bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-acting versus short-acting methylphenidate for paediatric ADHD: a systematic review and meta-analysis of comparative efficacy
Authors: Punja Salima , Zorzela Liliane , Hartling Lisa , Urichuk Liana , Vohra Sunita
Published: March 2013

Objective

To synthesise existing knowledge of the efficacy and safety of long-acting versus short-acting methylphenidate for paediatric attention deficit hyperactivity disorder (ADHD).

Design

Systematic review and meta-analysis.

Data sources

Electronic literature search of CENTRAL, MEDLINE, PreMEDLINE, CINAHL, EMBASE, PsychINFO, Scopus and Web of Science for articles published in the English language between 1950 and 2012. Reference lists of included studies were checked for additional studies.

Study selection

Randomised controlled trials of paediatric ADHD patients (<18 years), comparing a long-acting methylphenidate form to a short-acting methylphenidate form.

Data extraction

Two authors independently selected trials, extracted data and assessed risk of bias. Continuous outcomes were compared using standardised mean differences (SMDs) between treatment groups. Adverse events were compared using risk differences between treatment groups. Heterogeneity was explored by subgroup analysis based on the type of long-acting formulation used.

Results

Thirteen RCTs were included; data from 882 participants contributed to the analysis. Meta-analysis of three studies which used parent ratings to report on hyperactivity/impulsivity had an SMD of −0.30 (95% CI −0.51 to −0.08) favouring the long-acting forms. In contrast, three studies used teacher ratings to report on hyperactivity and had an SMD of 0.29 (95% CI 0.05 to 0.52) favouring the short-acting methylphenidate. In addition, subgroup analysis of three studies which used parent ratings to report on inattention/overactivity indicate that the osmotic release oral system generation long-acting formulation was favoured with an SMD of −0.35 (95% CI −0.52 to −0.17), while the second generation showed less efficacy than the short-acting formulation with an SMD of 0.42 (95% CI 0.17 to 0.68). The long-acting formulations presented with slightly more total reported adverse events (n=578) as compared with the short-acting formulation (n=566).

Conclusions

The findings from this systematic review indicate that the long-acting forms have a modest effect on the severity of inattention/overactivity and hyperactivity/impulsivity according to parent reports, whereas the short-acting methylphenidate was preferred according to teacher reports for hyperactivity.
The impact of advance care planning of place of death, a hospice retrospective cohort study
Authors: Abel Julian , Pring Andy , Rich Alison , Malik Tariq , Verne Julia
Published: March 2013

Objectives

There is limited evidence of the impact of advance care planning (ACP) on outcomes. We conducted a retrospective cohort study on deaths of all patients known to a hospice in a 2.5-year period to see if use of ACP affected actual place of death, hospital use and cost of hospital care in the last year.

Results

969 patients were included. 550 (57%) people completed ACP. 414 (75%) achieved their choice of place of death. For those who chose home, 34 (11.3%) died in hospital; a care home 2 (1.7%) died in hospital; a hospice 14 (11.2%) died in hospital and 6 (86%) who chose to die in hospital did so. 112 (26.5%) of people without ACP died in hospital. Mean number of days in hospital in the last year of life was 18.1 in the ACP group and 26.5 in the non-ACP group(p<0.001). Mean cost of hospital treatment during the last year of life for those who died in hospital was £11,299, those dying outside of hospital £7,730 (p<0.001). Mean number of emergency admissions for those who died in hospital was 2.2 and who died elsewhere was 1.7 (p<0.001).

Conclusions

ACP can be used routinely in a hospice setting. Those who used ACP spent less time in hospital in their last year. ACP is associated with a reduction in the number of days in hospital in the last year of life with less hospital costs, supporting the assumptions made in the End of Life Care Strategy 2008.
Initial experience using the Penumbra coil 400: comparison of aneurysm packing, cost effectiveness, and coil efficiency
Authors: Milburn James , Pansara Ankit Limba , Vidal Gabriel , Martinez Raisa Coral
Published: March 2013

Background/objective

This was a retrospective single operator experience of aneurysm coiling at the Ochsner Clinic, comparing the Penumbra coil 400 with the other most commonly used coil types, Orbit and Galaxy.

Methods

40 aneurysms treated exclusively with Orbit or Galaxy coils and 18 aneurysms treated only with Penumbra coils from 2010 to February 2012 were compared. Measurements included packing density, number of coils per unit aneurysm volume, and total coil length per unit aneurysm volume.

Results

Mean packing density of 33.7% using Penumbra coils was significantly greater than 24.4% for Orbit/Galaxy coils. The number of coils per aneurysm volume of 0.026 coils/mm3for the Penumbra coil was significantly lower than 0.114 coils/mm3for the Orbit/Galaxy coils. Aneurysm occlusion rates were similar in both groups.

Conclusions

Compared with the Orbit/Galaxy coils, our analysis suggests that the Penumbra coil is more efficient and cost effective in the treatment of intracranial aneurysms.
The Betic-Rif Arc and Its Orogenic Hinterland: A Review
Authors: Platt John P. , Behr Whitney M. , Johanesen Katherine , Williams Jason R.
Published: March 2013

The Betic-Rif arc is one of the smallest and tightest orogenic arcs on Earth, and together with its extensional hinterland, the Alborán Domain, it formed between two colliding continents. The region provides examples of a range of tectonic processes that are not predictable from the rules of rigid-plate tectonics. The Alborán Domain reveals two stages of subduction and accretion, with different thermal histories and mechanisms of exhumation. The external Betic-Rif thrust belt illustrates four processes that create an arcuate orogen and a strongly divergent pattern of slip vectors: (a) the interaction between the westward moving Alborán Domain and the converging African and Iberian margins, (b) divergence in relative motion due to extension within the Alborán Domain, (c) slip partitioning onto strike-slip faults within the arc, and (d) vertical-axis rotations resulting from oblique convergence on the limbs of the arc.
Phosphodiesterase 5 inhibition-induced coronary vasodilation is reduced after myocardial infarction
Authors: Merkus Daphne , Visser Marleen , Houweling Birgit , Zhou Zhichao , Nelson Jessica , Duncker Dirk J.
Published: March 2013

The balance between the production and removal of cGMP in coronary vascular smooth muscle is of critical importance in determining coronary vasomotor tone and thus in the regulation of coronary blood flow. cGMP production by soluble guanylyl cyclase is activated by nitric oxide (NO), whereas cGMP breakdown occurs through phosphodiesterase 5 (PDE5). We hypothesized that myocardial infarction (MI) alters the balance between the production and removal of cGMP in the coronary vasculature and thereby alters the control of coronary vasomotor tone. Chronically instrumented swine with and without a 2-wk-old MI were exercised on a treadmill in the absence and presence of the PDE5 inhibitor EMD-360527 (300 μg·kg−1·min−1 iv). Inhibition of PDE5 produced coronary resistance vessel dilation, which was more pronounced at rest than during exercise in normal swine. PDE5 gene expression was markedly reduced in coronary resistance vessels isolated from the remote myocardium of MI swine, which was accompanied by a similarly marked attenuation of coronary vasodilation by PDE5 inhibition in MI swine. The coronary vasoconstriction produced by inhibition of NO synthesis with Nω-nitro-l-arginine (20 mg/kg iv) was only slightly smaller in swine with MI. Interestingly, inhibition of NO synthesis reduced the vasodilator response to subsequent PDE5 inhibition in normal swine but not in MI swine. Conversely, PDE5 inhibition enhanced the coronary vasoconstriction produced by NO synthesis inhibition in normal swine but not in MI swine, suggesting that downregulation of PDE5 mitigated the loss of NO vasodilator influence. In conclusion, the expression and vasoconstrictor influence of PDE5 are markedly attenuated in coronary resistance vessels in the remote myocardium after MI, which appears to serve as a compensatory mechanism to mitigate the loss of NO vasodilator influence.
Patient-specific computational modeling of subendothelial LDL accumulation in a stenosed right coronary artery: effect of hemodynamic and biological factors
Authors: Sakellarios Antonis I. , Papafaklis Michail I. , Siogkas Panagiotis , Athanasiou Lambros S. , Exarchos Themistoklis P. , Stefanou Konstantinos , Bourantas Christos V. , Naka Katerina K. , Michalis Lampros K. , Parodi Oberdan , Fotiadis Dimitrios I.
Published: March 2013

Atherosclerosis is a systemic disease with local manifestations. Low-density lipoprotein (LDL) accumulation in the subendothelial layer is one of the hallmarks of atherosclerosis onset and ignites plaque development and progression. Blood flow-induced endothelial shear stress (ESS) is causally related to the heterogenic distribution of atherosclerotic lesions and critically affects LDL deposition in the vessel wall. In this work we modeled blood flow and LDL transport in the coronary arterial wall and investigated the influence of several hemodynamic and biological factors that may regulate LDL accumulation. We used a three-dimensional model of a stenosed right coronary artery reconstructed from angiographic and intravascular ultrasound patient data. We also reconstructed a second model after restoring the patency of the stenosed lumen to its nondiseased state to assess the effect of the stenosis on LDL accumulation. Furthermore, we implemented a new model for LDL penetration across the endothelial membrane, assuming that endothelial permeability depends on the local lumen LDL concentration. The results showed that the presence of the stenosis had a dramatic effect on the local ESS distribution and LDL accumulation along the artery, and areas of increased LDL accumulation were observed in the downstream region where flow recirculation and low ESS were present. Of the studied factors influencing LDL accumulation, 1) hypertension, 2) increased endothelial permeability (a surrogate of endothelial dysfunction), and 3) increased serum LDL levels, especially when the new model of variable endothelial permeability was applied, had the largest effects, thereby supporting their role as major cardiovascular risk factors.
Physiologic and molecular characterization of a murine model of right ventricular volume overload
Authors: Reddy Sushma , Zhao Mingming , Hu Dong-Qing , Fajardo Giovanni , Katznelson Ethan , Punn Rajesh , Spin Joshua M. , Chan Frandics P. , Bernstein Daniel
Published: March 2013

Pulmonary insufficiency (PI) is a common long-term sequel after repair of tetralogy of Fallot, causing progressive right ventricular (RV) dilation and failure. We describe the physiologic and molecular characteristics of the first murine model of RV volume overload. PI was created by entrapping the pulmonary valve leaflets with sutures. Imaging, catheterization, and exercise testing were performed at 1, 3, and 6 mo and compared with sham controls. RNA from the RV free wall was hybridized to Agilent whole genome oligonucleotide microarrays. Volume overload resulted in RV enlargement, decreased RV outflow tract shortening fraction at 1 mo followed by normalization at 3 and 6 mo (39 ± 2, 44 ± 2, and 41 ± 2 vs. 46 ± 3% in sham), early reversal of early and late diastolic filling velocities (E/A ratio) followed by pseudonormalization (0.87 ± 0.08, 0.82 ± 0.08, and 0.96 ± 0.08 vs. 1.04 ± 0.03; P < 0.05), elevated end-diastolic pressure (7.6 ± 0.7, 6.9 ± 0.8, and 7 ± 0.5 vs. 2.7 ± 0.2 mmHg; P < 0.05), and decreased exercise duration (26 ± 0.4, 26 ± 1, and 22 ± 1.3 vs. 30 ± 1.1 min; P < 0.05). Subendocardial RV fibrosis was evident by 1 mo. At 1 mo, 372 genes were significantly downregulated. Mitochondrial pathways and G protein-coupled receptor signaling were the most represented categories. At 3 mo, 434 genes were upregulated and 307 downregulated. While many of the same pathways continued to be downregulated, TNF-α, transforming growth factor-β1 (TGF-β1), p53-signaling, and extracellular matrix (ECM) remodeling transitioned from down- to upregulated. We describe a novel murine model of chronic RV volume overload recapitulating aspects of the clinical disease with gene expression changes suggesting early mitochondrial bioenergetic dysfunction, enhanced TGF-β signaling, ECM remodeling, and apoptosis.
Effect of hyperpolarization-activated current If on robustness of sinoatrial node pacemaking: theoretical study on influence of intracellular Na+ concentration
Authors: Kurata Yasutaka , Hisatome Ichiro , Tanida Mamoru , Shibamoto Toshishige
Published: March 2013

To elucidate the effects of hyperpolarization-activated current If on robustness of sinoatrial node (SAN) pacemaking in connection with intracellular Na+ concentration ( Nai) changes, we theoretically investigated 1) the impacts of If on dynamical properties of SAN model cells during inhibition of L-type Ca2+ channel currents ( ICaL) or hyperpolarizing loads and 2) If-dependent changes in Nai and their effects on dynamical properties of model cells. Bifurcation analyses were performed for Nai-variable and Nai-fixed versions of mathematical models for rabbit SAN cells; equilibrium points (EPs), limit cycles (LCs), and their stability were determined as functions of model parameters. Increasing If conductance ( gf) shrank ICaL conductance ( gCaL) regions of unstable EPs and stable LCs (rhythmic firings) in the Nai-variable system but slightly broadened that of rhythmic firings at lower gf in the Nai-fixed system. In the Nai-variable system, increased gf yielded elevations in Nai at EPs and during spontaneous oscillations, which caused EP stabilization and shrinkage in the parameter regions of unstable EPs and rhythmic firings. As gf increased, parameter regions of unstable EPs and stable LCs determined for hyperpolarizing loads shrank in the Nai-variable system but were enlarged in the Nai-fixed system. These findings suggest that 1) If does not enhance but rather attenuates robustness of rabbit SAN cells via facilitating EP stabilization and LC destabilization even in physiological gf ranges; and 2) the enhancing effect of If on robustness of pacemaker activity, which could be observed at lower gf when Nai was fixed, is actually reversed by If-dependent changes in Nai.
Pyruvate restores β-adrenergic sensitivity of L-type Ca2+channels in failing rat heart: role of protein phosphatase
Authors: Zheng Ming-Qi , Li Xun , Tang Kang , Sharma Neeru M. , Wyatt Todd A. , Patel Kaushik P. , Gao Lie , Bidasee Keshore R. , Rozanski George J.
Published: March 2013

Oxidative stress plays a major role in the pathogenesis of heart failure, where the contractile response to β-adrenergic stimulation is profoundly depressed. This condition involves L-type Ca2+channels, but the mechanisms underlying their impaired adrenergic regulation are unclear. Thus the present study explored the basis for impaired adrenergic control of Ca2+channels in a rat infarction model of heart failure. Patch-clamp recordings of L-type Ca2+current ( ICa,L) from ventricular myocytes isolated from infarcted hearts showed a blunted response to intracellular cAMP that was reversed by treatment with exogenous pyruvate. Biochemical studies showed that basal and cAMP-stimulated protein kinase A activities were similar in infarcted and sham-operated hearts, whereas molecular analysis also found that binding of protein kinase A to the α1Csubunit of voltage-gated Ca2+channel isoform 1.2 was not different between groups. By contrast, protein phosphatase 2A (PP2A) activity and binding to α1Cwere significantly less in infarcted hearts. The PP2A inhibitor okadaic acid markedly increased ICa,Lin sham-operated myocytes, but this response was significantly less in myocytes from infarcted hearts. However, pyruvate normalized ICa,Lstimulation by okadaic acid, and this effect was blocked by inhibitors of thioredoxin reductase, implicating a functional role for the redox-active thioredoxin system. Our data suggest that blunted β-adrenergic stimulation of ICaLin failing hearts results from hyperphosphorylation of Ca2+channels secondary to oxidation-induced impairment of PP2A function. We propose that the redox state of Ca2+channels or PP2A is controlled by the thioredoxin system which plays a key role in Ca2+channel remodeling of the failing heart.
Exact Solution of the Dirac Equation for the Yukawa Potential with Scalar and Vector Potentials and Tensor Interaction
Authors: Azizi Mona , Salehi Nasrin , Rajabi Ali Akbar
Published: March 2013

We present exact solutions of the Dirac equation with Yukawa potential in the presence of a Coulomb-like tensor potential. For this goal we expand the Yukawa form of the nuclear potential in its mesonic clouds by using Taylor extension to the power of seventh and bring out its simple form. In order to obtain the energy eigenvalue and the corresponding wave functions in closed forms for this potential (with great powers and inverse exponent), we use ansatz method. We also regard the effects of spin-spin, spin-isospin, and isospin-isospin interactions on the relativistic energy spectra of nucleon. By using the obtained results, we have calculated the deuteron mass. The results of our model show that the deuteron spectrum is very close to the ones obtained in experiments.
Analysis of the mRNA Expression of Chemotherapy-Related Genes in Colorectal Carcinoma Using the Danenberg Tumor Profile Method
Authors: Sasaki Shin , Watanabe Toshiyuki , Nakayama Hiroshi
Published: March 2013

The establishment of individualized chemotherapy for colorectal carcinoma based on the expression of genes involved in chemotherapeutic sensitivity or prognosis is necessary. To achieve this, the expression profiles of genes within tumors and their relationship to clinicopathological factors must be elucidated. Here, we selected 10 genes (TS, DPD, TP, FPGS, GGH, DHFR, ERCC1, TOPO-1, VEGF, andEGFR), examined differences in their mRNA expression between the upper and lower thirds of tumors by laser-captured microdissection and real-time RT-PCR (the Danenberg tumor profile), and analyzed the relationships between their expression profiles and clinicopathological factors. Interestingly, the mRNA expression ofDPD, TP, andVEGFwas significantly higher in the lower third than in the upper third of tumors (P=0.044,0.023, and0.013, resp.). Furthermore, increasedERCC1mRNA expression in the lower third of tumors correlated with recurrence (P=0.049), andVEGFmRNA expression was significantly higher in cases with recurrence than in cases without recurrence, both in the upper and lower thirds of tumors (P=0.018and0.036, resp.). These results implied that heterogeneity inDPD, TP, andVEGFexpression may exist in colorectal carcinoma and thatERCC-1andVEGFmay be markers predicting recurrence after curative operation.
18F-fluoro-L-thymidine Positron Emission Tomography for Mucosal Head and Neck Squamous Cell Carcinoma Treated with Definitive Chemoradiation: A Pilot Study of Nodal Assessment and Tracer Safety
Authors: Lin Charles , Ravi Kumar Aravind , Keller Jacqui , O’Rourke Peter , McFarlane David , Gwynne Raymond , Kenny Lizbeth , Buddle Nicole , Martin Jarad , Hughes Brett , Thomas Paul
Published: March 2013

We aim to assess the utility and safety of 18F-fluoro-L-thymidine- positron emission tomography (FLT-PET), in reference to 18F-2-fluoro-2-deoxy-D-glucose (FDG-PET) in the assessment of nodal involvement for mucosal head and neck SCC (HNSCC). Methods. Ten patients with HNSCC receiving definitive chemoradiation (CRT) were enrolled. Baseline FLT-PET and FDG-PET were obtained. The total number of involved lymph nodes and ultimate nodal staging by the baseline FDG-PET and FLT-PET was compared. Receiver Operating Characteristics (ROC) analysis for the matched nodes was performed to identify an optimal maximal standardized uptake value (SUVmax) cutpoint. Results. The tracer uptake by the involved nodes on FDG-PET was higher than those judged to be involved by FLT-PET (mean SUVmax: 5.9 versus 3.4; P<0.001). More abnormal lymph nodes were detected by FLT-PET than FDG-PET (Odds ratio = 3.67; P=0.004). The optimal SUVmax cutpoint for FLT-PET to correspond with positive FDG-PET for the matched lymph nodes was 3.25 (range 3.1–3.4). Conclusions. It is unlikely that FLT-PET will be a more accurate staging investigation than FDG-PET. A SUVmax of 3.25 may be considered as a reference cut-off in determining if a cervical lymph node is involved for HNSCC. Validation in a surgical cohort with pathological correlation is warranted.
Multivariate Padé Approximation for Solving Nonlinear Partial Differential Equations of Fractional Order
Authors: Turut Veyis , Güzel Nuran
Published: March 2013

Two tecHniques were implemented, the Adomian decomposition method (ADM) and multivariate Padé approximation (MPA), for solving nonlinear partial differential equations of fractional order. The fractional derivatives are described in Caputo sense. First, the fractional differential equation has been solved and converted to power series by Adomian decomposition method (ADM), then power series solution of fractional differential equation was put into multivariate Padé series. Finally, numerical results were compared and presented in tables and figures.
Warming Moxibustion Relieves Chronic Visceral Hyperalgesia in Rats: Relations to Spinal Dynorphin and Orphanin-FQ System
Authors: Qi Li , Liu Hui-Rong , Yi Tao , Wu Lu-Yi , Liu Xi-Ru , Zhao Chen , Shi Yin , Ma Xiao-Peng , Wu Huan-Gan
Published: March 2013

As a twin therapy of acupuncture in traditional Chinese medicine, moxibustion has shown its effects in relieving abdominal pain in irritable bowel syndrome (IBS) patients and IBS rat models, but its mechanisms are largely unknown. In this paper, we determined the role of spinal dynorphin and orphanin-FQ system in analgesic effect of warming moxibustion (WM) on chronic visceral hyperalgesia (CVH) in IBS-like rat model. Here, we show that (1) repeated WM at bilateral ST25 and ST37 acupoints markedly attenuated the abdominal withdrawal reflex scores in CVH rats; (2) intrathecal administration ofκreceptor antagonist prior to WM significantly attenuated the WM analgesia and dynorphinA (1-17) enhanced the WM analgesia. WM significantly reinforced the upregulation of spinal dynorphin mRNA/protein andκreceptor mRNA levels in CVH rats; (3) intrathecal administration of orphanin-FQ receptor antagonist prior to WM significantly attenuated the WM analgesia and orphanin-FQ enhanced the WM analgesia. WM reinforced the upregulation of spinal orphanin-FQ mRNA/protein and orphanin-FQ receptor mRNA levels in CVH rats. These results suggest that moxibustion may relieve CVH at least in part by activating spinal dynorphin and orphanin-FQ system.
LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells
Authors: Talab Fatima , Allen John C. , Thompson Victoria , Lin Ke , Slupsky Joseph R.
Published: March 2013

B-cell receptor (BCR) signals promote survival of chronic lymphocytic leukemia (CLL) cells, and it is believed that overexpressed and constitutively active Lyn mediates this signaling. Here, we show that CLL cells express lymphocyte-specific protein tyrosine kinase (LCK) and that inhibition of this Src family tyrosine kinase with the specific inhibitor [4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[3,2-d]pyrimidin-7-yl-cyclopentane (Lck-i)], or reduction of its expression with siRNA, blocks the induction of CD79a, Syk, inhibitor of IκB kinase (IKK), Akt, and extracellular signal–regulated kinase (ERK) phosphorylation by BCR cross-linking in these cells. Furthermore, we show that CLL cells with high levels of LCK expression have higher levels of BCR-mediated IKK, Akt, and ERK phosphorylation as well as cell survival than CLL cells with low levels of LCK expression. We also show that treatment of CLL cells with Lck-i inhibits BCR cross-linking–induced cell survival. Taken together, these data show a major role for LCK in proximal and distal BCR-mediated signaling in CLL cells and suggest that LCK expression is important in the pathogenesis of this disease. On a clinical level, these studies advocate the use of specific LCK inhibitors in the treatment of progressive CLL. Mol Cancer Res; 11(5); 541–54. ©2013 AACR.
Telomerase Suppresses Formation of ALT-Associated Single-Stranded Telomeric C-Circles
Authors: Plantinga Matthew J. , Pascarelli Kara M. , Merkel Anna S. , Lazar Alexander J. , von Mehren Margaret , Lev Dina , Broccoli Dominique
Published: March 2013

Telomere maintenance is an essential characteristic of cancer cells, most commonly achieved by activation of telomerase. Telomeres can also be maintained by a recombination-based mechanism, alternative lengthening of telomeres (ALT). Cells using ALT are characterized by the presence of ALT-associated promyelocytic leukemia (PML) bodies (APB), long, heterogeneously sized telomeres, extrachromosomal telomeric circular DNA, and elevated telomeric recombination. Consistent with other reports, we found that liposarcomas containing APBs, but lacking telomerase expression, always contained C-rich circles (C-circles), and these C-circles were never present in the absence of APBs, indicating a tight link between these features in ALT cells. However, a rare subgroup of tumors showing evidence of telomere maintenance by both telomerase and ALT did not contain C-circles. To test the hypothesis that telomerase expression disrupts the tight link between APBs and C-circles, we used ALT cell lines that were engineered to express telomerase. Introduction of telomerase activity in these ALT cells resulted in, on average, shorter telomeres with retention of APBs. However, at high passage, the level of C-circles was significantly reduced, which was paralleled by a switch from C-strand overhangs to G-strand overhangs. We propose that by extending critically short telomeres in these cells, telomerase is disrupting a key step in the ALT pathway necessary for production and/or maintenance of C-circles. Mol Cancer Res; 11(6); 557–67. ©2013 AACR.
Tumor Suppressor microRNAs, miR-100 and -125b, Are Regulated by 1,25-dihydroxyvitamin D in Primary Prostate Cells and in Patient Tissue
Authors: Giangreco Angeline A. , Vaishnav Avani , Wagner Dennis , Finelli Antonio , Fleshner Neil , Van der Kwast Theodorus , Vieth Reinhold , Nonn Larisa
Published: March 2013

MiR-100 and miR-125b are lost in many cancers and have potential function as tumor suppressors. Using both primary prostatic epithelial cultures and laser capture-microdissected prostate epithelium from 45 patients enrolled in a vitamin D3 randomized trial, we identified miR-100 and -125b as targets of 1,25-dihydroxyvitamin D3 (1,25D). In patients, miR-100 and -125b levels were significantly lower in tumor tissue than in benign prostate. Similarly, miR-100 and -125b were lower in primary prostate cancer cells than in cells derived from benign prostate. Prostatic concentrations of 1,25D positively correlated with these miRNA levels in both prostate cancer and benign epithelium, showing that patients with prostate cancer may still benefit from vitamin D3. In cell assays, upregulation of these miRNAs by 1,25D was vitamin D receptor dependent. Transfection of pre-miR-100 and pre-miR-125b in the presence or absence of 1,25D decreased invasiveness of cancer cell, RWPE-2. Pre-miR-100 and pre-miR-125b decreased proliferation in primary cells and cancer cells respectively. Pre-miR-125b transfection suppressed migration and clonal growth of prostate cancer cells, whereas knockdown of miR-125b in normal cells increased migration indicates a tumor suppressor function. 1,25D suppressed expression of previously bona fide mRNA targets of these miRNAs, E2F3 and Plk1, in a miRNA-dependent manner. Together, these findings show that vitamin D3 supplementation augments tumor suppressive miRNAs in patient prostate tissue, providing evidence that miRNAs could be key physiologic mediators of vitamin D3 activity in prevention and early treatment of prostate cancer. Cancer Prev Res; 6(5); 483–94. ©2013 AACR.
Association of Tooth Loss and Oral Hygiene with Risk of Gastric Adenocarcinoma
Authors: Shakeri Ramin , Malekzadeh Reza , Etemadi Arash , Nasrollahzadeh Dariush , Abedi-Ardekani Behnoush , Khoshnia Masoud , Islami Farhad , Pourshams Akram , Pawlita Michael , Boffetta Paolo , Dawsey Sanford M. , Kamangar Farin , Abnet Christian C.
Published: March 2013

Poor oral health and tooth loss have been proposed as possible risk factors for some chronic diseases, including gastric cancer. However, a small number of studies have tested these associations. We conducted a case–control study in Golestan Province, Iran, that enrolled 309 cases diagnosed with gastric adenocarcinoma (118 noncardia, 161 cardia, and 30 mixed-locations) and 613 sex, age, and neighborhood matched controls. Data on oral health were obtained through physical examination and questionnaire including tooth loss, the number of decayed, missing, and filled teeth, and frequency of tooth brushing. ORs and 95% confidence intervals (95% CI) were obtained using conditional logistic regression models adjusted for potential confounders. Standard one degree-of-freedom linear trend test and a multiple degree-of-freedom global test of the effect of adding oral hygiene variables to the model were also calculated. Our results showed apparent associations between tooth loss and decayed, missing, filled teeth (DMFT) score with risk of gastric cancer, overall and at each anatomic subsite. However, these associations were not monotonic and were strongly confounded by age. The results also showed that subjects who brushed their teeth less than daily were at significantly higher risk for gastric cardia adenocarcinoma ORs (95% CI) of 5.6 (1.6–19.3). We found evidence for an association between oral health and gastric cancer, but the nonmonotonic association, the relatively strong effect of confounder adjustment, and inconsistent results across studies must temper the strength of any conclusions. Cancer Prev Res; 6(5); 477–82. ©2013 AACR.
Preoperative Assessment of High-Risk Candidates to Predict Survival After Heart Transplantation
Authors: Schulze P. Christian , Jiang Jeffrey , Yang Jonathan , Cheema Faisal H. , Schaeffle Kenneth , Kato Tomoko S. , Farr Maryjane , Restaino Susan , Deng Mario , Maurer Mathew , Horn Evelyn , Latif Farhana , Colombo Paolo C. , Jorde Ulrich , Uriel Nir , Haythe Jennifer , Bijou Rachel , Drusin Ron , Lee Sun Hi , Takayama Hiroo , Naka Yoshifumi , Mancini Donna M.
Published: March 2013

Background—

Alternate waiting list strategies expand listing criteria for patients awaiting heart transplantation (HTx). We retrospectively analyzed clinical events and outcome of patients listed as high-risk recipients for HTx.

Methods and Results—

We analyzed 822 adult patients who underwent HTx of whom 111 patients met high-risk criteria. Clinical data were collected from medical records and outcome factors calculated for 61 characteristics. Significant factors were summarized in a prognostic score. Age >65 years (67%) and amyloidosis (19%) were the most common reasons for alternate listing. High-risk recipients were older (63.2±10.2 versus 51.4±11.8 years;
P
<0.001), had more renal dysfunction, prior cancer, and smoking. Survival analysis revealed lower post-HTx survival in high-risk recipients (82.2% versus 87.4% at 1-year; 59.8% versus 76.3% at 5-year post-HTx;
P
=0.0005). Prior cerebral vascular accident, albumin <3.5 mg/dL, re-HTx, renal dysfunction (glomerular filtration rate <40 mL/min), and >2 prior sternotomies were associated with poor survival after HTx. A prognostic risk score (CARRS [CVA, albumin, re-HTx, renal dysfunction, and sternotomies]) derived from these factors stratified survival post-HTx in high-risk (3+ points) versus low-risk (0–2 points) patients (87.9% versus 52.9% at 1-year; 65.9% versus 28.4% at 5-year post-HTx;
P
<0.001). Low-risk alternate patients had survival comparable with regular patients (87.9% versus 87.0% at 1-year and 65.9% versus 74.5% at 5-year post-HTx;
P
=0.46).

Conclusions—

High-risk patients had reduced survival compared with regular patients post-HTx. Among patients previously accepted for alternate donor listing, application of the CARRS score identifies patients with unacceptably high mortality after HTx and those with a survival similar to regularly listed patients.
Galectin-3 and Cardiac Function in Survivors of Acute Myocardial Infarction
Authors: Weir Robin A.P. , Petrie Colin J. , Murphy C. Aengus , Clements Suzanne , Steedman Tracey , Miller Ashley M. , McInnes Iain B. , Squire Iain B. , Ng Leong L. , Dargie Henry J. , McMurray John J.V.
Published: March 2013

Background—

Galectin-3 is a biomarker associated with inflammation and fibrosis that predicts adverse outcome and relates to biomarkers of extracellular matrix turnover in patients with heart failure, particularly when left ventricular (LV) systolic function is preserved. Whether galectin-3 is related to LV remodeling after acute myocardial infarction is unknown.

Methods and Results—

Circulating galectin-3 and various extracellular matrix biomarkers were measured in 100 patients (age, 58.9±12.0 years; 77% men) admitted with acute myocardial infarction and LV dysfunction, at baseline (mean 46 hours) and at 24 weeks, with cardiac MRI at each time-point. LV remodeling was defined as change in LV end-systolic volume index. Relationships among galectin-3, biomarkers, and LV remodeling were analyzed across the entire cohort, then according to median baseline LV ejection fraction. Galectin-3 levels were elevated in 22 patients (22%) at baseline and increased significantly over time from 14.7±5.5 to 16.3±6.6 ng/mL (
P
=0.007). Baseline galectin-3 did not correlate with any LV parameters at baseline or change in any parameter over time. Galectin-3 was positively associated with remodeling in patients with supramedian baseline LV ejection fraction (ie, >49.2%;
r
=0.40;
P
=0.01) but not when LV ejection fraction was ≤49.2%. Galectin-3 correlated significantly with matrix metalloproteinase-3 and monocyte chemoattractant protein-1 at baseline, biomarkers that have been shown to relate to LV remodeling in this cohort.

Conclusions—

Galectin-3 correlated significantly with certain biomarkers involved in extracellular matrix turnover, although no definite relationship was identified with LV remodeling. Whether galectin-3 plays a pathological role in remodeling remains unclear but merits further study.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00132093.
Apolipoprotein AI and High-Density Lipoprotein Have Anti-Inflammatory Effects on Adipocytes via Cholesterol Transporters
Authors: Umemoto Tomio , Han Chang Yeop , Mitra Poulami , Averill Michelle M. , Tang Chongren , Goodspeed Leela , Omer Mohamed , Subramanian Savitha , Wang Shari , Den Hartigh Laura J. , Wei Hao , Kim Eung Ju , Kim Jinkyu , O’Brien Kevin D. , Chait Alan
Published: March 2013

Rationale:

Macrophage accumulation in adipose tissue associates with insulin resistance and increased cardiovascular disease risk. We previously have shown that generation of reactive oxygen species and monocyte chemotactic factors after exposure of adipocytes to saturated fatty acids, such as palmitate, occurs via translocation of NADPH oxidase 4 into lipid rafts (LRs). The anti-inflammatory effects of apolipoprotein AI (apoAI) and high-density lipoprotein (HDL) on macrophages and endothelial cells seem to occur via cholesterol depletion of LRs. However, little is known concerning anti-inflammatory effects of HDL and apoAI on adipocytes.

Objective:

To determine whether apoAI and HDL inhibit inflammation in adipocytes and adipose tissue, and whether this is dependent on LRs.

Methods and Results:

In 3T3L-1 adipocytes, apoAI, HDL, and methyl-β-cyclodextrin inhibited chemotactic factor expression. ApoAI and HDL also disrupted LRs, reduced plasma membrane cholesterol content, inhibited NADPH oxidase 4 translocation into LRs, and reduced palmitate-induced reactive oxygen species generation and monocyte chemotactic factor expression. Silencing ATP-binding cassette A-1 abrogated the effect of apoAI, but not HDL, whereas silencing ATP-binding cassette G-1 or scavenger receptor B-1 abrogated the effect of HDL but not apoAI. In vivo, apoAI transgenic mice fed a high-fat, high-sucrose, cholesterol-containing diet showed reduced chemotactic factor and proinflammatory cytokine expression and reduced macrophage accumulation in adipose tissue.

Conclusions:

ApoAI and HDL have anti-inflammatory effects in adipocytes and adipose tissue similar to their effects in other cell types. These effects are consistent with disruption and removal of cholesterol from LRs, which are regulated by cholesterol transporters, such as ATP-binding cassette A-1, ATP-binding cassette G-1, and scavenger receptor B-1.
Vorapaxar in Patients With Peripheral Artery Disease
Authors: Bonaca Marc P. , Scirica Benjamin M. , Creager Mark A. , Olin Jeffrey , Bounameaux Henri , Dellborg Mikael , Lamp Jessica M. , Murphy Sabina A. , Braunwald Eugene , Morrow David A.
Published: March 2013

Background—

Vorapaxar is a novel antagonist of protease-activated receptor-1, the primary receptor for thrombin on human platelets that is also present on vascular endothelium and smooth muscle. Patients with peripheral artery disease are at risk of systemic atherothrombotic events, as well as acute and chronic limb ischemia and the need for peripheral revascularization.

Methods and Results—

The Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Atherosclerosis (TRA2°P-TIMI 50) was a randomized, double-blind, placebo-controlled trial of vorapaxar in 26 449 patients with stable atherosclerotic vascular disease (myocardial infarction, stroke, or peripheral artery disease). Patients with qualifying peripheral artery disease (n=3787) had a history of claudication and an ankle-brachial index of <0.85 or prior revascularization for limb ischemia. The primary efficacy end point was cardiovascular death, myocardial infarction, or stroke, and the principal safety end point was Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) bleeding. In the peripheral artery disease cohort, the primary end point did not differ significantly with vorapaxar (11.3% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.78–1.14;
P
=0.53). However, rates of hospitalization for acute limb ischemia (2.3% versus 3.9%; hazard ratio, 0.58; 95% confidence interval, 0.39–0.86;
P
=0.006) and peripheral artery revascularization (18.4% versus 22.2%; hazard ratio, 0.84; 95% confidence interval, 0.73–0.97;
P
=0.017) were significantly lower in patients randomized to vorapaxar. Bleeding occurred more frequently with vorapaxar compared with placebo (7.4% versus 4.5%; hazard ratio, 1.62; 95% confidence interval, 1.21–2.18;
P
=0.001).

Conclusions—

Vorapaxar did not reduce the risk of cardiovascular death, myocardial infarction, or stroke in patients with peripheral artery disease; however, vorapaxar significantly reduced acute limb ischemia and peripheral revascularization. The beneficial effects of protease-activated receptor-1 antagonism on limb vascular events were accompanied by an increased risk of bleeding.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00526474.
Reporting and Representation: Intra-EU Diplomacy and Dutch Bilateral Embassies
Authors: Uilenreef Arjan D.
Published: March 2013

Summary

Embassies of the Netherlands within the European Union operate in another political and diplomatic environment than Dutch embassies in other parts of the world. There is a lack of comprehensive studies on the change dynamics of bilateral diplomacy within the EU. This article aims to contribute to the study of intra-EU diplomacy by looking at one of the key tasks of embassies abroad, namely reporting back to the capital. An analysis of the addressees, the type of reporting, and the interlocutors of embassy staff across Europe, reveals characteristics of the work of representations in a ‘post-Westphalian’ order. The results show that the diplomatic environment of Dutch bilateral embassies within the European Union does in several important ways indeed differ from that of Dutch embassies outside the Union.
CMIP5 Simulations of Low-Level Tropospheric Temperature and Moisture over the Tropical Americas
Authors: Carvalho Leila M. V. , Jones Charles
Published: March 2013

Global warming has been linked to systematic changes in North and South America's climates and may severely impact the North American monsoon system (NAMS) and South American monsoon system (SAMS). This study examines interannual-to-decadal variations and changes in the low-troposphere (850 hPa) temperature (T850) and specific humidity (Q850) and relationships with daily precipitation over the tropical Americas using the NCEP–NCAR reanalysis, the Climate Forecast System Reanalysis (CFSR), and phase 5 of the Coupled Model Intercomparison Project (CMIP5) simulations for two scenarios: “historic” and high-emission representative concentration pathway 8.5 (RCP8.5). Trends in the magnitude and area of the 85th percentiles were distinctly examined over North America (NA) and South America (SA) during the peak of the respective monsoon season. The historic simulations (1951–2005) and the two reanalyses agree well and indicate that significant warming has occurred over tropical SA with a remarkable increase in the area and magnitude of the 85th percentile in the last decade (1996–2005). The RCP8.5 CMIP5 ensemble mean projects an increase in the T850 85th percentile of about 2.5°C (2.8°C) by 2050 and 4.8°C (5.5°C) over SA (NA) by 2095 relative to 1955. The area of SA (NA) with T850 ≥ the 85th percentile is projected to increase from ~10% (15%) in 1955 to ~58% (~33%) by 2050 and ~80% (~50%) by 2095. The respective increase in the 85th percentile of Q850 is about 3 g kg−1 over SAMS and NAMS by 2095. CMIP5 models project variable changes in daily precipitation over the tropical Americas. The most consistent is increased rainfall in the intertropical convergence zone in December–February (DJF) and June–August (JJA) and decreased precipitation over NAMS in JJA.
Seasonal Forecasts of the Pan-Arctic Sea Ice Extent Using a GCM-Based Seasonal Prediction System
Authors: Chevallier Matthieu , Salas y Mélia David , Voldoire Aurore , Déqué Michel , Garric Gilles
Published: March 2013

An ocean–sea ice model reconstruction spanning the period 1990–2009 is used to initialize ensemble seasonal forecasts with the Centre National de Recherches Météorologiques Coupled Global Climate Model version 5.1 (CNRM-CM5.1) coupled atmosphere–ocean general circulation model. The aim of this study is to assess the skill of fully initialized September and March pan-Arctic sea ice forecasts in terms of climatology and interannual anomalies. The predictions are initialized using “full field initialization” of each component of the system. In spite of a drift due to radiative biases in the coupled model during the melt season, the full initialization of the sea ice cover on 1 May leads to skillful forecasts of the September sea ice extent (SIE) anomalies. The skill of the prediction is also significantly high when considering anomalies of the SIE relative to the long-term linear trend. It confirms that the anomaly of spring sea ice cover in itself plays a role in preconditioning a September SIE anomaly. The skill of predictions for March SIE initialized on 1 November is also encouraging, and it can be partly attributed to persistent features of the fall sea ice cover. The present study gives insight into the current ability of state-of-the-art coupled climate systems to perform operational seasonal forecasts of the Arctic sea ice cover up to 5 months in advance.
Uncertainty in Ranking the Hottest Years of U.S. Surface Temperatures
Authors: Guttorp Peter , Kim Tae Yen
Published: March 2013

Ranking years based on statistical estimates of regional and temporal averages is subject to uncertainty. This uncertainty can in fact be quite substantial and can be described by the rank distribution of an ensemble of such averages. The authors develop a method for estimating it using simulation. The effect of temporal correlation is quite limited in the case studied in this paper: the contiguous United States' annual-mean temperature. The method also allows assessment of derived quantities such as the probability of a given year being one of the 10 warmest in the historical record.
The Influence of the Amundsen–Bellingshausen Seas Low on the Climate of West Antarctica and Its Representation in Coupled Climate Model Simulations
Authors: Hosking J. Scott , Orr Andrew , Marshall Gareth J. , Turner John , Phillips Tony
Published: March 2013

In contrast to earlier studies, the authors describe the climatological deep low pressure system that exists over the South Pacific sector of the Southern Ocean, referred to as the Amundsen–Bellingshausen Seas low (ABSL), in terms of its relative (rather than actual) central pressure by removing the background area-averaged mean sea level pressure (MSLP). Doing so removes much of the influence of large-scale variability across the ABSL sector region (e.g., due to the southern annular mode), allowing a clearer understanding of ABSL variability and its effect on the regional climate of West Antarctica. Using ECMWF Interim Re-Analysis (ERA-Interim) fields, the annual cycle of the relative central pressure of the ABSL for the period from 1979 to 2011 shows a minimum (maximum) during winter (summer), differing considerably from the earlier studies based on actual central pressure, which suggests a semiannual oscillation. The annual cycle of the longitudinal position of the ABSL is insensitive to the background pressure, and shows it shifting westward from ∼250° to ∼220°E between summer and winter, in agreement with earlier studies. The authors demonstrate that ABSL variability, and in particular its longitudinal position, play an important role in controlling the surface climate of West Antarctica and the surrounding ocean by quantifying its influence on key meteorological parameters. Examination of the ABSL annual cycle in 17 CMIP5 climate models run with historical forcing shows that the majority of them have definite biases, especially in terms of longitudinal position, and a correspondingly poor representation of West Antarctic climate.
Diagnosing Surface Mixed Layer Dynamics from High-Resolution Satellite Observations: Numerical Insights
Authors: Ponte Aurelien L. , Klein Patrice , Capet Xavier , Le Traon Pierre-Yves , Chapron Bertrand , Lherminier Pascale
Published: March 2013

High-resolution numerical experiments of ocean mesoscale eddy turbulence show that the wind-driven mixed layer (ML) dynamics affects mesoscale motions in the surface layers at scales lower than O(60 km). At these scales, surface horizontal currents are still coherent to, but weaker than, those derived from sea surface height using geostrophy. Vertical motions, on the other hand, are stronger than those diagnosed using the adiabatic quasigeotrophic (QG) framework. An analytical model, based on a scaling analysis and on simple dynamical arguments, provides a physical understanding and leads to a parameterization of these features in terms of vertical mixing. These results are valid when the wind-driven velocity scale is much smaller than that associated with eddies and the Ekman number (related to the ratio between the Ekman and ML depth) is not small. This suggests that, in these specific situations, three-dimensional ML motions (including the vertical velocity) can be diagnosed from high-resolution satellite observations combined with a climatological knowledge of ML conditions and interior stratification.