bluuebunny/crossref_metadata_2025_split huggingface dataset:
Weighting Components of Composite End Points in Clinical Trials
Authors: Hong Keun-Sik , Ali Latisha K. , Selco Scott L. , Fonarow Gregg C. , Saver Jeffrey L. 
Published: April 2011

Background and Purpose—
Conventional analysis of vascular prevention trials assigns equal weight to disparate vascular events in a composite end point at variance with the public's perception of their differential impact on health outcome. This study sought to apply the disability-adjusted life-year (DALY) metric to differential weighting individual vascular end points in trial analyses.

Methods—
DALY values for the most common major end points in vascular prevention trials (nonfatal myocardial infarction, nonfatal stroke, and vascular death), were derived by using World Health Organization Global Burden of Disease Project methodology. The standardized DALYs for each event were applied to recent major primary and secondary vascular prevention trials and to hypothetical model trials.

Results—
Standardized DALYs lost were 7.63 for nonfatal stroke, 5.14 for nonfatal myocardial infarction, and 11.59 for vascular death. In the published trials analyses, the direction of treatment effects was consistent between DALY and standard event analysis, but the rank order of treatment effect changed for 10 of 18 trials. The DALY analysis also permitted derivation of number-needed-to-treat values to gain 1 DALY: 2.1 for anticoagulation in atrial fibrillation, 2.7 for carotid endarterectomy in symptomatic stenosis, and 4.7 for clopidogrel added to aspirin in acute coronary syndrome. Hypothetical trial analyses demonstrated that the DALY metric more finely discriminates treatment effects.

Conclusions—
Compared with a nonfatal myocardial infarction, a nonfatal stroke causes a 1.48-fold greater loss and vascular death a 2.25-fold greater loss of DALY. DALY analysis integrates these valuations in a summary metric reflecting the net impact of therapy on patient and societal health, complementing conventional end point analyses.
Interobserver Variability of Grading Scales for Aneurysmal Subarachnoid Hemorrhage
Authors: Degen Lieveke A.R. , Dorhout Mees Sanne M. , Algra Ale , Rinkel Gabriël J.E. 
Published: April 2011

Background and Purpose—
Worldwide, different scales are used to assess the clinical condition on admission after aneurysmal subarachnoid hemorrhage. In addition to the prognostic value, the inter-rater variability should be taken into account when deciding which scale preferably should be used. We assessed the interobserver agreement of the commonly used World Federation of Neurological Surgeons, the Hunt and Hess, and the Prognosis on Admission of Aneurysmal Subarachnoid Hemorrhage scales.

Methods—
In a cohort of 50 subarachnoid hemorrhage patients, 103 paired assessments were performed on the 3 admission scales by 2 independent observers per assessment with a total of 57 different raters. Patients were assessed during the first week after the hemorrhage. The interobserver agreement was calculated using quadratic (weighted) kappa statistics.

Results—
The weighted kappa value of the Prognosis on Admission of Aneurysmal Subarachnoid Hemorrhage scale was 0.64 (95% CI, 0.49–0.79), of the World Federation of Neurological Surgeons scale was 0.60 (95% CI, 0.48–0.73), and of the Hunt and Hess scale was 0.48 (95% CI, 0.36–0.59).

Conclusions—
The Hunt and Hess scale showed the lowest interobserver agreement, whereas agreement of the World Federation of Neurological Surgeons and Prognosis on Admission of Aneurysmal Subarachnoid Hemorrhage scales was similar with overlapping CI.
Transfer Delay Is a Major Factor Limiting the Use of Intra-Arterial Treatment in Acute Ischemic Stroke
Authors: Prabhakaran Shyam , Ward Edward , John Sayona , Lopes Demetrius K. , Chen Michael , Temes Richard E. , Mohammad Yousef , Lee Vivien H. , Bleck Thomas P. 
Published: April 2011

Background and Purpose—
The development of comprehensive stroke centers within hub-and-spoke stroke networks offers the opportunity to increase the proportion of acute ischemic stroke patients treated with intra-arterial therapies (IAT). Interhospital transfer delays will be critical in evaluating the success of this strategy.

Methods—
We collected data on consecutive patients who were transferred to our institution for possible IAT. We defined transfer time as time elapsed from initial transfer call to arrival at our hospital and assessed whether transfer time was a predictor of emergent angiography using multivariable logistic regression.

Results—

Among 132 patients referred for IAT, 53 (40.2%) were excluded on clinical grounds. The remaining 79 (59.8%) patients (mean age, 61 years; median National Institutes of Health Stroke Scale score, 18; 49.4% male) were analyzed. Sixty-one of 79 (77%) patients underwent emergent angiography for IAT. The median hospital-to-hospital distance was 14.7 (interquartile range, 8.5–21.9) miles and median transfer time was 104 (interquartile range, 80–135) minutes. Transfer time was 33% lower among those who underwent emergent angiography (100.6 versus 149.0 minutes;
P
<0.001). Adjusting for relevant covariates, transfer time remained an independent predictor of emergent angiography (OR, 0.975; 95% CI, 0.956–0.995;
P
=0.014). The odds of treatment decrease by 2.5% for every minute of transfer time.

Conclusions—
Delay in hospital-to-hospital transfer is a common reason that acute ischemic stroke patients are excluded from interventional therapy. The likelihood of receiving IAT decreases rapidly by increasing transfer time. Specific goals for transfer time should be considered in future quality standards for hub-and-spoke–organized stroke networks.
A New Therapeutic Strategy for Acute Ischemic Stroke
Authors: Smadja Didier , Chausson Nicolas , Joux Julien , Saint-Vil Martine , Signaté Aïssatou , Edimonana Mireille , Jeannin Séverine , Bartoli Blaise , Aveillan Mathieu , Cabre Philippe , Olindo Stéphane 
Published: April 2011

Background and Purpose—
Intravenous tissue-type plasminogen activator (IV tPA) frequently fails to recanalize proximal middle cerebral artery (MCA-M1) obstructions, preventing favorable outcomes. Only neurointerventional procedures prevail in these cases, but well-equipped centers remain scarce. A new therapeutic strategy consisting of a second IV thrombolysis with low-dose tenecteplase was applied.

Methods—
Consecutive patients with an MCA-M1 occlusion that did not reopen at the end of IV tPA perfusion received IV tenecteplase (0.1 mg/kg). Partial or complete thrombolysis in myocardial infarction recanalization (Thrombolysis In Myocardial Infarction grade 2/3) and intracerebral hemorrhage were assessed by magnetic resonance imaging ≈24 hours later. Clinical outcomes at 3 months were evaluated with the modified Rankin score.

Results—
Among 40 patients with MCA-M1 occlusions who received IV tPA, 13 were treated according to the protocol of sequential combined IV thrombolytics. Baseline National Institutes of Health Stroke Scale score was 15. At a mean of 16.8 hours after IV thrombolysis, the recanalization rate was 100% (2 with Thrombolysis In Myocardial Infarction grade 2, 11 with Thrombolysis In Myocardial Infarction grade 3). Intracerebral hemorrhage occurred in 4 of 13 (31%) patients, with no symptomatic hemorrhage. Good clinical outcomes (modified Rankin score=0/1) were achieved in 9 of 13 (69%) patients. Functional outcomes were very similar to those of 13 patients with early IV-tPA recanalization. Among 4 patients treated as protocol violations, 1 presented with a lack of recanalization and a parenchymal hematoma type 2.

Conclusions—
For patients with MCA-M1 occlusions treated with IV tPA but without early recanalization, a second bolus of IV tenecteplase (0.1 mg/kg) may be a relatively safe, effective, and easy option in carefully selected cases, but additional studies are needed to confirm these findings.
Ocean Preconditioning of Cyclone Nargis in the Bay of Bengal: Interaction between Rossby Waves, Surface Fresh Waters, and Sea Surface Temperatures*
Authors: Yu Lisan , McPhaden Michael J. 
Published: April 2011

Abstract
An in-depth data analysis was conducted to understand the occurrence of a strong sea surface temperature (SST) front in the central Bay of Bengal before the formation of Cyclone Nargis in April 2008. Nargis changed its course after encountering the front and tracked along the front until making landfall. One unique feature of this SST front was its coupling with high sea surface height anomalies (SSHAs), which is unusual for a basin where SST is normally uncorrelated with SSHA. The high SSHAs were associated with downwelling Rossby waves, and the interaction between downwelling and surface fresh waters was a key mechanism to account for the observed SST–SSHA coupling.
The near-surface salinity field in the bay is characterized by strong stratification and a pronounced horizontal gradient, with low salinity in the northeast. During the passage of downwelling Rossby waves, freshening of the surface layer was observed when surface velocities were southwestward. Horizontal convergence of freshwater associated with downwelling Rossby waves increased the buoyancy of the upper layer and caused the mixed layer to shoal to within a few meters of the surface. Surface heating trapped in the thin mixed layer caused the fresh layer to warm, whereas the increase in buoyancy from low-salinity waters enhanced the high SSHA associated with Rossby waves. Thus, high SST coincided with high SSHA.
The dominant role of salinity in controlling high SSHA suggests that caution should be exercised when computing hurricane heat potential in the bay from SSHA. This situation is different from most tropical oceans, where temperature has the dominant effect on SSHA.
High-Resolution Imaging of the Ocean Surface Backscatter by Inversion of Altimeter Waveforms
Authors: Tournadre Jean , Chapron Bertrand , Reul Nicolas 
Published: April 2011

Abstract
This paper presents a new method to analyze high-resolution altimeter waveforms in terms of surface backscatter. Over the ocean, a basic assumption of modeling altimeter echo waveforms is to consider a homogeneous sea surface within the altimeter footprint that can be described by a mean backscatter coefficient. When the surface backscatter varies strongly at scales smaller than the altimeter footprint size, such as in the presence of surface slicks, rain, small islands, and altimeter echoes can be interpreted as high-resolution images of the surface whose geometry is annular and not rectangular. A method based on the computation of the imaging matrix and its pseudoinverse to infer the surface backscatter at high resolution (~300 m) from the measured waveforms is presented. The method is tested using synthetic waveforms for different surface backscatter fields and is shown to be unbiased and accurate. Several applications can be foreseen to refine the analysis of rain patterns, surface slicks, and lake surfaces. The authors choose here to focus on the small-scale variability of backscatter induced by a submerged reef smaller than the altimeter footprint as the function of tide, significant wave height, and wind.
Using impedance cardiography with postural change to stratify patients with hypertension
Authors: DeMarzo Arthur P. 
Published: April 2011

Background: Early detection of cardiovascular disease in patients with hypertension could initiate appropriate treatment to control blood pressure and prevent the progression of cardiovascular disease. Objective: The goal of this study was to show how impedance cardiography waveform analysis with postural change can be used to detect subclinical cardiovascular disease in patients with high blood pressure. Methods: Patients with high blood pressure had impedance cardiography data obtained in two positions, standing upright and supine. Results: In 50 adults, impedance cardiography indicated that all patients had abnormal data, with 44 (88%) having multiple abnormalities. Impedance cardiography showed 32 (64%) had ventricular dysfunction, 48 (96%) had vascular load abnormalities, 34 (68%) had hemodynamic abnormalities, 2 (4%) had hypovolemia, and 3 (6%) had hypervolemia. Conclusions: Hypertensive patients have diverse cardiovascular abnormalities that can be quantified by impedance cardiography. By stratifying patients with ventricular, vascular, and hemodynamic abnormalities, treatment could be customized based on the abnormal underlying mechanisms with the potential to rapidly control blood pressure, prevent progression of cardiovascular disease, and possibly reverse remodeling.
Examination and Treatment of Cuboid Syndrome
Authors: Durall Chris J. 
Published: April 2011

Context: Cuboid syndrome is thought to be a common source of lateral midfoot pain in athletes. Evidence Acquisition: A Medline search was performed via PubMed (through June 2010) using the search terms cuboid, syndrome, subluxed, locked, fault, dropped, peroneal, lateral, plantar, and neuritis with the Boolean term AND in all possible combinations. Retrieved articles were hand searched for additional relevant references. Results: Cuboid syndrome is thought to arise from subtle disruption of the arthrokinematics or structural congruity of the calcaneocuboid joint, although the precise pathomechanic mechanism has not been elucidated. Fibroadipose synovial folds (or labra) within the calcaneocuboid joint may play a role in the cause of cuboid syndrome, but this is highly speculative. The symptoms of cuboid syndrome resemble those of a ligament sprain. Currently, there are no definitive diagnostic tests for this condition. Case reports suggest that cuboid syndrome often responds favorably to manipulation and/or external support. Conclusions: Evidence-based guidelines regarding cuboid syndrome are lacking. Consequently, the diagnosis of cuboid syndrome is often based on a constellation of signs and symptoms and a high index of suspicion. Unless contraindicated, manipulation of the cuboid should be considered as an initial treatment.
A CK2-dependent mechanism for activation of the JAK-STAT signaling pathway
Authors: Zheng Ying , Qin Hongwei , Frank Stuart J. , Deng Luqin , Litchfield David W. , Tefferi Ayalew , Pardanani Animesh , Lin Fang-Tsyr , Li Jingzhi , Sha Bingdong , Benveniste Etty N. 
Published: April 2011

AbstractJAK-STAT signaling is involved in the regulation of cell survival, proliferation, and differentiation. JAK tyrosine kinases can be transiently activated by cytokines or growth factors in normal cells, whereas they become constitutively activated as a result of mutations that affect their function in tumors. Specifically, the JAK2V617F mutation is present in the majority of patients with myeloproliferative disorders (MPDs) and is implicated in the pathogenesis of these diseases. In the present study, we report that the kinase CK2 is a novel interaction partner of JAKs and is essential for JAK-STAT activation. We demonstrate that cytokine-induced activation of JAKs and STATs and the expression of suppressor of cytokine signaling 3 (SOCS-3), a downstream target, are inhibited by CK2 small interfering RNAs or pharmacologic inhibitors. Endogenous CK2 is associated with JAK2 and JAK1 and phosphorylates JAK2 in vitro. To extend these findings, we demonstrate that CK2 interacts with JAK2V617F and that CK2 inhibitors suppress JAK2V617F autophosphorylation and downstream signaling in HEL92.1.7 cells (HEL) and primary cells from polycythemia vera (PV) patients. Furthermore, CK2 inhibitors potently induce apoptosis of HEL cells and PV cells. Our data provide evidence for novel cross-talk between CK2 and JAK-STAT signaling, with implications for therapeutic intervention in JAK2V617F-positive MPDs.
Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A
Authors: Salas Arelis , Ponnusamy Suriyan , Senkal Can E. , Meyers-Needham Marisa , Selvam Shanmugam Panneer , Saddoughi Sahar A. , Apohan Elif , Sentelle R. David , Smith Charles , Gault Christopher R. , Obeid Lina M. , El-Shewy Hesham M. , Oaks Joshua , Santhanam Ramasamy , Marcucci Guido , Baran Yusuf , Mahajan Sandeep , Fernandes Daniel , Stuart Robert , Perrotti Danilo , Ogretmen Besim 
Published: April 2011

Abstract
The mechanisms by which sphingosine kinase-1 (SK-1)/sphingosine 1-phosphate (S1P) activation contributes to imatinib resistance in chronic myeloid leukemia (CML) are unknown. We show herein that increased SK-1/S1P enhances Bcr-Abl1 protein stability, through inhibition of its proteasomal degradation in imatinib-resistant K562/IMA-3 and LAMA-4/IMA human CML cells. In fact, Bcr-Abl1 stability was enhanced by ectopic SK-1 expression. Conversely, siRNA-mediated SK-1 knockdown in K562/IMA-3 cells, or its genetic loss in SK-1−/− MEFs, significantly reduced Bcr-Abl1 stability. Regulation of Bcr-Abl1 by SK-1/S1P was dependent on S1P receptor 2 (S1P2) signaling, which prevented Bcr-Abl1 dephosphorylation, and degradation via inhibition of PP2A. Molecular or pharmacologic interference with SK-1/S1P2 restored PP2A-dependent Bcr-Abl1 dephosphorylation, and enhanced imatinib- or nilotinib-induced growth inhibition in primary CD34+ mononuclear cells obtained from chronic phase and blast crisis CML patients, K562/IMA-3 or LAMA4/IMA cells, and 32Dcl3 murine progenitor cells, expressing the wild-type or mutant (Y253H or T315I) Bcr-Abl1 in situ. Accordingly, impaired SK-1/S1P2 signaling enhanced the growth-inhibitory effects of nilotinib against 32D/T315I-Bcr-Abl1–derived mouse allografts. Since SK-1/S1P/S1P2 signaling regulates Bcr-Abl1 stability via modulation of PP2A, inhibition of SK-1/S1P2 axis represents a novel approach to target wild-type- or mutant-Bcr–Abl1 thereby overcoming drug resistance.
Dexamethasone and lenalidomide have distinct functional effects on erythropoiesis
Authors: Narla Anupama , Dutt Shilpee , McAuley J. Randall , Al-Shahrour Fatima , Hurst Slater , McConkey Marie , Neuberg Donna , Ebert Benjamin L. 
Published: April 2011

AbstractCorticosteroids and lenalidomide decrease red blood cell transfusion dependence in patients with Diamond-Blackfan anemia (DBA) and myelodysplastic syndrome (MDS), respectively. We explored the effects of dexamethasone and lenalidomide, individually and in combination, on the differentiation of primary human bone marrow progenitor cells in vitro. Both agents promote erythropoiesis, increasing the absolute number of erythroid cells produced from normal CD34+ cells and from CD34+ cells with the types of ribosome dysfunction found in DBA and del(5q) MDS. However, the drugs had distinct effects on the production of erythroid progenitor colonies; dexamethasone selectively increased the number of burst-forming units-erythroid (BFU-E), whereas lenalidomide specifically increased colony-forming unit-erythroid (CFU-E). Use of the drugs in combination demonstrated that their effects are not redundant. In addition, dexamethasone and lenalidomide induced distinct gene-expression profiles. In coculture experiments, we examined the role of the microenvironment in response to both drugs and found that the presence of macrophages, the central cells in erythroblastic islands, accentuated the effects of both agents. Our findings indicate that dexamethasone and lenalidomide promote different stages of erythropoiesis and support the potential clinical utility of combination therapy for patients with bone marrow failure.
Serum hepcidin: reference ranges and biochemical correlates in the general population
Authors: Galesloot Tessel E. , Vermeulen Sita H. , Geurts-Moespot Anneke J. , Klaver Siem M. , Kroot Joyce J. , van Tienoven Dorlene , Wetzels Jack F. M. , Kiemeney Lambertus A. L. M. , Sweep Fred C. , den Heijer Martin , Swinkels Dorine W. 
Published: April 2011

AbstractTo date, concentrations of the promising biomarker hepcidin have only been assessed in serum of relatively small series of healthy volunteers and patients. We assessed age- and sex-stratified reference ranges of serum hepcidin concentration in a selected reference set and performed regression analyses to study associations between hepcidin and (biochemical) variables in a large, well-phenotyped sample of the general population (n = 2998). All participants filled out a questionnaire on lifestyle, health status, and medical history. Serum measurements of iron parameters, liver enzyme alanine aminotransferase, creatinine and C-reactive protein were available. Serum hepcidin concentrations were lower for premenopausal than for postmenopausal women (median, 4.1nM vs 8.5nM, respectively). Hepcidin concentrations in men were constant over age (median, 7.8nM). Serum hepcidin was strongly associated with serum ferritin in men and women: β-coefficient of log-transformed variables (95% confidence interval): 0.78 (0.74-0.82) and 0.83 (0.78-0.88), respectively. Additional significant, though less strong, associations were observed for C-reactive protein and total iron binding capacity in men and for total iron binding capacity, alanine aminotransferase, and glomerular filtration rate in women. Our study provides age- and sex-specific reference ranges of serum hepcidin concentration and indicates ferritin as the primary correlate of serum hepcidin concentration.
The testosterone-dependent and independent transcriptional networks in the hypothalamus of Gpr54 and Kiss1 knockout male mice are not fully equivalent
Authors: Prentice Leah M , d'Anglemont de Tassigny Xavier , McKinney Steven , Ruiz de Algara Teresa , Yap Damian , Turashvili Gulisa , Poon Steven , Sutcliffe Margaret , Allard Pat , Burleigh Angela , Fee John , Huntsman David G , Colledge William H , Aparicio Samuel AJ 
Published: April 2011

Abstract

Background
Humans and mice with loss of function mutations in GPR54 (KISS1R) or kisspeptin do not progress through puberty, caused by a failure to release GnRH. The transcriptional networks regulated by these proteins in the hypothalamus have yet to be explored by genome-wide methods.

Results
We show here, using 1 million exon mouse arrays (Exon 1.0 Affymetrix) and quantitative polymerase chain reaction (QPCR) validation to analyse microdissected hypothalamic tissue from Gpr54 and Kiss1 knockout mice, the extent of transcriptional regulation in the hypothalamus. The sensitivity to detect important transcript differences in microdissected RNA was confirmed by the observation of counter-regulation of Kiss1 expression in Gpr54 knockouts and confirmed by immunohistochemistry (IHC). Since Gpr54 and Kiss1 knockout animals are effectively pre-pubertal with low testosterone (T) levels, we also determined which of the validated transcripts were T-responsive and which varied according to genotype alone. We observed four types of transcriptional regulation (i) genotype only dependent regulation, (ii) T only dependent regulation, (iii) genotype and T-dependent regulation with interaction between these variables, (iv) genotype and T-dependent regulation with no interaction between these variables. The results implicate for the first time several transcription factors (e.g. Npas4, Esr2), proteases (Klk1b22), and the orphan 10-transmembrane transporter TMEM144 in the biology of GPR54/kisspeptin function in the hypothalamus. We show for the neuronal activity regulated transcription factor NPAS4, that distinct protein over-expression is seen in the hypothalamus and hippocampus in Gpr54 knockout mice. This links for the first time the hypothalamic-gonadal axis with this important regulator of inhibitory synapse formation. Similarly we confirm TMEM144 up-regulation in the hypothalamus by RNA in situ hybridization and western blot.

Conclusions
Taken together, global transcriptional profiling shows that loss of GPR54 and kisspeptin are not fully equivalent in the mouse hypothalamus.