediated by key glycolytic enzymes, and provide a framework to interpret effects on this key parameter in clinical imaging. Cancer Res; 74(24); 7583–98. ©2014 AACR.
TRAP1 Is Involved in BRAF Regulation and Downstream Attenuation of ERK Phosphorylation and Cell-Cycle Progression: A Novel Target for BRAF-Mutated Colorectal Tumors
Authors: Condelli Valentina , Piscazzi Annamaria , Sisinni Lorenza , Matassa Danilo Swann , Maddalena Francesca , Lettini Giacomo , Simeon Vittorio , Palladino Giuseppe , Amoroso Maria Rosaria , Trino Stefania , Esposito Franca , Landriscina Matteo
Published: September 2014

Human BRAF-driven tumors are aggressive malignancies with poor clinical outcome and lack of sensitivity to therapies. TRAP1 is a HSP90 molecular chaperone deregulated in human tumors and responsible for specific features of cancer cells, i.e., protection from apoptosis, drug resistance, metabolic regulation, and protein quality control/ubiquitination. The hypothesis that TRAP1 plays a regulatory function on the BRAF pathway, arising from the observation that BRAF levels are decreased upon TRAP1 interference, was tested in human breast and colorectal carcinoma in vitro and in vivo. This study shows that TRAP1 is involved in the regulation of BRAF synthesis/ubiquitination, without affecting its stability. Indeed, BRAF synthesis is facilitated in a TRAP1-rich background, whereas increased ubiquitination occurs upon disruption of the TRAP1 network that correlates with decreased protein levels. Remarkably, BRAF downstream pathway is modulated by TRAP1 regulatory activity: indeed, TRAP1 silencing induces (i) ERK phosphorylation attenuation, (ii) cell-cycle inhibition with cell accumulation in G0–G1 and G2–M transitions, and (iii) extensive reprogramming of gene expression. Interestingly, a genome-wide profiling of TRAP1-knockdown cells identified cell growth and cell-cycle regulation as the most significant biofunctions controlled by the TRAP1 network. It is worth noting that TRAP1 regulation on BRAF is conserved in human colorectal carcinomas, with the two proteins being frequently coexpressed. Finally, the dual HSP90/TRAP1 inhibitor HSP990 showed activity against the TRAP1 network and high cytostatic potential in BRAF-mutated colorectal carcinoma cells. Therefore, this novel TRAP1 function represents an attractive therapeutic window to target dependency of BRAF-driven tumors on TRAP1 translational/quality control machinery. Cancer Res; 74(22); 6693–704. ©2014 AACR.
Paclitaxel-Loaded PEG-PE–Based Micellar Nanopreparations Targeted with Tumor-Specific Landscape Phage Fusion Protein Enhance Apoptosis and Efficiently Reduce Tumors
Authors: Wang Tao , Yang Shenghong , Mei Leslie A. , Parmar Chirag K. , Gillespie James W. , Praveen Kulkarni P. , Petrenko Valery A. , Torchilin Vladimir P.
Published: September 2014

In an effort to improve the therapeutic index of cancer chemotherapy, we developed an advanced nanopreparation based on the combination of landscape phage display to obtain new targeting ligands with micellar nanoparticles for tumor targeting of water-insoluble neoplastic agents. With paclitaxel as a drug, this self-assembled nanopreparation composed of MCF-7–specific phage protein and polyethylene glycol–phosphatidylethanolamine (PEG-PE) micelles showed selective toxicity to target cancer cells rather than nontarget, non cancer cells in vitro. In vivo, the targeted phage micelles triggered a dramatic tumor reduction and extensive necrosis as a result of improved tumor delivery of paclitaxel. The enhanced anticancer effect was also verified by an enhanced apoptosis and reduced tumor cell proliferation following the treatment with the targeted micellar paclitaxel both in vitro and in vivo. The absence of hepatotoxicity and pathologic changes in tissue sections of vital organs, together with maintenance of overall health of mice following the treatment, further support its translational potential as an effective and safe chemotherapy for improved breast cancer treatment. Mol Cancer Ther; 13(12); 2864–75. ©2014 AACR.
Efficacy of RG7787, a Next-Generation Mesothelin-Targeted Immunotoxin, against Triple-Negative Breast and Gastric Cancers
Authors: Alewine Christine , Xiang Laiman , Yamori Takao , Niederfellner Gerhard , Bosslet Klaus , Pastan Ira
Published: September 2014

The RG7787 mesothelin-targeted recombinant immunotoxin (RIT) consists of an antibody fragment targeting mesothelin (MSLN) fused to a 24-kD fragment of Pseudomonas exotoxin A for cell killing. Compared with prior RITs, RG7787 has improved properties for clinical development including decreased nonspecific toxicity and immunogenicity and resistance to degradation by lysosomal proteases. MSLN is a cell surface glycoprotein highly expressed by many solid tumor malignancies. New reports have demonstrated that MSLN is expressed by a significant percentage of triple-negative breast and gastric cancer clinical specimens. Here, panels of triple-negative breast and gastric cancer cell lines were tested for surface MSLN expression, and for sensitivity to RG7787 in vitro and in animal models. RG7787 produced >95% cell killing of the HCC70 and SUM149 breast cancer cell lines in vitro with IC50 < 100 pmol/L. RG7787 was also effective against gastric cancer cell lines MKN28, MKN45, and MKN74 in vitro, with subnanomolar IC50s. In a nude mouse model, RG7787 treatment (2.5 mg/kg i.v. qod ×3–4) resulted in a statistically significant 41% decrease in volumes of HCC70 xenograft tumors (P < 0.0001) and an 18% decrease in MKN28 tumors (P < 0.0001). Pretreatment with paclitaxel (50 mg/kg i.p.) enhanced efficacy, producing 88% and 70% reduction in tumor volumes for HCC70 and MKN28, respectively, a statistically significant improvement over paclitaxel alone (P < 0.0001 for both). RG7787 merits clinical testing for triple-negative breast and gastric cancers. Mol Cancer Ther; 13(11); 2653–61. ©2014 AACR.
The Risk of Malignancy Anywhere in the Body after Linear Accelerator (LINAC) Stereotactic Radiosurgery
Authors: Rahman Maryam , Neal Dan , Baruch William , Bova Frank J. , Frentzen Barbara H. , Friedman William A.
Published: September 2014

Background: Despite the conformity of stereotactic radiosurgery (SRS) treatment, there are concerns about the risk of malignancy. Objective: We compared the number of cancer cases observed after treatment in a group of SRS patients to the number of cancer cases that would be expected in an age- and gender-matched group. Methods: We collected data from the University of Florida SRS database for patients treated for meningiomas, intracranial schwannomas, arteriovenous malformations (AVMs), trigeminal neuralgia, pituitary adenomas, cavernous angiomas, and metastases. We used the Florida Cancer Data System (FCDS) to determine the actual cancer rates for SRS-treated patients, and we compared these to the cancer rates in similar groups of non-SRS-treated patients based on rates available from the SEER (surveillance epidemiology and end results) database. Results: A total of 2,369 patients were analyzed. Of these, 862 were patients with metastases who were analyzed only to ensure the sensitivity of using the FCDS to determine malignancy rates. The results for patients with more than 5 years of follow-up are reported. Without the metastases patients, a total of 627 patients had more than 5 years of follow-up data. Follow-up in patient-years was 1,711 for the meningioma patients, 1,851 for the schwannoma patients, 1,407 for the AVM patients and 338 for patients with a diagnosis of ‘other'. The observed cancer rate in the meningioma patients was 3.96% compared to the expected rate of 10% (binomial 95% confidence interval, CI = 1.85-7.94). The observed cancer rate in the schwannoma patients was 4.93% compared to the expected rate of 12.5% (95% CI = 2.61-8.89). The observed cancer rate in the AVM patients was 3.64% compared to the expected rate of 4.43% (95% CI = 1.49-8.10). The observed cancer rate in patients treated for other diagnoses (e.g. pituitary adenoma or trigeminal neuralgia) was 0% compared to the expected rate of 6.36% (95% CI = 0-11.7). Conclusions: In a large population of SRS-treated patients, there was no increased risk of malignancy compared to the general population.
Occurrence of Rabl-Like Telomere Clustering in the Holocentric Chromosomes of the Peach Potato Aphid Myzus persicae (Hemiptera; Aphididae)
Authors: Mandrioli Mauro , Bandinelli Sarah , Manicardi Gian Carlo
Published: September 2014

Several studies demonstrated that chromosome anchoring to nuclear structures is involved in the organization of the interphase nucleus. The Rabl configuration, a well-studied chromosome organization in the interphase nucleus, has been deeply studied in organisms with monocentric chromosomes but just slightly touched in species with holocentric chromosomes. In the present paper, by means of the isolation and chromosomal mapping of the C₀t DNA fraction and chromatin immunoprecipitation with anti-LEM-2 antibodies, we evidenced the presence of few foci where telomeres and subtelomeric regions cluster in the aphid interphase nuclei, suggesting the occurrence of a Rabl-like chromosome configuration. The same experimental approaches also evidenced that most of the repetitive DNA of the 2 X chromosomes is located at the periphery of the nucleus, whereas the ribosomal genes, located at 1 telomere of each X chromosome, are present towards the inner portion of the nucleus, favoring their transcriptional activity.
Hereditary Angioedema in Greece: The First Results of the Greek Hereditary Angioedema Registry
Authors: Psarros Fotis , Koutsostathis Nick , Farmaki Evangelia , Speletas Matthaios G. , Germenis Anastasios E.
Published: September 2014

Background: No published data presently exist concerning hereditary angioedema (HAE) in Greece. The aim of this study was to present the results from patients recorded by the Greek Hereditary Angioedema Registry over the last 3 years (July 2010 to June 2013). Methods: A systematic recording of HAE cases was undertaken following a physician awareness campaign and confirmation of diagnosis. A questionnaire was also used for the assessment of key parameters of the patients' disease-specific quality of life. Results: One hundred and sixteen patients from 41 non-related families were recorded. There were 33 (80.5%) families with type I HAE, 7 (17%) with type II HAE and 1 (2.5%) with non-C1 inhibitor (C1-INH), non-FXII HAE. Two further non-C1-INH, non-FXII HAE sporadic cases were recorded. An investigation of non-symptomatic family members revealed another 6 asymptomatic individuals with C1-INH deficiency. The average delay in diagnosis was 16.5 years and the incidence of death in the families of patients was 1 for every 2 families. The use of newer therapeutic agents seems to fall significantly short of the existing needs. HAE was found to affect the quality of life slightly in 14%, greatly in 63% and significantly in 23% of the patients. Conclusion: Until recently, there has been a significant degree of underdiagnosis of HAE in Greece. Very low compliance with the provisions of the applicable international guidelines and consensus positions, with adverse consequences on the patients' quality of life, was also observed. The centralized model we used to uncover the patients could be effective in other countries presenting with comparable disease characteristics. © 2014 S. Karger AG, Basel
Conserved MHC Gene Orthologs Genetically Map to the Turkey MHC-B
Authors: Reed Kent M. , Benoit Benjamin , Wang Xiong , Greenshields Molly A. , Hughes Camilla H.K. , Mendoza Kristelle M.
Published: September 2014

The avian MHC-associated gene set includes orthologs to genes found throughout the human major histocompatibility complex (MHC), including some loci of the evolutionarily conserved class III region. In the turkey and other Galliformes, genes linked to the MHC have been identified because they are closely associated with class I or class II genes. This study was designed to evaluate additional class III genes for linkage to the avian MHC to further determine conservation of these loci in birds. BLAST searches were used to locate sequences in the turkey genome with similarity to genes shared between the MHC of Xenopus and humans. Primers were designed to target 25 genes, and putative orthologs were amplified by PCR and sequenced. Sequence polymorphisms were identified for 15 genes in turkey reference mapping families, and 8 genes showed significant genetic linkage to the turkey MHC-B locus. These new genetic markers and linkage relationships broaden our understanding of the composition of the avian MHC and expand the gene content for the turkey MHC-B.
A Case of Blind Loop Syndrome Caused by Infection with Giardia duodenalis Diagnosed with Double Balloon Enteroscopy
Authors: Nakagawa Tomoo , Katsuno Tatsuro , Mandai Yasushi , Saito Masaya , Yoshihama Sayuri , Saito Keiko , Minemura Shoko , Maruoka Daisuke , Matsumura Tomoaki , Arai Makoto , Yokosuka Osamu
Published: September 2014

A 75-year-old man who had undergone partial gastrectomy was referred to our hospital due to worsening leg edema, loose stools and malnutrition. Double balloon enteroscopy followed by insertion of an indwelling ileus tube was performed to investigate the microbial flora and for washing inside the blind loop. Trophozoites of Giardia were detected in the sampled fluid from the blind loop and DNA analysis disclosed an assemblage of genotype A-II of Giardia duodenalis. Treatment with oral metronidazole was effective. This case emphasizes the importance of a correct diagnosis when treating patients with blind loop syndrome in the digestive tract.
Genome-Wide Association Study of
l
-Arginine and Dimethylarginines Reveals Novel Metabolic Pathway for Symmetric Dimethylarginine
Authors: Lüneburg Nicole , Lieb Wolfgang , Zeller Tanja , Chen Ming-Huei , Maas Renke , Carter Angela M. , Xanthakis Vanessa , Glazer Nicole L. , Schwedhelm Edzard , Seshadri Sudha , Ikram Mohammad Arfan , Longstreth William T. , Fornage Myriam , König Inke R. , Loley Christina , Ojeda Francisco M. , Schillert Arne , Wang Thomas J. , Sticht Heinrich , Kittel Anja , König Jörg , Benjamin Emelia J. , Sullivan Lisa M. , Bernges Isabel , Anderssohn Maike , Ziegler Andreas , Gieger Christian , Illig Thomas , Meisinger Christa , Wichmann H.-Erich , Wild Philipp S. , Schunkert Heribert , Psaty Bruce M. , Wiggins Kerri L. , Heckbert Susan R. , Smith Nicholas , Lackner Karl , Lunetta Kathryn L. , Blankenberg Stefan , Erdmann Jeanette , Munzel Thomas , Grant Peter J. , Vasan Ramachandran S. , Böger Rainer H.
Published: September 2014

Background—

Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA [ADMA]) and
l
-arginine uptake into the cell (ADMA and symmetrical DMA [SDMA]). In prospective clinical studies, ADMA has been characterized as a cardiovascular risk marker, whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterize the environmental and genetic contributions to interindividual variability of these biomarkers.

Methods and Results—

This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (Framingham Heart Study [FHS; n=2992], Gutenberg Health Study [GHS; n=4354], and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study [MONICA]/Cooperative Health Research in the Augsburg Area, Augsburg, Bavaria, Germany [KORA] F3 [n=581]) and identified replicated loci (
DDAH1, MED23, Arg1
, and
AGXT2
) associated with the interindividual variability in ADMA,
l
-arginine, and SDMA. Experimental in silico and in vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants, and various cardiometabolic risk factors. AGXT2 variants were not associated with poststroke survival in the Leeds study or were they associated with incident stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

Conclusions—

These genome-wide association study support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and
l
-arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation.
Ankyrin-G Coordinates Intercalated Disc Signaling Platform to Regulate Cardiac Excitability In Vivo
Authors: Makara Michael A. , Curran Jerry , Little Sean C. , Musa Hassan , Polina Iuliia , Smith Sakima A. , Wright Patrick J. , Unudurthi Sathya D. , Snyder Jed , Bennett Vann , Hund Thomas J. , Mohler Peter J.
Published: September 2014

Rationale:

Na
v
1.5 (
SCN5A
) is the primary cardiac voltage-gated Na
v
channel. Na
v
1.5 is critical for cardiac excitability and conduction, and human
SCN5A
mutations cause sinus node dysfunction, atrial fibrillation, conductional abnormalities, and ventricular arrhythmias. Further, defects in Na
v
1.5 regulation are linked with malignant arrhythmias associated with human heart failure. Consequently, therapies to target select Na
v
1.5 properties have remained at the forefront of cardiovascular medicine. However, despite years of investigation, the fundamental pathways governing Na
v
1.5 membrane targeting, assembly, and regulation are still largely undefined.

Objective:

Define the in vivo mechanisms underlying Na
v
1.5 membrane regulation.

Methods and Results:

Here, we define the molecular basis of an Na
v
channel regulatory platform in heart. Using new cardiac-selective ankyrin-G
-/-
mice (conditional knock-out mouse), we report that ankyrin-G targets Na
v
1.5 and its regulatory protein calcium/calmodulin–dependent kinase II to the intercalated disc. Mechanistically, β
IV
-spectrin is requisite for ankyrin-dependent targeting of calcium/calmodulin–dependent kinase II-δ; however, β
IV
-spectrin is not essential for ankyrin-G expression. Ankyrin-G conditional knock-out mouse myocytes display decreased Na
v
1.5 expression/membrane localization and reduced
I

Na

associated with pronounced bradycardia, conduction abnormalities, and ventricular arrhythmia in response to Na
v
channel antagonists. Moreover, we report that ankyrin-G links Na
v
channels with broader intercalated disc signaling/structural nodes, as ankyrin-G loss results in reorganization of plakophilin-2 and lethal arrhythmias in response to β-adrenergic stimulation.

Conclusions:

Our findings provide the first in vivo data for the molecular pathway required for intercalated disc Na
v
1.5 targeting/regulation in heart. Further, these new data identify the basis of an in vivo cellular platform critical for membrane recruitment and regulation of Na
v
1.5.
Gastrointestinal Intervention Ameliorates High Blood Pressure Through Antagonizing Overdrive of the Sympathetic Nerve in Hypertensive Patients and Rats
Authors: Zhang Hexuan , Pu Yunfei , Chen Jing , Tong Weidong , Cui Yuanting , Sun Fang , Zheng Zhou , Li Qiang , Yang Tao , Meng Changyuan , Lu Zongshi , Li Li , Yan Zhencheng , Liu Daoyan , Zhu Zhiming
Published: September 2014

Background

We investigated the hypothesis that the favorable effects of gastrointestinal (
GI
) intervention on hypertension (
HTN
) and cardiovascular (
CV
) disturbances are mediated by antagonizing overdrive of the sympathetic nervous system (
SNS
).

Methods and Results

Hypertensive patients with metabolic disturbances underwent laparoscopic Roux‐en‐Y gastric bypass surgery, and spontaneously hypertensive rats (
SHR
s) underwent
RYGB
or sham surgery. Blood pressure (
BP
), heart rate (
HR
), endothelium‐dependent flow‐mediated dilation, and anthropometric as well as laboratory parameters were measured at baseline and during follow‐up. Changes of
BP
and
HR
in response to cold stress, renal sympathetic nervous activity (
RSNA
), vasoconstriction induced by electrical field stimulation, microinjection of nucleus of the solitary tract (
NTS
), and
CV
function and structure were examined in
SHR
s with or without surgery. Compared with baseline,
BP
and
HR
were significantly reduced in both hypertensive patients with type 2 diabetes and rats. Impaired endothelial‐dependent vasodilatation and metabolic disturbances in hypertensive patients were also ameliorated after surgery.
CV
disturbances were reversed by surgery in
SHR
s. Under acute cold exposure, the variations in
BP
and
HR
were smaller in surgically treated
SHR
s, compared to sham
SHR
s.
RSNA
and vasoconstriction induced by perivascular nerve stimulation as well as
NTS
‐mediated changes of
BP
were decreased in surgically treated
SHR
s, compared to sham
SHR
. Weight loss did not affect
BP
and
RSNA
in sham
SHR
s.

Conclusions

GI
intervention ameliorates
HTN
in both hypertensive patients and rats by inhibiting overdrive of the
SNS
. Therefore, targeting gastrointestine could be a novel strategy to treat
HTN
with metabolic disturbances.
Single Intracoronary Injection of Encapsulated Antagomir‐92a Promotes Angiogenesis and Prevents Adverse Infarct Remodeling
Authors: Bellera Neus , Barba Ignasi , Rodriguez‐Sinovas Antonio , Ferret Eulalia , Asín Miguel Angel , Gonzalez‐Alujas MªTeresa , Pérez‐Rodon Jordi , Esteves Marielle , Fonseca Carla , Toran Nuria , Garcia del Blanco Bruno , Pérez Amadeo , Garcia‐Dorado David
Published: September 2014

Background

Small and large preclinical animal models have shown that antagomir‐92a‐based therapy reduces early postischemic loss of function, but its effect on postinfarction remodeling is not known. In addition, the reported remote miR‐92a inhibition in noncardiac organs prevents the translation of nonvectorized miR‐targeted therapy to the clinical setting. We investigated whether a single intracoronary administration of antagomir‐92a encapsulated in microspheres could prevent deleterious remodeling of myocardium 1 month after acute myocardial infarction
AUTHOR
: Should “acute” be added before “myocardial infarction” (since abbreviation is
AMI
)? Also check at first mention in main text (
AMI
) without adverse effects.

Methods and Results

In a percutaneous pig model of reperfused
AMI
, a single intracoronary administration of antagomir‐92a encapsulated in specific microspheres (9 μm poly‐
d
,‐lactide‐co‐glycolide [
PLGA
]) inhibited miR‐92a in a local, selective, and sustained manner (n=3 pigs euthanized 1, 3, and 10 days after treatment; 8×, 2×, and 5×‐fold inhibition at 1, 3, and 10 days). Downregulation of miR‐92a resulted in significant vessel growth (n=27 adult minipigs randomly allocated to blind receive encapsulated antagomir‐92a, encapsulated placebo, or saline [n=8, 9, 9];
P
=0.001), reduced regional wall‐motion dysfunction (
P
=0.03), and prevented adverse remodeling in the infarct area 1 month after injury (
P
=0.03). Intracoronary injection of microspheres had no significant adverse effect in downstream myocardium in healthy pigs (n=2), and fluorescein isothiocyanate albumin‐
PLGA
microspheres were not found in myocardium outside the left anterior descending coronary artery territory (n=4) or in other organs (n=2).

Conclusions

Early single intracoronary administration of encapsulated antagomir‐92a in an adult pig model of reperfused
AMI
prevents left ventricular remodeling with no local or distant adverse effects, emerging as a promising therapeutic approach to translate to patients who suffer a large
AMI
.
Topological Sparse Learning of Dynamic Form Patterns
Authors: Guthier T. , Willert V. , Eggert J.
Published: September 2014

Motion is a crucial source of information for a variety of tasks in social interactions. The process of how humans recognize complex articulated movements such as gestures or face expressions remains largely unclear. There is an ongoing discussion if and how explicit low-level motion information, such as optical flow, is involved in the recognition process. Motivated by this discussion, we introduce a computational model that classifies the spatial configuration of gradient and optical flow patterns. The patterns are learned with an unsupervised learning algorithm based on translation-invariant nonnegative sparse coding called VNMF that extracts prototypical optical flow patterns shaped, for example, as moving heads or limb parts. A key element of the proposed system is a lateral inhibition term that suppresses activations of competing patterns in the learning process, leading to a low number of dominant and topological sparse activations. We analyze the classification performance of the gradient and optical flow patterns on three real-world human action recognition and one face expression recognition data set. The results indicate that the recognition of human actions can be achieved by gradient patterns alone, but adding optical flow patterns increases the classification performance. The combined patterns outperform other biological-inspired models and are competitive with current computer vision approaches.
Understanding Ideas of Toxicity in Tibetan Medical Processing of Mercury
Authors: Dolma Sonam
Published: September 2014

Duk (dug) in Tibetan language means ‘poison’ and has the connotation of a substance being harmful. In the Tibetan medical tradition, anything which adversely affects our system and causes suffering and pain can be referred to as a poison; for example, the afflictive emotions are labelled ‘mental poisons’. The term duk is coined based on its harmful effects, just like medicine is called men (sman) because of it being beneficial. Tibetan medical practitioners know that mercury is highly toxic. Nevertheless, Tibetan medicine still uses it in the particular form of mercury sulphide as an important ingredient in some multi-compound medicines to treat severe diseases. This is possible because Tibetan pharmacology describes detailed methods of processing mercury, which are complex and long and demand the involvement of highly skilled people and a particular environment. The ability to transform a virtual toxin into a tonic is an invaluable skill based on the in-depth understanding of the characteristics of the various types of duk contained in unprocessed mercury as this article will explore.
The Social Life of Tsotel
Authors: Gerke Barbara
Published: September 2014

No other compound in Tibetan medical pharmacology seems to be as fascinating, controversial, and enigmatic astsotel(btso thal, lit. ‘cooked ash’), the processed mercury sulphide ash that provides the base material of many of the popular Tibetan ‘precious pills’ (rin chen ril bu). The compound contains—apart from numerous herbs and other ingredients—eight metals and eight rock components.Tsotelpractices, which can be traced back to the thirteenth century in Tibet, are considered the pinnacle of Tibetan pharmacology. The commercial value oftsotelgives it a strong economic and social life of its own. This paper analyses the social life oftsotelfrom an anthropological perspective and sketches key aspects oftsotel’s biography, which in one way or the other are linked to medical, political, and religious perceptions of mercury:tsotelevents with their political and institutional agendas; the value oftsotelas a medical, religious, and political commodity; safety and toxicity debates; andtsotel’s religious and political efficacy. I argue that the social life oftsotelis increasingly linked to perceptions of toxicity and safety because of its chief ingredient, mercury, being contested in a globalised arena of tightened international regulations as well as the recent attention given to heavy metal toxicity issues in Asian medicines. Also, several fundamental misconceptions of the substance of mercury itself, its processed form of mercury sulphide, and of the contamination of herbal ingredients with heavy metals will be highlighted. Examples are based on ethnographic fieldwork with Tibetan medical practitioners and pharmacologists in India and Nepal.
Politics of Knowledge in the Debates on Toxicity in Ayurvedic Medicines
Authors: Banerjee Madhulika
Published: September 2014

In the last decade, a controversy has arisen over a specific type of herbo-mineral ayurvedic preparations called bhasmas (Skt. bhasman). The controversy mainly concerned serious complications or even the death of patients after having taken these medicines. Since these medicines were metal-based preparations, and specifically included lead or mercury, their toxicity was interpreted as causing the patients’ suffering. In response to that, in public discourse a plethora of writing on the issue of toxicity in ayurvedic medicines ensued, both accusatory and defensive in tone. This laid out the potential for their condemnation, with serious implications for their credibility, not to speak of their markets. This article attempts to analyse this writing, focusing mainly on the academic publications, from the perspective of the politics of knowledge. It will argue that hierarchies in the epistemologies of medical knowledge systems guide the scientific analysis of these herbo-mineral preparations, some of which contain mercury, illustrating how this happens through publications that are unequivocally critical of bhasmas, those that are defensive of them, and those that indicate a median position. It will also analyse the possible regulatory and manufacturing regimes that can emerge when a certain kind of balanced analysis informs policy-making. Focusing on the modes of translation between epistemologies of different knowledge systems that have characterised the process of making ‘traditional’ knowledge contemporary, it shows how this principally reflects the hierarchy between dominant and marginal knowledge on an everyday basis, affecting most production and marketing decisions, that backfire not only on specific products, but affect an evaluation of the system as a whole.
On the History of Refining Mercury in Tibetan Medicine
Authors: Czaja Olaf
Published: September 2014

In this brief study, the origin and spread of the alchemical process of refining mercury in Tibetan medicine will be explored. Beginning with early sources from the eighth to the twelfth centuries, it will be argued that Orgyenpa Rinchenpel (O rgyan pa Rin chen dpal) caused a turning-point in the processing of mercury in Tibet by introducing a complex alchemical process previously unknown. This knowledge, including the manufacturing of new pills containing mercury, soon spread through Tibet and was incorporated into the medical expertise of local schools such as the Drangti school (Brang ti). Later it was most prominently practised by Nyamnyi Dorjé (Mnyam nyid rdo rje) in southern Tibet. This particular tradition was upheld by Chökyi Drakpa (Chos kyi grags pa) of the Drigung school, who taught it to his gifted student Könchok Dropen Wangpo (Dkon mchog ’gro phan dbang po). During the seventeenth century, two main transmission lines for refining mercury emerged, one associated with the Gelukpa school (Dge lugs pa) in Central Tibet and one with the Kagyüpa school (Bka’ brgyud pa) and the Rimé movement (Ris med) in eastern Tibet. Both will be discussed in detail, highlighting important proponents and major events in their development. Finally, the situation in the twentieth century will be briefly explained.