bluuebunny/crossref_metadata_2025 huggingface dataset:
A rare presentation of Hodgkin's lymphoma in a very young child, with involvement of the appendix
Authors: Ghosal Anirban , Acharyya Saugata
Published: July 2014

Hodgkin's lymphoma involving the appendix in young children is an exceptionally rare disease. We report a case of a child less than 3 years who presented to us with gradual weight loss, progressive pallor and diffuse abdominal pain. The symptoms were preceded by a history of varicella infection about 6 months ago. The clinical progression was marked by intermittent episodes of acute abdominal pain and fever, mimicking acute intra-abdominal inflammatory process such as appendicitis. Investigations revealed that the child had direct Coomb's test positive haemolytic anaemia, raised platelet counts, lymphopenia and hypergammaglobulinaemia. The CT of the abdomen showed the presence of significant lymph nodes. Abdominal laparoscopy and biopsy of the lymph nodes showed mixed cellularity Hodgkin's lymphoma that also involved the appendix. Subsequent staging detected an advanced stage IV disease. The child was referred immediately to a specialised oncology centre for further management. Unfortunately he was lost in follow-up.
HIV in India: the Jogini culture
Authors: Borick Joseph
Published: July 2014

Jogini is the name for a female sexually exploited temple attendant and is used interchangeably with Devadasi in the state of Andhra Pradesh, India. Jogini are twice more likely than other women who are used for sexual intercourse in India to be HIV positive, and their rate of mortality from HIV is 10 times the total mortality rate for all women in India. The four states in India with the most Jogini also have the highest prevalence of HIV. The following case is unfortunately typical of the Jogini and sheds light on a potentially disastrous public health problem in rural South India.
Successful removal of strangulating metal penile ring using a dental handpiece
Authors: Etetafia Mabel Okiemute , Nwajei Charles Onochie
Published: July 2014

Background

Under emergency conditions, the dental handpiece can be a useful tool for removing a strangulating penile ring.

Objective

To report the successful use of a dental handpiece (dental drill) to remove a strangulating penile ring in an emergency.

Method

A case report of a strangulating metal penile ring in a psychiatric patient who presented at the accident and emergency unit of Delta State University Teaching Hospital.

Result

The metal ring was removed using a diamond bur in a dental handpiece.

Conclusions

In case of emergency, the dental handpiece is a useful tool for removing a strangulating penile ring.
Traumatic subchondral fracture of the femoral head in a healed trochanteric fracture
Authors: Lee Sang Yang , Niikura Takahiro , Iwakura Takashi , Kurosaka Masahiro
Published: July 2014

An 82-year-old woman sustained a trochanteric fracture of the left femur after a fall. Fracture fixation was performed using proximal femoral nail antirotation (PFNA) II, and she was able to walk with a T-cane after 3 months. Eleven months following the operation, the patient presented with left hip pain after a fall. Radiographs showed a subchondral collapse of the femoral head located above the blade tip. The authors removed the PFNA-II and subsequently performed cemented bipolar hemiarthroplasty. Histological evaluation of the femoral head showed osteoporosis with no evidence of osteonecrosis. Repair tissue, granulation tissue and callus formation were seen at the collapsed subchondral area. Based on these findings, a traumatic subchondral fracture of the femoral head in a healed trochanteric fracture was diagnosed. A traumatic subchondral fracture of the femoral head may need to be considered as a possible diagnosis after internal fixation of the trochanteric fracture.
Palliative care development in the Asia-Pacific region: an international survey from the Asia Pacific Hospice Palliative Care Network (APHN)
Authors: Yamaguchi Takashi , Kuriya Meiko , Morita Tatsuya , Agar Meera , Choi Youn Seon , Goh Cynthia , Lingegowda K B , Lim Richard , Liu Rico K Y , MacLeod Roderick , Ocampo Rhodora , Cheng Shao-Yi , Phungrassami Temsak , Nguyen Yen-Phi , Tsuneto Satoru
Published: July 2014

Background

Although palliative care is an important public healthcare issue worldwide, the current situation in the Asia-Pacific region has not been systematically evaluated.

Objectives

This survey aimed to clarify the current status of palliative care in the Asia-Pacific region.

Methods

Questionnaires were sent to a representative physician of each member country/region of the Asia Pacific Hospice Palliative Care Network (APHN). The questionnaire examined palliative care service provision, information regarding physician certification in palliative care, the availability of essential drugs for palliative care listed by the International Association for Hospice and Palliative Care (IAHPC) and the regulation of opioid-prescribing practice.

Results

Of the 14 member countries/regions of the APHN, 12 (86%) responded. Some form of specialist palliative care services had developed in all the responding countries/regions. Eight member countries/regions had physician certifications for palliative care. Most essential drugs for palliative care listed by the IAHPC were available, whereas hydromorphone, oxycodone and transmucosal fentanyl were unavailable in most countries/regions. Six member countries/regions required permission to prescribe and receive opioids.

Conclusions

The development of palliative care is in different stages across the surveyed countries/regions in the Asia-Pacific region. Data from this survey can be used as baseline data for monitoring the development of palliative care in this region.
Hypertension: empirical evidence and implications in 2014
Authors: Makridakis Spyros , DiNicolantonio James J
Published: July 2014

High blood pressure (HBP) or hypertension (HTN) is one of the leading causes of cardiovascular (CV) morbidity and mortality throughout the world. Despite this fact, there is widespread agreement that the treatment of HBP, over the last half century, has been a great achievement. However, after the release of the new Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure-8 (JNC-8) guidelines, there have been heated debates with regard to what are the most evidence-based blood pressure goals. While JNC-8 claims that the goal blood pressure for otherwise healthy patients with mild hypertension (systolic blood pressure ≥140–159 mm Hg and diastolic blood pressure ≥90–99 mm Hg) should be <140/90 mm Hg; a recent Cochrane meta-analysis is in direct conflict with these recommendations. Indeed, a 2012 Cochrane meta-analysis indicated that there is no evidence that treating otherwise healthy mild hypertension patients with antihypertensive therapy will reduce CV events or mortality. Additionally, the Cochrane meta-analysis showed that antihypertensive therapy was associated with a significant increase in withdrawal due to adverse events. Thus, the current evidence in the literature does not support the goals set by the JNC-8 guidelines. In this review we discussed the strengths and limitations of both lines of evidence and why it takes an evidence-based medication to reduce CV events/mortality (eg, how a goal blood pressure is achieved is more important than getting to the goal). As medications inherently cause side effects and come at a cost to the patient, the practice of evidence-based medicine becomes exceedingly important. Although the majority of HTN studies claim great advantages by lowering HBP, this review finds severe conflicts in the findings among the various HTN studies, as well as serious epistemological, methodological and statistical problems that cast doubt to such claims.
Direct oral anticoagulants: integration into clinical practice
Authors: Cowell Richard P W
Published: July 2014

The introduction of direct oral anticoagulants (OACs) for the treatment and prevention of thromboembolic disease represents a shift from the traditional vitamin K antagonist-based therapies, which have been the mainstay of treatment for almost 60 years. A challenge for hospital formularies will be to manage the use of direct OACs from hospital to outpatient settings. Three direct OACs—apixaban, dabigatran and rivaroxaban—are widely approved across different indications, with rivaroxaban approved across the widest breadth of indications. A fourth direct OAC, edoxaban, has also completed phase III trials. Implementation of these agents by physicians will require an understanding of the efficacy and safety profile of these drugs, as well as an awareness of renal function, comedication use, patient adherence and compliance. Optimal implementation of direct OACs in the hospital setting will provide improved patient outcomes when compared with traditional anticoagulants and will simplify the treatment and prevention of thromboembolic diseases.
Enhanced open circuit voltage in photovoltaic effect of polycrystalline La and Ni co-doped BiFeO3 film
Authors: Peng Zeng-Wei , Wang Ying-Long , Liu Bao-Ting
Published: July 2014

Photovoltaic (PV) effect of polycrystalline Bi 0.975 La 0.025 Fe 0.975 Ni 0.025 O 3 (BLFNO) film grown on Pt (111)/ Ti/SiO 2/ Si (001) substrate using sol–gel method has been investigated. The BLFNO film possesses good ferroelectric property and large twice-remanent polarization. It is found that PV response exhibited a strong dependence on the potential of top indium tin oxide (ITO) and bottom Pt electrode. The open circuit voltage is -0.67 V when the potential of ITO electrode is higher than that of Pt electrode and 0.45 V when the potential of ITO electrode is lower than that of Pt electrode. This can be interpreted by the variation of barrier heights at both ITO/BLFNO and BLFNO/ Pt interfaces.
Multivariate analysis of stream sediment data from Nanling metallogenic belt, South China
Authors: Liu Yue , Cheng Qiuming , Xia Qinglin , Wang Xinqing
Published: July 2014

Multivariate statistical methods can be applied to analyse a complete set of multidimensional geochemical data and to identify latent relationships among these data. In this paper, we used multivariate statistical analysis, including k-means clustering, principal component analysis (PCA) and factor analysis (FA), to study the similarity of the sampling points and the relationships between metal mineralization and geological environment in the Nanling metallogenic belt, South China. The dataset consists of 1617 sediment samples analysed for 39 elements. The dataset was divided into three clusters by k-means clustering which were strongly associated with the distribution of lithostratigraphic units and the level of metal mineralization. Each cluster was analysed by PCA to identified principal components. Three factors extracted by the factor analysis explained
c.
62% of the total variance and allow identification of the dominant ore-forming environment. Factor 1 describes
c.
30% of the common variance and is highly loaded by Zn, Cu, Cr, Co, Ni, Mn, P, Ti, V, Mg and Fe. Factor 2 includes rare metals, rare earth elements (REE) and radioactive elements with Y, La, Nb, Zr and U, explaining
c.
19% of the common variance. Factor 3 describes
c.
14% of the common variance and is highly loaded by W, Sn, Mo, Pb, Be and Bi, representing tungsten polymetallic mineralization. In this paper, the Student’s t-test derived from weights-of-evidence modeling was used to measure the significance of spatial correlation between factor scores and mineral deposits.
Node-Weighted Steiner Tree and Group Steiner Tree in Planar Graphs
Authors: Demaine Erik D. , Hajiaghayi Mohammadtaghi , Klein Philip N.
Published: July 2014

We improve the approximation ratios for two optimization problems in planar graphs. For node-weighted Steiner tree, a classical network-optimization problem, the best achievable approximation ratio in general graphs is Θ (log
n
), and nothing better was previously known for planar graphs. We give a constant-factor approximation for planar graphs. Our algorithm generalizes to allow as input any nontrivial minor-closed graph family, and also generalizes to address other optimization problems such as Steiner forest, prize-collecting Steiner tree, and network-formation games.

The second problem we address is group Steiner tree: given a graph with edge weights and a collection of groups (subsets of nodes), find a minimum-weight connected subgraph that includes at least one node from each group. The best approximation ratio known in general graphs is
O
(log
3
n
), or
O
(log
2
n
) when the host graph is a tree. We obtain an
O
(log
n
polyloglog
n
) approximation algorithm for the special case where the graph is planar embedded and each group is the set of nodes on a face. We obtain the same approximation ratio for the minimum-weight tour that must visit each group.
Adaptive Resource Provisioning for Virtualized Servers Using Kalman Filters
Authors: Kalyvianaki Evangelia , Charalambous Themistoklis , Hand Steven
Published: July 2014

Resource management of virtualized servers in data centers has become a critical task, since it enables cost-effective consolidation of server applications. Resource management is an important and challenging task, especially for multitier applications with unpredictable time-varying workloads. Work in resource management using control theory has shown clear benefits of dynamically adjusting resource allocations to match fluctuating workloads. However, little work has been done toward adaptive controllers for unknown workload types. This work presents a new resource management scheme that incorporates the Kalman filter into feedback controllers to dynamically allocate CPU resources to virtual machines hosting server applications. We present a set of controllers that continuously detect and self-adapt to unforeseen workload changes. Furthermore, our most advanced controller also self-configures itself without any
a priori
information and with a small 4.8% performance penalty in the case of high-intensity workload changes. In addition, our controllers are enhanced to deal with multitier server applications: by using the pair-wise resource coupling between tiers, they improve server response to large workload increases as compared to controllers with no such resource-coupling mechanism. Our approaches are evaluated and their performance is illustrated on a 3-tier Rubis benchmark website deployed on a prototype Xen-virtualized cluster.
Quadratic interval refinement for real roots
Authors: Abbott John
Published: July 2014

We present a new algorithm for refining a real interval containing a single real root: the new method combines the robustness of the classical Bisection algorithm with the speed of the Newton-Raphson method; that is, our method exhibits quadratic convergence when refining isolating intervals of simple roots of polynomials (and other well-behaved functions). We assume the use of arbitrary precision rational arithmetic. Unlike Newton-Raphson our method does not need to evaluate the derivative.
Branch cuts in maple 17
Authors: England M. , Cheb-Terrab E. , Bradford R. , Davenport J. H. , Wilson D.
Published: July 2014

Accurate and comprehensible knowledge about the position of branch cuts is essential for correctly working with multi-valued functions, such as the square root and logarithm. We discuss the new tools in Maple 17 for calculating and visualising the branch cuts of such functions, and others built up from them. The cuts are described in an intuitive and accurate form, offering substantial improvement on the descriptions previously available.
Kolchin seminar in differential algebra
Authors: Ovchinnikov Alexey
Published: July 2014

The productive past and lively present of the Kolchin Seminar in Differential Algebra, as well as its perspectives are touched on in this article.
Journey mapping
Authors: Howard Tharon
Published: July 2014

If you've been in the field of user experience design, usability testing, or marketing for anytime at all, you've almost certainly come across the use of personas to help members of a cross functional design team communicate with one another about the impacts that design decisions will have on a particular user demographic. As Adlin and Pruitt (2006) explain, personas are useful because they put an individual, human face on demographic and ethnographic data which would otherwise be difficult to explain to software engineers, project managers, information product developers, and other stakeholders in a way they can easily conceptualize and apply. Usually on one sheet of paper, a persona will provide a photo of the character for the persona; a memorable name for the persona; a short bio or background information about the persona; the persona's goals for using the product being developed; a short and memorable quote from the persona which usually conveys their
ethos
; and other information relevant to the use of the product being designed such as training; previous experience with similar products, or physical disabilities (such as arthritis or poor eye sight---see http://www.clemson.edu/caah/caah_mockups/persona_clemsongrad.html for an example of personas developed for the redesign of a College's website).
"That usability course"
Authors: Zhou Quan
Published: July 2014

The approach to usability adopted by many technical communication programs often conceptually separates usability from other subject matter areas and places it at the tail-end of a project. Such an approach creates conceptual barriers with regard to how usability fits in a design project. As a result, students do not engage in the critical work of designing and testing iteratively in the formative phase of a product. We should broaden usability into user experience, enable students to see user experience as an iterative and agile process, and provide in-depth knowledge of user research methods.
Comparison of manual and semiautomated techniques for analyzing gastric volumes with MRI in humans
Authors: Bharucha Adil E. , Karwoski Ronald A. , Fidler Jeff , Holmes David R. , Robb Richard A. , Riederer Stephen J. , Zinsmeister Alan R.
Published: July 2014

Gastric emptying, accommodation, and motility can be quantified with magnetic resonance imaging (MRI). The first step in image analysis entails segmenting the stomach from surrounding structures, usually by a time-consuming manual process. We have developed a semiautomated process to segment and measure gastric volumes with MRI. Gastric images were acquired with a three-dimensional gradient echo MRI sequence at 5, 10, 20, and 30 min after ingestion of a liquid nutrient (Ensure, 296 ml) labeled with gadolinium in 20 healthy volunteers and 29 patients with dyspeptic symptoms. The agreement between gastric volumes measured by manual segmentation and our new semiautomated algorithm was assessed with Lin's concordance correlation coefficient (CCC) and the Bland Altman test. At 5 min after a meal, food volumes measured by manual (352 ± 4 ml) and semiautomated (346 ± 4 ml) techniques were correlated {CCC[95% confidence interval (CI)] 0.70 (0.52, 0.81)}; air volumes measured by manual (88 ± 6 ml) and semiautomated (84 ± 6 ml) techniques were also correlated [CCC (95% CI) 0.89 (0.82, 0.94)]. Findings were similar at subsequent time points. The Bland Altman test was not significant. The time required for semiautomated segmentation ranged from an average of 204 s for the 5-min images to 233 s for the 20-min images. These times were appreciably smaller than the typical times of many tens of minutes, even hours, required for manual segmentation. To conclude, a semiautomated process can measure gastric food and air volume using MRI with comparable accuracy and far better efficiency than a manual process.
The ryanodine receptor is expressed in human pancreatic acinar cells and contributes to acinar cell injury
Authors: Lewarchik Christopher M. , Orabi Abrahim I. , Jin Shunqian , Wang Dong , Muili Kamaldeen A. , Shah Ahsan U. , Eisses John F. , Malik Adeel , Bottino Rita , Jayaraman Thottala , Husain Sohail Z.
Published: July 2014

Physiological calcium (Ca2+) signals within the pancreatic acinar cell regulate enzyme secretion, whereas aberrant Ca2+signals are associated with acinar cell injury. We have previously identified the ryanodine receptor (RyR), a Ca2+release channel on the endoplasmic reticulum, as a modulator of these pathological signals. In the present study, we establish that the RyR is expressed in human acinar cells and mediates acinar cell injury. We obtained pancreatic tissue from cadaveric donors and identified isoforms of RyR1 and RyR2 by qPCR. Immunofluorescence staining of the pancreas showed that the RyR is localized to the basal region of the acinar cell. Furthermore, the presence of RyR was confirmed from isolated human acinar cells by tritiated ryanodine binding. To determine whether the RyR is functionally active, mouse or human acinar cells were loaded with the high-affinity Ca2+dye (Fluo-4 AM) and stimulated with taurolithocholic acid 3-sulfate (TLCS) (500 μM) or carbachol (1 mM). Ryanodine (100 μM) pretreatment reduced the magnitude of the Ca2+signal and the area under the curve. To determine the effect of RyR blockade on injury, human acinar cells were stimulated with pathological stimuli, the bile acid TLCS (500 μM) or the muscarinic agonist carbachol (1 mM) in the presence or absence of the RyR inhibitor ryanodine. Ryanodine (100 μM) caused an 81% and 47% reduction in acinar cell injury, respectively, as measured by lactate dehydrogenase leakage ( P < 0.05). Taken together, these data establish that the RyR is expressed in human acinar cells and that it modulates acinar Ca2+signals and cell injury.
Tumor necrosis factor-α inhibition attenuates middle cerebral artery remodeling but increases cerebral ischemic damage in hypertensive rats
Authors: Pires Paulo W. , Girgla Saavia S. , Moreno Guillermo , McClain Jonathon L. , Dorrance Anne M.
Published: July 2014

Hypertension causes vascular inflammation evidenced by an increase in perivascular macrophages and proinflammatory cytokines in the arterial wall. Perivascular macrophage depletion reduced tumor necrosis factor (TNF)-α expression in cerebral arteries of hypertensive rats and attenuated inward remodeling, suggesting that TNF-α might play a role in the remodeling process. We hypothesized that TNF-α inhibition would improve middle cerebral artery (MCA) structure and reduce damage after cerebral ischemia in hypertensive rats. Six-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were treated with the TNF-α inhibitor etanercept (ETN; 1.25 mg·kg−1·day−1 ip daily) or PBS (equivolume) for 6 wk. The myogenic tone generation, postischemic dilation, and passive structure of MCAs were assessed by pressure myography. Cerebral ischemia was induced by MCA occlusion (MCAO). Myogenic tone was unchanged, but MCAs from SHRSP + ETN had larger passive lumen diameter and reduced wall thickness and wall-to-lumen ratio. Cerebral infarct size was increased in SHRSP + ETN after transient MCAO, despite an improvement in dilation of nonischemic MCA. The increase in infarct size was linked to a reduction in the number of microglia in the infarct core and upregulation of markers of classical macrophage/microglia polarization. There was no difference in infarct size after permanent MCAO or when untreated SHRSP subjected to transient MCAO were given ETN at reperfusion. Our data suggests that TNF-α inhibition attenuates hypertensive MCA remodeling but exacerbates cerebral damage following ischemia/reperfusion injury likely due to inhibition of the innate immune response of the brain.
Androgen Receptor Polymorphism-Dependent Variation in Prostate-Specific Antigen Concentrations of European Men
Authors: Bentmar Holgersson Magdalena , Giwercman Aleksander ,   for the EMAS group, Bjartell Anders , Wu Frederick C.W. , Huhtaniemi Ilpo T. , O'Neill Terence W. , Pendleton Neil , Vanderschueren Dirk , Lean Michael E.J. , Han Thang S. , Finn Joseph D. , Kula Krzysztof , Forti Gianni , Casanueva Felipe F. , Bartfai György , Punab Margus ,   for the EMAS group, Lundberg Giwercman Yvonne
Published: July 2014

Background: Androgens acting via the androgen receptor (AR) stimulate production of PSA, which is a clinical marker of prostate cancer. Because genetic variants in the AR may have a significant impact on the risk of being diagnosed with prostate cancer, the aim was to investigate whether AR variants were associated with the risk of having PSA above clinically used cutoff thresholds of 3 or 4 ng/mL in men without prostate cancer.

Methods: Men without prostate cancer history (n = 1,744) were selected from the European Male Ageing Study cohort of 40 to 79-year-old men from eight different European centers. Using linear and logistic regression models, with age and center as covariates, we investigated whether AR variants (CAG repeat-length and/or SNP genotype) were associated with having serum PSA concentrations above 3 or 4 ng/mL, which often are set as cutoff concentrations for further investigation of prostate cancer.

Results: Carriers of the SNP rs1204038 A-allele (16% of the men) were more likely to have PSA>3 and 4 ng/mL (OR; 95% confidence intervals, 1.65; 1.13–2.40 and 1.87; 1.18–2.96, respectively) than G-allele carriers. They also had shorter CAG repeats (median 20 vs. 23, P < 0.0005), but CAG repeat length per se did not affect the PSA concentrations.

Conclusion: The A-allele of the SNP rs1204038 gives a 65% higher risk of having PSA above 3 ng/mL than the G-allele in men without prostate cancer, and thereby an increased risk of being referred for further examination on suspicion of prostate cancer.

Impact: Serum PSA as a clinical marker could be improved by adjustment for AR-genotype. Cancer Epidemiol Biomarkers Prev; 23(10); 2048–56. ©2014 AACR.
Noninvasive Diagnosis of Actionable Mutations by Deep Sequencing of Circulating Free DNA in Lung Cancer from Never-Smokers: A Proof-of-Concept Study from BioCAST/IFCT-1002
Authors: Couraud Sébastien , Vaca-Paniagua Felipe , Villar Stéphanie , Oliver Javier , Schuster Tibor , Blanché Hélène , Girard Nicolas , Trédaniel Jean , Guilleminault Laurent , Gervais Radj , Prim Nathalie , Vincent Michel , Margery Jacques , Larivé Sébastien , Foucher Pascal , Duvert Bernard , Vallee Maxime , Le Calvez-Kelm Florence , McKay James , Missy Pascale , Morin Franck , Zalcman Gérard , Olivier Magali , Souquet Pierre-Jean
Published: July 2014

Purpose: Tumor somatic mutation analysis is part of the standard management of metastatic lung cancer. However, physicians often have to deal with small biopsies and consequently with challenging mutation testing. Circulating free DNA (cfDNA) is a promising tool for accessing the tumor genome as a liquid biopsy. Here, we evaluated next-generation sequencing (NGS) on cfDNA samples obtained from a consecutive series of patients for the screening of a range of clinically relevant mutations.

Experimental Design: A total of 107 plasma samples were collected from the BioCAST/IFCT-1002 lung cancer study (never-smokers cohort). Matched tumor DNA (tDNA) was obtained for 68 cases. Multiplex PCR-based assays were designed to target specific coding regions in EGFR, KRAS, BRAF, ERBB2, and PI3KCA genes, and amplicon sequencing was performed at deep coverage on the cfDNA/tDNA pairs using the NGS IonTorrent Personal Genome Machine Platform.

Results: CfDNA concentration in plasma was significantly associated with both stage and number of metastatic sites. In tDNA, 50 mutations (36 EGFR, 5 ERBB2, 4 KRAS, 3 BRAF, and 2 PIK3CA) were identified, of which 26 were detected in cfDNA. Sensitivity of the test was 58% (95% confidence interval, 43%–71%) and the estimated specificity was 87% (62%–96%).

Conclusion: These data demonstrate the feasibility and potential utility of mutation screening in cfDNA using IonTorrent NGS for the detection of a range of tumor biomarkers in patients with metastatic lung cancer. Clin Cancer Res; 20(17); 4613–24. ©2014 AACR.
Cell and Molecular Determinants ofIn VivoEfficacy of the BH3 Mimetic ABT-263 against Pediatric Acute Lymphoblastic Leukemia Xenografts
Authors: Suryani Santi , Carol Hernan , Chonghaile Triona Ni , Frismantas Viktoras , Sarmah Chintanu , High Laura , Bornhauser Beat , Cowley Mark J. , Szymanska Barbara , Evans Kathryn , Boehm Ingrid , Tonna Elise , Jones Luke , Manesh Donya Moradi , Kurmasheva Raushan T. , Billups Catherine , Kaplan Warren , Letai Anthony , Bourquin Jean-Pierre , Houghton Peter J. , Smith Malcolm A. , Lock Richard B.
Published: July 2014

Purpose: Predictive biomarkers are required to identify patients who may benefit from the use of BH3 mimetics such as ABT-263. This study investigated the efficacy of ABT-263 against a panel of patient-derived pediatric acute lymphoblastic leukemia (ALL) xenografts and utilized cell and molecular approaches to identify biomarkers that predict in vivo ABT-263 sensitivity.

Experimental Design: The in vivo efficacy of ABT-263 was tested against a panel of 31 patient-derived ALL xenografts composed of MLL-, BCP-, and T-ALL subtypes. Basal gene expression profiles of ALL xenografts were analyzed and confirmed by quantitative RT-PCR, protein expression and BH3 profiling. An in vitro coculture assay with immortalized human mesenchymal cells was utilized to build a predictive model of in vivo ABT-263 sensitivity.

Results: ABT-263 demonstrated impressive activity against pediatric ALL xenografts, with 19 of 31 achieving objective responses. Among BCL2 family members, in vivo ABT-263 sensitivity correlated best with low MCL1 mRNA expression levels. BH3 profiling revealed that resistance to ABT-263 correlated with mitochondrial priming by NOXA peptide, suggesting a functional role for MCL1 protein. Using an in vitro coculture assay, a predictive model of in vivo ABT-263 sensitivity was built. Testing this model against 11 xenografts predicted in vivo ABT-263 responses with high sensitivity (50%) and specificity (100%).

Conclusion: These results highlight the in vivo efficacy of ABT-263 against a broad range of pediatric ALL subtypes and shows that a combination of in vitro functional assays can be used to predict its in vivo efficacy. Clin Cancer Res; 20(17); 4520–31. ©2014 AACR.
Febuxostat Ameliorates Diabetic Renal Injury in a Streptozotocin-Induced Diabetic Rat Model
Authors: Lee Hong-Joo , Jeong Kyung Hwan , Kim Yang Gyun , Moon Joo Young , Lee Sang Ho , Ihm Chun Gyoo , Sung Ji Youn , Lee Tae Won
Published: July 2014

Background: Oxidative stress and inflammation are known to play central roles in the development of diabetic nephropathy (DN). Febuxostat is a novel non-purine xanthine oxidase (XO)-specific inhibitor developed to treat hyperuricemia. In this study, we investigated whether febuxostat could ameliorate DN via renoprotective mechanisms such as alleviation of oxidative stress and anti-inflammatory actions. Methods: Male Sprague-Dawley rats were divided into three groups: a normal group, a diabetes group (DM group), and a febuxostat-treated diabetes group (DM+Fx group). We administered 5 mg/kg of febuxostat to experimental rats for 7 weeks and evaluated clinical and biochemical parameters and XO and xanthine dehydrogenase (XDH) activity in hepatic tissue. The degree of oxidative stress and extent of inflammation were evaluated from urine samples and renal tissue collected from each group. Results: Diabetic rats (DM and DM+Fx groups) had higher blood glucose and kidney weight relative to body weight than normal rats. Albuminuria was significantly reduced in febuxostat-treated diabetic rats compared with untreated diabetic rats. Quantitative analysis showed that hepatic XO and XDH activities were higher in the DM groups, but decreased after treatment with febuxostat. Urinary 8-OHdG concentrations and renal cortical nitrotyrosine also indicated reduced oxidative stress in the DM+Fx group relative to the DM group. The number of ED-1-stained cells in the glomerulus and tubule of diabetic renal tissue decreased in febuxostat-treated diabetic rats relative to that of non-treated diabetic rats. Diabetic rats also expressed higher transcript levels of inflammatory genes (E-selectin and VCAM-1), an inflammation-induced enzyme (COX-2), and inflammatory mediators (ED-1 and NF-κB) than control rats; expression of these genes was significantly reduced by treatment with febuxostat. Conclusions: Febuxostat prevents diabetic renal injury such as albuminuria. This renoprotective effect appears to be due to attenuation of the inflammatory and oxidative effects of diabetes-induced renal damage through inhibition of XO and XDH activities.
Role of p53 Pathway Alterations in Uterine Carcinosarcomas (Malignant Mixed Müllerian Tumors)
Authors: Semczuk Andrzej , Ignatov Atanas , Obrzut Bogdan , Reventos Jaume , Rechberger Tomasz
Published: July 2014

Carcinosarcomas (CSs; malignant mixed Müllerian tumors) of the uterus are highly malignant neoplasms characterized by an unfavorable outcome. They represent less than 5% of all uterine malignancies, and the median patient survival rate is only 21 months. p53 pathway alterations have been studied in CSs originating from the uterus, supporting the monoclonal nature of most but not all of these neoplasms. This paper gives an overview of the current knowledge of p53 pathway distortions in patients with uterine CSs. The survival of patients with uterine CSs in relation to p53 pathway alterations is also briefly summarized.
Renal Function Is Associated with Bone Mineral Density and Arterial Stiffness in Healthy Postmenopausal Women
Authors: Jung Yeon Soo , Hwang Hee-jin , Yun Bo Hyon , Chon Seung Joo , Cho SiHyun , Choi Young Sik , Kim Young Tae , Lee Byung Seok , Seo Seok Kyo
Published: July 2014

Background/Aims: This study aimed to investigate the effect of renal function on bone mineral density (BMD) and arterial stiffness in postmenopausal women. Methods: This is a retrospective cross-sectional study. We studied 252 postmenopausal women who visited a health promotion center for a medical checkup. The estimated glomerular filtration rate (eGFR) was calculated using the Cockcroft-Gault (CG) formula and the modification of diet in renal disease (MDRD) formula. Areal BMD measurements were performed using dual-energy X-ray absorptiometry, and arterial stiffness was measured using the brachial-ankle pulse wave velocity (baPWV). Results: The eGFR according to the CG formula was significantly correlated with age, BMI, follicle-stimulating hormone, thyroid-stimulating hormone, high-density lipoprotein cholesterol, baPWV, and BMD at the lumbar spine, femoral neck, and total hip sites. However, the eGFR according to the MDRD formula was significantly correlated with age and baPWV but not with BMD at the lumbar spine, femoral neck, and total hip sites. Decreased renal function (eGFR <60 ml/min/1.73 m2 according to the CG formula) was independently associated with decreased BMD at the femoral neck site and with increased baPWV (>1,500 cm/s) after adjusting for confounding variables. Conclusion: Postmenopausal women with decreased renal function are more likely to have a decreased BMD and greater arterial stiffness.
Serum Metabolomic Biomarkers of Dementia
Authors: Mousavi Malahat , Jonsson Pär , Antti Henrik , Adolfsson Rolf , Nordin Annelie , Bergdahl Jan , Eriksson Kåre , Moritz Thomas , Nilsson Lars-Göran , Nyberg Lars
Published: July 2014

Aims: This study compared serum metabolites of demented patients (Alzheimer's disease and vascular dementia) and controls, and explored serum metabolite profiles of nondemented individuals 5 years preceding the diagnosis. Methods: Cognitively healthy participants were followed up for 5-20 years. Cognitive assessment, serum sampling, and diagnosis were completed every 5 years. Multivariate analyses were conducted on the metabolite profiles generated by gas chromatography/time-of-flight mass spectrometry. Results: A significant group separation was found between demented patients and controls, and between incident cases and controls. Metabolites that contributed in both analyses were 3,4-dihydroxybutanoic acid, docosapentaenoic acid, and uric acid. Conclusions: Serum metabolite profiles are altered in demented patients, and detectable up to 5 years preceding the diagnosis. Blood sampling can make an important contribution to the early prediction of conversion to dementia.
Repeat Descemetopexy after Descemet's Membrane Detachment following Phacoemulsification
Authors: Datar Sameer , Kelkar Aditya , Jain Ashish K. , Kelkar Jai , Kelkar Shreekant , Gandhi Poonam , Shah Rachna , Kedia Ruchika
Published: July 2014

Descemet's membrane detachment (DMD) is an uncommon condition with a wide range of possible etiologies. Probably the commonest cause is a localized detachment occurring after cataract extraction surgery. Descemetopexy gives good anatomic attachment rates and visual outcomes and has become the standard treatment for DMD. However, in cases with failed initial descemetopexy, the next step in the management of such cases remains unclear. Before initiating a complex surgical procedure like keratoplasty, which requires good postoperative care and regular follow-ups, repeat descemetopexy with a long-term tamponade using 14% C3F8 gas for recurrent DMD is definitely a worthwhile attempt.
Cross Talk Between Vascular Smooth Muscle Cells and Monocytes Through Interleukin-1β/Interleukin-18 Signaling Promotes Vein Graft Thickening
Authors: Li Ping , Li Yu-lin , Li Zhen-ya , Wu Yi-na , Zhang Cong-cong , A Xi , Wang Chun-xiao , Shi Hong-tao , Hui Mi-zhou , Xie Bo , Ahmed Mohammed , Du Jie
Published: July 2014

Objective—

Interleukin (IL)-1β and IL-18 are key proinflammatory cytokines that play important roles in the pathophysiology of vein graft remodeling. However, the mechanism of IL-1β/IL-18 production and its role in the development of graft remodeling remain unclear.

Approach and Results—

IL-1β/IL-18 were rapidly expressed in venous interposition grafts. Vascular smooth muscle cell (VSMC) death and monocytic inflammasome activation occurred in grafted veins. Necrotic VSMCs induced the expression of IL-1β, IL-18, and other inflammasome-associated proteins in monocytes, which was partially inhibited by their antagonist, recombinant IL-1ra-Fc-IL-18bp. Activated monocytes stimulated proliferation of VSMCs by activating cell growth–related signaling molecules (AKT, STAT3, ERK1/2, and mTOR [AKT/protein kinase B, signal transducer and activator of transcription 3, extracellular signal-regulated kinase 1/2, mammalian target of rapamycin]) and increasing production of platelet-derived growth factor-bb; these effects were suppressed by IL-1ra-Fc-IL-18bp. Activated monocytes also promoted migration of VSMCs, which was independent of IL-1β/IL-18 signaling. Importantly, administration of IL-1ra-Fc-IL-18bp inhibited activation of cell growth–related signaling molecules, VSMC proliferation, and vein graft thickening in vivo.

Conclusions—

Our work identified an interaction among necrotic VSMCs, monocytes, and viable VSMCs through IL-1β/IL-18 signaling, which might be exploited as a therapeutic target in vein graft remodeling.
Perivascular Adipose Tissue, Potassium Channels, and Vascular Dysfunction
Authors: Tano Jean-Yves , Schleifenbaum Johanna , Gollasch Maik
Published: July 2014

Perivascular adipose tissue has been recognized unequivocally as a major player in the pathology of metabolic and cardiovascular diseases. Through its production of adipokines and the release of other thus far unidentified factors, this recently discovered adipose tissue modulates vascular regulation and the myogenic response. After the discovery of its ability to diminish the vessel’s response to vasoconstrictors, a new paradigm established adipose-derived relaxing factor (ADRF) as a paracrine smooth muscle cells’ potassium channel opener that could potentially help combat vascular dysfunction. This review will discuss the role of ADRF in vascular dysfunction in obesity and hypertension, the different potassium channels that can be activated by this factor, and describes new pharmacological tools that can mimic the ADRF effect and thus can be beneficial against vascular dysfunction in cardiovascular disease.
Chronic Stress, Depressive Symptoms, Anger, Hostility, and Risk of Stroke and Transient Ischemic Attack in the Multi-Ethnic Study of Atherosclerosis
Authors: Everson-Rose Susan A. , Roetker Nicholas S. , Lutsey Pamela L. , Kershaw Kiarri N. , Longstreth W.T. , Sacco Ralph L. , Diez Roux Ana V. , Alonso Alvaro
Published: July 2014

Background and Purpose—

This study investigated chronic stress, depressive symptoms, anger, and hostility in relation to incident stroke and transient ischemic attacks in middle-aged and older adults.

Methods—

Data were from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based cohort study of 6749 adults, aged 45 to 84 years and free of clinical cardiovascular disease at baseline, conducted at 6 US sites. Chronic stress, depressive symptoms, trait anger, and hostility were assessed with standard questionnaires. The primary outcome was clinically adjudicated incident stroke or transient ischemic attacks during a median follow-up of 8.5 years.

Results—

One hundred ninety-five incident events (147 strokes; 48 transient ischemic attacks) occurred during follow-up. A gradient of increasing risk was observed for depressive symptoms, chronic stress, and hostility (all
P
for trend ≤0.02) but not for trait anger (
P
>0.10). Hazard ratios (HRs) and 95% confidence intervals indicated significantly elevated risk for the highest-scoring relative to the lowest-scoring group for depressive symptoms (HR, 1.86; 95% confidence interval, 1.16–2.96), chronic stress (HR, 1.59; 95% confidence interval, 1.11–2.27), and hostility (HR, 2.22; 95% confidence interval, 1.29–3.81) adjusting for age, demographics, and site. HRs were attenuated but remained significant in risk factor–adjusted models. Associations were similar in models limited to stroke and in secondary analyses using time-varying variables.

Conclusions—

Higher levels of stress, hostility, and depressive symptoms are associated with significantly increased risk of incident stroke or transient ischemic attacks in middle-aged and older adults. Associations are not explained by known stroke risk factors.
A New Micro–Computed Tomography–Based High-Resolution Blood–Brain Barrier Imaging Technique to Study Ischemic Stroke
Authors: Park Jin-Yong , Lee Su-Kyoung , Kim Jeong-Yeon , Je Kang-Hoon , Schellingerhout Dawid , Kim Dong-Eog
Published: July 2014

Background and Purpose—

Micro–computed tomography (mCT) offers high-resolution images, but it suffers from low contrast sensitivity and poor soft tissue contrast. We introduce a new mCT imaging technique with improved sensitivity for the dynamic spatial and temporal characterization of poststroke blood–brain barrier (BBB) dysfunction in small animals in vivo.

Methods—

Transient middle cerebral artery occlusion was induced for 1 hour in 10- to 12-week-old C57BL/6 mice (n=35). At 4, 24, and 48 hours after ischemic stroke, serial in vivo mCT imaging was performed 5 minutes after intravenous infusion (n=3) or intracarotid infusion of iopromide (240 μL) for 5 minutes (n=32). After intravenous injection of 2% Evans blue, we performed ex vivo near-infrared fluorescent imaging of parenchymal Evans blue leakage, visual assessment of poststroke parenchymal hematoma, triphenyltetrazolium chloride staining of the brain tissue, and quantitative mapping of stroke-related brain lesions.

Results—

Infarct-related BBB dysfunction could be demonstrated with intra-arterial but not with intravenous infusion of iopromide. Iopromide leakage across the dysfunctional BBB showed a monophasic (not biphasic) course for 48 hours after ischemic insult in both the parenchymal hematoma (n=5) and the non–parenchymal hematoma (n=24) groups, with relatively severe leakiness and greater hemispheric midline shift in animals with hemorrhage. Parenchymal staining on in vivo mCT overlapped with ex vivo fluorescent staining because of Evans blue. Multivariable analyses showed that midline shift and the amount of iopromide leakage at each of the 3 time points predicted the final infarct size at 48 hours.

Conclusions—

The new mCT BBB imaging technique, based on the intra-arterial infusion of clinically available iopromide, allows serial quantitative visualization of poststroke BBB dysfunction in mice, with high resolution and in a sensitive manner.
State Aid Dispute on Germany’s Support for Renewables
Authors: Gawel Erik , Strunz Sebastian
Published: July 2014

The Commission is concerned that renewable support schemes may distort competition and trade between Member States. Thus, the Commission has recently proposed guidelines on how to make renewable support schemes compliant with state aid rules. Moreover, it has opened in-depth proceedings to investigate whether the German support scheme counts as inappropriate state aid in the meaning of Article 107 (1) tfeu. The Commission believes that, in particular, Germany’s concessions to energy-intensive industries, which pay only reduced levies to finance the renewables scheme, are distortive. This paper reviews the Commission’s arguments in this case as well as the proposed guidelines on state aid. It concludes that Germany’s support scheme does not constitute inappropriate state aid and that the Commission’s guidelines should be open to further discussion.
Stock-taking of the International Climate Negotiations after Warsaw
Authors: Wellershoff Jan-Kristof , Morgenstern Lutz
Published: July 2014

The international climate negotiations are in a crucial phase. One and a half years before the un climate conference in Paris where the new climate protection agreement is supposed to be agreed many questions remain open. The international climate conference in Warsaw in fall 2013 brought some clarity with regard to the process towards Paris. In particular, it was agreed that Parties should submit their intended nationally determined (greenhouse gas mitigation) contributions well before Paris. However, with regard to the substance of the new agreement only little progress was made. One of the most important achievements of the Warsaw conference was the Warsaw Mechanism on loss and damage.
St. Christopher as a Trade Hub for Dutch Merchants, 1624–1667
Authors: Klarenbeek Monique
Published: July 2014

Since the early seventeenth century a large part of the West Indian trade was in the hands of private entrepreneurs from the Dutch Republic. They were connected through a transnational Atlantic network, not limiting themselves by national boundaries. In this network the Caribbean Islands played an important role as trade hubs; like the Island of St. Christopher, where in the first half of the seventeenth century a significant community of private entrepreneurs emerged, dominating the intra-Caribbean trade by the mid-seventeenth century. Although in the course of the seventeenth century the role as a free port was taken over by the Dutch island of St. Eustatius, St. Christopher played in the first half of the same century a significant part in the development of the transnational Atlantic trade network, that remained intact for centuries, despite, or sometimes even because of, the monopolistic strategies of the emerging nation-states.