bluuebunny/crossref_metadata_2025 huggingface dataset:
Basic Principles of MLC
Authors: Rambla-Alegre Maria
Published: March 2012

Micellar liquid chromatography (MLC) is an efficient alternative to conventional reversed-phase liquid chromatography with hydro-organic mobile phases. Almost three decades of experience have resulted in an increasing production of analytical applications. Current concern about the environment also reveals MLC as an interesting technique for “green” chemistry because it uses mobile phases containing 90% or more water. These micellar mobile phases have a low toxicity and are not producing hazardous wastes. The stationary phase is modified with an approximately constant amount of surfactant monomers, and the solubilising capability of the mobile phase is altered by the presence of micelles, giving rise to a great variety of interactions (hydrophobic, ionic, and steric) with major implications in retention and selectivity. From its beginnings in 1980, the technique has evolved up to becoming in a real alternative in some instances (and a complement in others) to classical RPLC with aqueous-organic mixtures, owing to its peculiar features and unique advantages. The addition of an organic solvent to the mobile phase was, however, soon suggested in order to enhance the low efficiencies and weak elution strength associated with the mobile phases that contained only micelles.
Impact of Previous ART and of ART Initiation on Outcome of HIV-Associated Tuberculosis
Authors: Girardi Enrico , Palmieri Fabrizio , Angeletti Claudio , Vanacore Paola , Matteelli Alberto , Gori Andrea , Carbonara Sergio , Ippolito Giuseppe
Published: March 2012

Background. Combination antiretroviral therapy (cART) has progressively decreased mortality of HIV-associated tuberculosis .To date, however, limited data on tuberculosis treatment outcomes among coinfected patients who are not ART-naive at the time of tuberculosis diagnosis are available.Methods. A multicenter, observational study enrolled 246 HIV-infected patients diagnosed with tuberculosis, in 96 Italian infectious diseases hospital units, who started tuberculosis treatment. A polytomous logistic regression model was used to identify baseline factors associated with the outcome. A Poisson regression model was used to explain the effect of ART during tuberculosis treatment on mortality, as a time-varying covariate, adjusting for baseline characteristics.Results. Outcomes of tuberculosis treatment were as follows: 130 (52.8%) were successfully treated, 36 (14.6%) patients died in a median time of 2 months (range: 0–16), and 80 (32.6%) had an unsuccessful outcome. Being foreign born or injecting drug users was associated with unsuccessful outcomes. In multivariable Poisson regression, cART during tuberculosis treatment decreased the risk of death, while this risk increased for those who were not ART-naive at tuberculosis diagnosis.Conclusions. ART during tuberculosis treatment is associated with a substantial reduction of death rate among HIV-infected patients. However, patients who are not ART-naive when they develop tuberculosis remain at elevated risk of death.
Plasticity of Adult Sensorimotor System in Severe Brain Infarcts: Challenges and Opportunities
Authors: Sterr Annette , Conforto Adriana Bastos
Published: March 2012

Functional reorganization forms the critical mechanism for the recovery of function after brain damage. These processes are driven by inherent changes within the central nervous system (CNS) triggered by the insult and further depend on the neural input the recovering system is processing. Therefore these processes interact with not only the interventions a patient receives, but also the activities and behaviors a patient engages in. In recent years, a wide range of research programs has addressed the association between functional reorganization and the spontaneous and treatment-induced recovery. The bulk of this work has focused on upper-limb and hand function, and today there are new treatments available that capitalize on the neuroplasticity of the brain. However, this is only true for patients with mild to moderated impairments; for those with very limited hand function, the basic understanding is much poorer and directly translates into limited treatment opportunities for these patients. The present paper aims to highlight the knowledge gap on severe stroke with a brief summary of the literature followed by a discussion of the challenges involved in the study and treatment of severe stroke and poor long-term outcome.
Rapid, Simultaneous Detection ofClostridium sordelliiandClostridium perfringensin Archived Tissues by a Novel PCR-Based Microsphere Assay: Diagnostic Implications for Pregnancy-Associated Toxic Shock Syndrome Cases
Authors: Bhatnagar Julu , DeLeon-Carnes Marlene , Kellar Kathryn L. , Bandyopadhyay Kakali , Antoniadou Zoi-Anna , Shieh Wun-Ju , Paddock Christopher D. , Zaki Sherif R.
Published: March 2012

Clostridium sordelliiandClostridium perfringensare infrequent human pathogens; however, the case-fatality rates for the infections are very high, particularly in obstetricC. sordelliiinfections (>90%). Deaths fromClostridium sordelliiandClostridium perfringenstoxic shock (CTS) are sudden, and diagnosis is often challenging. Formalin-fixed, paraffin-embedded (FFPE) tissues usually are the only specimens available for sudden fatal cases, and immunohistochemistry (IHC) for Clostridia is generally performed but it cannot identify species. A clear need exists for a rapid, species-specific diagnostic assay for FFPE tissues. We developed a duplex PCR-based microsphere assay for simultaneous detection ofC. sordelliiandC. perfringensand evaluated DNA extracted from 42Clostridiumisolates and FFPE tissues of 28 patients with toxic shock/endometritis (20 CTS, 8 non-CTS, as confirmed by PCR and sequencing). The microsphere assay correctly identifiedC. sordelliiandC. perfringensin all known isolates and in all CTS patients (10C. sordellii, 8C. perfringens, 2 both) and showed 100% concordance with PCR and sequencing results. The microsphere assay is a rapid, specific, and cost-effective method for the diagnosis of CTS and offers the advantage of simultaneous testing forC. sordelliiandC. perfringensin FFPE tissues using a limited amount of DNA.
Will Hsp90 Inhibitors Prove Effective in BRAF-Mutant Melanomas?
Authors: Catalanotti Federica , Solit David B.
Published: March 2012

The RAF inhibitor vemurafenib has unprecedented activity in BRAF-mutant melanomas, but resistance invariably develops. As Hsp90 is required for the stability of several of the oncoproteins that mediate RAF inhibitor resistance, inhibitors of this cellular chaperone may be effective in patients with intrinsic or acquired resistance to RAF inhibitors. Clin Cancer Res; 18(9); 2420–2. ©2012 AACR.
Therapeutic Significance of Estrogen Receptor β Agonists in Gliomas
Authors: Sareddy Gangadhara R. , Nair Binoj C. , Gonugunta Vijay K. , Zhang Quan-guang , Brenner Andrew , Brann Darrell W. , Tekmal Rajeshwar Rao , Vadlamudi Ratna K.
Published: March 2012

Gliomas are the most common and devastating central nervous system neoplasms. A gender bias exists in their development: females are at lower risk than males, implicating estrogen-mediated protective effects. Estrogen functions are mediated by two estrogen receptor (ER) subtypes: ERα, which functions as tumor promoter, and ERβ, which functions as tumor suppressor. We examined the potential use of ERβ agonists as a novel therapeutic to curb the growth of gliomas. Western analysis of six glioma model cells showed detectable expression of ERβ with little or no ERα. Treatment of glioma cells with ERβ agonists resulted in significant decrease in proliferation. Immunohistochemical analysis of tumor tissues revealed that ERβ expression is downregulated in high-grade gliomas. We found that ERβ agonists promote both expression and tumor-suppressive functions of ERβ in glioma cells. Liquiritigenin, a plant-derived ERβ agonist significantly reduced in vivo tumor growth in a xenograft model. Compared with control mice, animals treated with liquiritigenin had greater than 50% reduction in tumor volume and size. Immunohistochemical analysis of tumors revealed a significant increase in the nuclear ERβ expression with a concomitant decrease in cell proliferation in the liquiritigenin-treated group. Our results suggest that ERβ signaling has a tumor-suppressive function in gliomas. Because ERβ agonists are currently in clinical trials and are well tolerated with fewer side effects, identification of an ERβ agonist as a therapeutic agent can be readily extended to clinical use with current chemotherapies, providing an additional tool for enhancing survival in glioma patients. Mol Cancer Ther; 11(5); 1174–82. ©2012 AACR.
Evading Pgp Activity in Drug-Resistant Cancer Cells: A Structural and Functional Study of Antitubulin Furan Metotica Compounds
Authors: Nguyen Tam Luong , Cera Maria Rosaria , Pinto Andrea , Lo Presti Leonardo , Hamel Ernest , Conti Paola , Gussio Rick , De Wulf Peter
Published: March 2012

Tumor resistance to antitubulin drugs resulting from P-glycoprotein (Pgp) drug-efflux activity, increased expression of the βIII tubulin isotype, and alterations in the drug-binding sites are major obstacles in cancer therapy. Consequently, novel antitubulin drugs that overcome these challenges are of substantial interest. Here, we study a novel chemotype named furan metotica that localizes to the colchicine-binding site in β-tubulin, inhibits tubulin polymerization, and is not antagonized by Pgp. To elucidate the structure–activity properties of this chiral chemotype, the enantiomers of its most potent member were separated and their absolute configurations determined by X-ray crystallography. Both isomers were active and inhibited all 60 primary cancer cell lines tested at the U.S. National Cancer Institute. They also efficiently killed drug-resistant cancer cells that overexpressed the Pgp drug-efflux pump 106-fold. In vitro, the R-isomer inhibited tubulin polymerization at least 4-fold more potently than the S-isomer, whereas in human cells the difference was 30-fold. Molecular modeling showed that the two isomers bind to β-tubulin in distinct manners: the R-isomer binds in a colchicine-like mode and the S-isomer in a podophyllotoxin-like fashion. In addition, the dynamic binding trajectory and occupancy state of the R-isomer were energetically more favorable then those of the S-isomer, explaining the observed differences in biologic activities. The ability of a racemic drug to assume the binding modes of two prototypical colchicine-site binders represents a novel mechanistic basis for antitubulin activity and paves the way toward a comprehensive design of novel anticancer agents. Mol Cancer Ther; 11(5); 1103–11. ©2012 AACR.
Negative Feedback and Adaptive Resistance to the Targeted Therapy of Cancer
Authors: Chandarlapaty Sarat
Published: March 2012

Mutational activation of growth factor signaling pathways is commonly observed and often necessary for oncogenic transformation. Under physiologic conditions, these pathways are subject to tight regulation through negative feedback, which limits the extent and duration of signaling events after physiologic stimulation. Until recently, the role of these negative feedback pathways in oncogene-driven cancers has been poorly understood. In this review, I discuss the evidence for the existence and relevance of negative feedback pathways within oncogenic signaling networks, the selective advantages such feedback pathways may confer, and the effects such feedback might have on therapies aimed at inhibiting oncogenic signaling.

Sigificance: Negative feedback pathways are ubiquitous features of growth factor signaling networks. Because growth factor signaling networks play essential roles in the majority of cancers, their therapeutic targeting has become a major emphasis of clinical oncology. Drugs targeting these networks are predicted to inhibit the pathway but also to relieve the negative feedback. This loss of negative feedback can itself promote oncogenic signals and cancer cell survival. Drug-induced relief of feedback may be viewed as one of the major consequences of targeted therapy and a key contributor to therapeutic resistance. Cancer Discov; 2(4): 311–9. ©2012 AACR.
Anhedonia in Borderline Personality Disorder and Its Relation to Symptoms of Impulsivity
Authors: Marissen Marlies A.E. , Arnold Nienke , Franken Ingmar H.A.
Published: March 2012

Background: Patients with borderline personality disorder (BPD) report strong negative affect and show impulsive, disruptive behaviors. The role of anhedonia, or the inability to experience positive affect, has been less examined in BPD. The present study examined the role of anhedonia in BPD patients and its relation to symptoms of impulsivity. Sampling and Methods: Anhedonia, affect, impulsivity and BPD symptoms were measured in BPD patients and healthy control participants. Results: It was found that BPD patients showed abnormally high anhedonia levels. In addition, anhedonia was found to be positively related to dysfunctional impulsivity in the BPD patient group, while in the control group, anhedonia was related to withdrawal behaviors. A strong relation was found between anhedonia and BPD symptoms, emphasizing the relevance of anhedonia as an important symptom of BPD. Finally, anhedonia was found to be an important contributor to the severity of borderline symptoms, independently of other factors such as affect and impulsivity. Conclusions: The results underline that anhedonia might be an important but currently overlooked feature of BPD. The results further suggest that anhedonia is associated with the impulsive behaviors that are typically observed in borderline patients.
Opticochiasmatic Apoplexy in a Five-Year-Old
Authors: Ball Bret Gene , Wetmore Cynthia , Giannini Caterina , Wetjen Nicolas M. , Meyer Fredric B.
Published: March 2012

A 5-year-old female presented to the emergency department with a 24-hour history of nausea, vomiting and mental status changes. Imaging demonstrated hemorrhage from a suprasellar mass consistent with an optic nerve glioma. The patient was taken to surgery for an open biopsy and hematoma evacuation. Pathology revealed a grade 3 fibrillary astrocytoma. She was subsequently treated with carboplatin and vincristine and is now 2 years out without evidence of recurrence. Apoplexy is a rare presentation for an optic pathway glioma. To the authors’ knowledge, this is the first reported case in the pediatric population. Clinical presentation appears similar to the symptoms observed in pituitary apoplexy. Timely surgery should be directed at obtaining diagnostic tissue, prevention of long-term nervous system damage and evacuation of the hematoma where feasible.
Precise Local Resection for Hepatocellular Carcinoma Based on Tumor-Surrounding Vascular Anatomy Revealed by 3D Analysis
Authors: Wang Yi , Zhang Youlei , Peitgen Heinz-Otto , Schenk Andrea , Yuan Lei , Wei Gongtian , Sun Yanfu
Published: March 2012

Purposes: Local resection for hepatocellular carcinoma (HCC) has been traditionally performed non-anatomically. The purpose of this study is to evaluate the feasibility of precise local resection of HCC according to the anatomy of tumor-surrounding vessels revealed by three-dimensional (3D) analysis technique. Methods: The CT datasets of the livers of the patients with HCC were analyzed three-dimensionally. The tumor-bearing vessels were identified and virtually resected, and the depending parenchymal volume was calculated for definition of an optimal liver division plane. The actual local resections were then carried out according to the simulations. Results: Precise local resection based on tumor-surrounding vascular anatomy was performed in 13 HCC patients. Both resection margin and volume were significantly correlated with those predicted by preoperative simulations. After precise local resection, neither ischemia nor congestion was observed in the remnant livers. All patients obtained adequate resection margins, without recurrences in the resection sites after a median follow-up time of 18 months. Conclusions: Local resection for HCC can be carried out precisely according to the anatomy of tumor-surrounding vessels when guided by a 3D analysis. This precise procedure will enhance both the accuracy and safety of traditional local resection.
Maternal High-Fat Diet Programs for Metabolic Disturbances in Offspring despite Leptin Sensitivity
Authors: Volpato Ana Maria , Schultz Alini , Magalhães-da-Costa Eduardo , Correia Marcelo Lima de Gusmão , Águila Márcia Barbosa , Mandarim-de-Lacerda Carlos Alberto
Published: March 2012

A fatty diet during pregnancy in mouse dams causes metabolic abnormalities (similar to metabolic syndrome in humans) in the rodents’ offspring. We tested the hypothesis that the offspring of dams fed a high-fat diet during pregnancy and lactation develop metabolic abnormalities and leptin resistance. Pregnant C57BL/6 mice (n = 20) were fed either standard chow (SC; 19% fat) or a high-fat diet (HF; 49% fat). After weaning, male offspring were divided into four groups, according to the diet of dams and offspring: SC(dams)/SC(offspring), SC/HF, HF/SC and HF/HF (n = 30/group). For a metabolic analysis, we evaluated body mass, fat mass depots, blood plasma and adipocyte structure at 12 weeks of age. To analyse leptin sensitivity, each group was divided into two groups (vehicle or leptin) to identify the feeding response and pSTAT3 expression after acute intracerebroventricular (ICV) treatment. The offspring of mothers fed a high-fat diet presented increased body mass and visceral fat, adipocyte hypertrophy and insulin resistance. This phenotype was not associated with central leptin resistance. Thus, maternal programming by HF predisposes offspring to metabolic abnormalities despite leptin sensitivity.
Gorham-Stout Disease and Cerebrospinal Fluid Otorrhea
Authors: Hernández-Marqués Carmen , Serrano González Ana , Cordobés Ortega Francisco , Alvarez-Coca Javier , Sirvent Cerda Sara , Carceller Lechón Fernando , Azorín Cuadrillero Daniel
Published: March 2012

Objective and Importance: Gorham-Stout disease is a rare entity characterized by vascular proliferation causing local destruction of bone tissue. Owing to its low incidence and variable clinical presentation, the diagnosis requires a high degree of awareness by the clinician. Clinical Presentation: We present the case of a 2-year-old boy diagnosed of Gorham-Stout syndrome with involvement of the temporal bone and secondary cerebrospinal fluid (CSF) leakage. Intervention: Because of the CSF leakage, the patient required two surgical interventions. The second intervention included mastectomy and placement of a patch and a lumbar drainage device during 50 days, after which the leakage ceased. Conclusion: Gorham-Stout disease is a rare condition that can affect the skull base and even present with CSF leakage.
Symptomatic Apoplexy in Intramedullary Ependymoma: A Report of a Pediatric Patient
Authors: Mohindra Sandeep , Rane Swapnil , Gupta Sunil Kumar
Published: March 2012

Spinal intramedullary ependymomas often harbor clinically asymptomatic intratumoral bleeds. Such tumors presenting with apoplectic events have not been described in the literature. The authors report on a 2-year-old female who presented with sudden loss of sensorimotor functions below the thoracic spine as a consequence of hemorrhage within an intramedullary ependymoma. The clinical, radiological, and surgical findings are described. Gross total resection provided near-normal spinal functions in the present case.
Caffeine induces endothelial tissue factor expression via phosphatidylinositol 3-kinase inhibition
Authors: Holy Erik W. , Camici Giovanni G. , Akhmedov Alexander , Stämpfli Simon F. , Stähli Barbara E. , von Rickenbach Bettina , Breitenstein Alexander , Greutert Helen , Yang Zhihong , Lüscher Thomas F. , Gebhard Cathérine , Tanner Felix C.
Published: March 2012

Tissue factor (TF) is the key activator of coagulation and is involved in acute coronary syndromes. Caffeine is often reported to increase cardiovascular risk; however, its effect on cardiovascular morbidity and mortality is controversial. Hence, this study was designed to investigate the impact of caffeine on endothelial TF expression in vitro. Caffeine concentration-dependently enhanced TF protein expression and surface activity in human endothelial cells stimulated by tumour necrosis factor (TNF)-α or thrombin. Caffeine inhibited phosphatidylinositol 3-kinase (PI3K) activity and this effect was comparable to that of the known PI3K inhibitor LY294002. Consistently, treatment of endothelial cells with LY294002 enhanced TNF-α induced TF expression to a similar extent as caffeine, and adenoviral expression of the active PI3K mutant (p110) reversed the effect of both caffeine and LY294002 on TF expression. Caffeine and LY294002 increased DNA binding capacity of the transcription factor nuclear factor κB, whereas the activation pattern of mitogen-activated protein kinases (MAPK) remained unaltered. Luciferase reporter assay revealed a caffeine dependent activation of the TF promoter, and RT-PCR revealed a dose dependent increase in TF mRNA levels when stimulated with caffeine in the presence of TNF-α. In conclusion, caffeine enhances TNF-α-induced endothelial TF protein expression as well as surface activity by inhibition of PI3K signalling. Since the caffeine concentrations applied in the present study are within the plasma range measured in humans, our findings indicate that caffeine enhances the prothrombotic potential of endothelial cells and underscore the importance of PI3K in mediating these effects.
Impact of dabigatran on a large panel of routine or specific coagulation assays
Authors: Robert Séverine , Chatelain Christian , Douxfils Jonathan , Mullier François , Chatelain Bernard , Dogné Jean-Michel
Published: March 2012

Due to low bioavailability and high inter-individual variability, monitoring of dabigatran may be required in specific situations to prevent the risk of bleedings or thrombosis. The aim of the study was to determine which coagulation assay(s) could be used to assess the impact of dabig-atran on secondary haemostasis. Dabigatran was spiked at concentrations ranging from 4.7 ng/ml to 943.0 ng/ml in pooled citrated human platelet-poor plasma. The following clotting assays were performed: prothrombin time (PT); activated partial thromboplastin time (aPTT); thrombin time (TT); ecarin clotting time (ECT); ecarin chromo-genic assay (ECA); prothrombinase-induced clotting time (PiCT); activated clotting time (ACT); Hemoclot Thrombin Inhibitor (HTI) and thrombin generation assay (TGA). A concentration-dependent prolongation of PT, dPT, and aPTT was observed with aPTT being the more sensitive test. The results varied mostly due to the clotting reagent. HTI, ECT and TGA were the most sensitive tests but are not available 24 hours a day. In addition, HTI showed a linear correlation with a good reproduci-bility. Dabigatran induced a concentration-dependent delay and inhibition of tissue factor-induced TGA. Cut-offs related with higher risk of bleedings or thrombosis were defined for each reagent of aPTT and HTI. In conclusion, aPTT could be used for the monitoring of dabigatran and as screening test for the risk of overdose. However, because of its higher sensitivity, good reproducibility, excellent linear correlation at all doses, its simplicity of use, and possibilities of automation, HTI should be considered as the gold-standard.
Fibrin formation by staphylothrombin facilitates Staphylococcus aureus-induced platelet aggregation
Authors: Vanassche Thomas , Kauskot Alexandre , Verhaegen Jan , Peetermans Willy , van Ryn Joanne , Schneewind Olaf , Hoylaerts Marc , Verhamme Peter
Published: March 2012

Interactions of Staphylococcus aureus (S. aureus) and platelets play an important role in the pathogenesis of intravascular infections such as infective endocarditis (IE). A typical feature of S. aureus is the ability to generate thrombin activity through the secretion of two prothrombin activating molecules, staphylocoagulase and von Willebrand factor-binding protein (vWbp), which bind to human prothrombin to form the enzymatically active staphylothrombin complex. The role of staphylothrombin in the interaction between S. aureus and platelets has not yet been studied. We found that in contrast with thrombin, staphylothrombin did not directly activate human platelets. However, the staphylothrombin-mediated conversion of fibrinogen to fibrin initiated platelet aggregation and secondary activation and facilitated S. aureus-platelet interactions. Both the genetic absence of staphylocoagulase and vWbp and pharmacological inhibition of staphylothrombin increased the lag time to aggregation, and reduced platelet trapping by S. aureus in high shear stress conditions. The combined inhibition of staphylothrombin and immunoglobulin binding to platelets completely abolished the ability of S. aureus to aggregate platelets in vitro. In conclusion, although staphylothrombin did not directly activate platelets, the formation of a fibrin scaffold facilitated bacteria-platelet interaction, and the inhibition of staphylothrombin resulted in a reduced activation of platelets by S. aureus.
Anxiety Sensitivity Moderates Prognostic Importance of Rhythm-Control Versus Rate-Control Strategies in Patients With Atrial Fibrillation and Congestive Heart Failure
Authors: Frasure-Smith Nancy , Lespérance François , Talajic Mario , Khairy Paul , Dorian Paul , O’Meara Eileen , Roy Denis
Published: March 2012

Background—

Patients with high anxiety sensitivity (AS) become extremely anxious with heart rate increases, palpitations, and symptoms of psychological arousal. AS predicts panic attacks. In atrial fibrillation (AF), AS correlates with symptom preoccupation and reduced quality of life. We assessed whether AS is associated with outcomes of rhythm-control versus rate-control in congestive heart failure (CHF) patients with AF.

Methods and Results—

Before random assignment, 933 participants (172 women) in the Atrial Fibrillation and Congestive Heart Failure Trial completed the Anxiety Sensitivity Inventory (ASI). Cox proportional hazards models showed no main effects of treatment (
P
=0.61) or AS (
P
=0.72) for time to cardiovascular death, but these factors interacted significantly (
P
=0.020). High AS patients (upper quartile, ASI ≥33) randomly assigned to rhythm-control had significantly lower cardiovascular mortality than those receiving rate-control (hazard ratio, 0.54; 95% confidence interval, 0.32–0.93;
P
=0.022). With lower ASI scores (<33), treatments did not differ (hazard ratio, 1.12; 95% confidence interval, 0.83–1.51;
P
=0.46). The interaction between treatment and dichotomized ASI scores remained significant (
P
=0.009) after adjustment for covariates including age, sex, hypertension, diabetes, creatinine, ejection fraction, time since first diagnosis of AF, New York Heart Association functional class, depression symptoms, marital status, and baseline β-blockers, angiotensin-converting enzyme inhibitors, oral anticoagulants, and implantable cardioverter-defibrillators.

Conclusions—

Atrial fibrillation and congestive heart failure patients with high AS had better long-term prognosis with rhythm- than rate-control. If replicated, AS should be considered in treatment selection. Research is also needed concerning mechanisms and possible joint AS-AF treatments.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT88597077.
Renal Dysfunction in Patients With Heart Failure With Preserved Versus Reduced Ejection Fraction
Authors: McAlister Finlay A. , Ezekowitz Justin , Tarantini Luigi , Squire Iain , Komajda Michel , Bayes-Genis Antoni , Gotsman Israel , Whalley Gillian , Earle Nikki , Poppe Katrina K. , Doughty Robert N. ,   Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) Investigators
Published: March 2012

Background—

Prior studies in heart failure (HF) have used the Modification of Diet in Renal Disease (MDRD) equation to calculate estimated glomerular filtration rate (eGFR). The Chronic Kidney Disease-Epidemiology Collaboration Group (CKD-EPI) equation provides a more-accurate eGFR than the MDRD when compared against the radionuclide gold standard. The prevalence and prognostic import of renal dysfunction in HF if the CKD-EPI equation is used rather than the MDRD is uncertain.

Methods and Results—

We used individual patient data from 25 prospective studies to stratify patients with HF by eGFR using the CKD-EPI and the MDRD equations and examined survival across eGFR strata. In 20 754 patients (15 962 with HF with reduced ejection fraction [HF-REF] and 4792 with HF with preserved ejection fraction [HF-PEF]; mean age, 68 years; deaths per 1000 patient-years, 151; 95% CI, 146–155), 10 589 (51%) and 11 422 (55%) had an eGFR <60 mL/min using the MDRD and CKD-EPI equations, respectively. Use of the CKD-EPI equation resulted in 3760 (18%) patients being reclassified into different eGFR risk strata; 3089 (82%) were placed in a lower eGFR category and exhibited higher all-cause mortality rates (net reclassification improvement with CKD-EPI, 3.7%; 95% CI, 1.5%–5.9%). Reduced eGFR was a stronger predictor of all-cause mortality in HF-REF than in HF-PEF.

Conclusions—

Use of the CKD-EPI rather than the MDRD equation to calculate eGFR leads to higher estimates of renal dysfunction in HF and a more-accurate categorization of mortality risk. Renal function is more closely related to outcomes in HF-REF than in HF-PEF.
Asymmetric Chromatid Segregation in Cardiac Progenitor Cells Is Enhanced by Pim-1 Kinase
Authors: Sundararaman Balaji , Avitabile Daniele , Konstandin Mathias H. , Cottage Christopher T. , Gude Natalie , Sussman Mark A.
Published: March 2012

Rationale:

Cardiac progenitor cells (CPCs) in the adult heart are used for cell-based treatment of myocardial damage, but factors determining stemness, self-renewal, and lineage commitment are poorly understood. Immortal DNA strands inherited through asymmetric chromatid segregation correlate with self-renewal of adult stem cells, but the capacity of CPCs for asymmetric segregation to retain immortal strands is unknown. Cardioprotective kinase Pim-1 increases asymmetric cell division in vivo, but the ability of Pim-1 to enhance asymmetric chromatid segregation is unknown.

Objective:

We aimed to demonstrate immortal strand segregation in CPCs and the enhancement of asymmetric chromatid distribution by Pim-1 kinase.

Methods and Results:

Asymmetric segregation is tracked by incorporation of bromodeoxyuridine. The CPC DNA was labeled for several generations and then blocked in second cytokinesis during chase to determine distribution of immortal versus newly synthesized strands. Intensity ratios of binucleated CPCs with bromodeoxyuridine of ≥70:30 between daughter nuclei indicative of asymmetric chromatid segregation occur with a frequency of 4.57, and asymmetric chromatid segregation is demonstrated at late mitotic phases. Asymmetric chromatid segregation is significantly enhanced by Pim-1 overexpression in CPCs (9.19 versus 4.79 in eGFP-expressing cells;
P
=0.006).

Conclusions:

Asymmetric segregation of chromatids in CPCs is increased nearly two-fold with Pim-1 kinase overexpression, indicating that Pim-1 promotes self-renewal of stem cells.
Predictors of Rapid Brain Imaging in Acute Stroke
Authors: Kelly Adam G. , Hellkamp Anne S. , Olson DaiWai , Smith Eric E. , Schwamm Lee H.
Published: March 2012

Background and Purpose—

National guidelines recommend patients with acute stroke undergo brain imaging within 25 minutes of emergency department arrival. Delayed brain imaging may reduce the effectiveness of thrombolysis or render patients ineligible.

Methods—

Data from the Get With The Guidelines–Stroke program from 2003 to 2009 were analyzed to determine overall imaging rates, temporal trends, and predictive variables associated with door-to-imaging times in patients who presented to an emergency department within 2 hours of stroke symptom onset and did not have clear reasons for withholding thrombolysis. Multivariable logistic regression adjusting for within-hospital clustering was performed to identify independent predictors of brain imaging within 25 minutes of emergency department arrival.

Results—

Brain imaging was performed within 25 minutes in 41.7% of patients. Rates of imaging within 25 minutes increased from 2003 to 2009 (33.3%–44.5%). In the multivariable model, the following variables were associated with less likelihood of imaging being completed within 25 minutes: age >70 years; female gender; nonwhite race; history of diabetes, peripheral vascular disease, or prosthetic heart valve; transportation other than ambulance; arrival >60 minutes after symptom onset; and hospital location in the Northeast. Patients with National Institutes of Health Stroke Scale scores of 16 to 25 (compared with other strata) were most likely to have imaging completed within 25 minutes.

Conclusions—

Most patients with acute stroke symptoms do not have brain imaging performed within the recommended 25 minutes. Future quality improvement initiatives should focus on reducing door-to-imaging times with a specific emphasis on the predictive variables identified in this analysis.
Single-Center Experience of Cerebral Artery Thrombectomy Using the TREVO Device in 60 Patients With Acute Ischemic Stroke
Authors: San Román Luis , Obach Victor , Blasco Jordi , Macho Juan , Lopez Antonio , Urra Xabier , Tomasello Alejandro , Cervera Alvaro , Amaro Sergio , Perandreu Joan , Branera Jordi , Capurro Sebastián , Oleaga Laura , Chamorro Angel
Published: March 2012

Background and Purpose—

We sought to explore the safety and efficacy of the new TREVO stent-like retriever in consecutive patients with acute stroke.

Methods—

We conducted a prospective, single-center study of 60 patients (mean age, 71.3 years; male 47%) with stroke lasting <8 hours in the anterior circulation (n=54) or <12 hours in the vertebrobasilar circulation (n=6) treated if CT perfusion/CT angiography confirmed a large artery occlusion, ruled out a malignant profile, or showed target mismatch if symptoms >4.5 hours. Successful recanalization (Thrombolysis In Cerebral Infarction 2b–3), good outcome (modified Rankin Scale score 0–2) and mortality at Day 90, device-related complications, and symptomatic hemorrhage (parenchymal hematoma Type 1 or parenchymal hematoma Type 2 and National Institutes of Health Stroke Scale score increment ≥4 points) were prospectively assessed.

Results—

Median (interquartile range) National Institutes of Health Stroke Scale score on admission was 18 (12–22). The median (interquartile range) time from stroke onset to groin puncture was 210 (173–296) minutes. Successful revascularization was obtained in 44 (73.3%) of the cases when only the TREVO device was used and in 52 (86.7%) when other devices or additional intra-arterial tissue-type plasminogen activator were also required. The median time (interquartile range) of the procedure was 80 (45–114) minutes. Good outcome was achieved in 27 (45%) of the patients and the mortality rate was 28.3%. Seven patients (11.7%) presented a symptomatic intracranial hemorrhage. No other major complications were detected.

Conclusions—

The TREVO device was reasonably safe and effective in patients with severe stroke. These results support further investigation of the TREVO device in multicentric registries and randomized clinical trials.
Application of the ABCD
2
Score to Identify Cerebrovascular Causes of Dizziness in the Emergency Department
Authors: Navi Babak B. , Kamel Hooman , Shah Maulik P. , Grossman Aaron W. , Wong Christine , Poisson Sharon N. , Whetstone William D. , Josephson S. Andrew , Johnston S. Claiborne , Kim Anthony S.
Published: March 2012

Background and Purpose—

Dizziness can herald a cerebrovascular event. The ABCD
2
score predicts the risk of stroke after transient ischemic attack partly by distinguishing transient ischemic attack from mimics. We evaluated whether this score would also identify cerebrovascular events among emergency department patients with dizziness.

Methods—

We retrospectively identified consecutive adults presenting to a university emergency department with a primary symptom of dizziness, vertigo, or imbalance. Two neurologists independently reviewed medical records to determine whether the presenting symptom was caused by a cerebrovascular event (ischemic stroke, transient ischemic attack, or intracranial hemorrhage). ABCD
2
scores were then assigned using clinical information from the medical record. The ability of the score to discriminate between patients with cerebrovascular events and those with other diagnoses was quantified using the c statistic.

Results—

Among 907 dizzy patients (mean age, 59 years; 58% female), 37 (4.1%) had a cerebrovascular cause, the majority of which were ischemic strokes (n=24). The median ABCD
2
score was 3 (interquartile range, 3–4). The ABCD
2
score predicted ultimate diagnosis of a cerebrovascular event (c statistic, 0.79; 95% CI, 0.73–0.85). Only 5 of 512 (1.0%) patients with a score of ≤3 had a cerebrovascular event compared to 25 of 369 patients (6.8%) with a score of 4 or 5 and 7 of 26 patients (27.0%) with a score of 6 or 7.

Conclusions—

The ABCD
2
score may provide useful information on dizzy emergency department patients at low-risk for having a cerebrovascular diagnosis and may aid frontline providers in acute management if validated prospectively.
Silent Infarcts and Cerebral Microbleeds Modify the Associations of White Matter Lesions With Gait and Postural Stability
Authors: Choi Philip , Ren Mandy , Phan Thanh G. , Callisaya Michele , Ly John V. , Beare Richard , Chong Winston , Srikanth Velandai
Published: March 2012

Background and Purpose—

Although cerebral white matter lesions (WMLs), silent infarcts (SIs), and microbleeds (MBs) are individually associated with poorer gait and balance, it is unknown if they interact. We studied the interactions of WML volume with SI and MB on gait and postural stability.

Methods—

Participants in a population-based study aged 60 to 86 years underwent brain MRI, computerized gait measurement, and a physiological profile assessment of postural stability. Segmentation procedures and standard rating methods were used to measure WML, SI, and MB. Linear regression was used to test interactions between lesions on gait and postural stability, adjusting for age, sex, and total intracranial volume.

Results—

There were 395 participants (mean age, 72 years; SD, 7.0). SIs were predominantly located in subcortical frontal white matter and in deep gray structures, and MBs were largely lobar. Participants with SI or MB had higher WML volumes than those without (
P
<0.001 and
P
=0.05, respectively). The presence of SI (
P
for interaction=0.01) or MB (
P
for interaction <0.01) magnified the adverse association of WML volume with gait. SI (
P
for interaction=0.02), but not MB, magnified the adverse association of WML volume with postural stability.

Conclusions—

Subclinical cerebrovascular lesions are adversely associated with gait and postural stability in older people in a cumulative fashion.
Changes in Western Pacific Tropical Cyclones Associated with the El Niño–Southern Oscillation Cycle
Authors: Li Richard C. Y. , Zhou Wen
Published: March 2012

This study examines the interannual variability of three groups of tropical cyclones (TCs)—super typhoons (STYs), typhoons (TYs), and tropical storms and tropical depressions (TSTDs)—and their relationship with the El Niño–Southern Oscillation (ENSO). Both wavelet analysis and correlation studies of upper-ocean heat content reveal significant differences for the three types of TCs. In particular, an increase (decrease) in the frequency of STYs is usually associated with the mature phase of El Niño (La Niña) events, while the converse is true for TSTDs. In contrast, the frequency of TYs increases (decreases) during the transition period from La Niña to El Niño (El Niño to La Niña) events. The results suggest that the timing with which ENSO impacts STYs, TYs, and TSTDs varies and that their corresponding changes in frequency closely follow the evolution of the ENSO cycle.

Empirical orthogonal function analysis is also conducted to investigate the impact of different environmental factors influenced by ENSO on TCs. The vertical wind shear and moist static energy associated with ENSO are identified as the dominant factors that control the frequency of STYs. In comparison, the frequency of TYs is found to be closely related to the relative vorticity and vertical wind shear associated with both the transition phase of ENSO and with other types of climate variability.
The Role of Windward-Side Diabatic Heating in Sierra Nevada Spillover Precipitation
Authors: Kaplan Michael L. , Vellore Ramesh K. , Marzette Phillip J. , Lewis John M.
Published: March 2012

This study focuses on the meso-α- and meso-β-scale manifestations of the latent-heat-induced reduction of windward-side blocking to two flood-producing precipitation events on the leeside of the Sierra Nevada. Two simulations were performed—one employing full microphysics [control (CTRL)] and a second in which the latent heating terms are turned off in the microphysics [no latent heating (NLH)]. The differences between the CTRL and NLH are consistent with upstream latent heating—the moist, divergent, and ascending flow dominates the leeside of the mountain range in the CTRL producing copious spillover precipitation while dry high-momentum/downslope-descending flow dominates the NLH simulation on the leeside. A comprehensive sequence of events for spillover precipitation is formulated as follows: 1) Ascent within the exit region of a polar jet streak develops in response to velocity divergence aloft. 2) This ascent phases with ascent from the windward-side flow to create a mesoscale region of heavy upslope precipitation. 3) The latent heat release from the upslope precipitation reduces the upstream static stability and blocking. 4) A mesoscale ridge in the thickness field builds in the upper troposphere and induces subgeostrophic flow in the jet’s exit region above the mountain range. 5) Adjustments to this ridge result in a cross-mountain midlevel jet that facilitates a river of midlevel moisture advected over to the leeside. 6) Stretching of moist isentropic surfaces in proximity to the plume of moisture fluxes causes destabilization on the leeside and formation of a leeside mesolow. 7) Boundary layer air accelerates into the leeside mesolow to form a mountain-parallel low-level flow.
Inertial Oscillations in Geostrophic Flow: Is the Inertial Frequency Shifted by ζ/2 or by ζ?
Authors: Chavanne Cédric P. , Firing Eric , Ascani François
Published: March 2012

The short answer to the question posed in the title is that it depends on the frame of reference chosen to describe the motions. In the inertial limit, the frequency in a rotating frame of reference corresponds to the rotation rate of the inertial current vectors relative to that frame. When described in a reference frame rotating with a geostrophic flow having a relative vertical vorticity ζ, inertial oscillations have a frequency f + ζ, equal to twice the fluid’s rotation rate around the local vertical axis. From a nonrotating frame of reference, one would measure only half this frequency; the other half arises from describing inertial motions in a reference frame rotating with the background flow. However, when described in a reference frame rotating with Earth, hence rotating at −ζ/2 relative to the geostrophic frame, inertial oscillations have a frequency reduced to f + ζ/2.
Relationships between Rain Characteristics and Environment. Part II: Atmospheric Disturbances Associated with Shallow Convection over the Eastern Tropical Pacific
Authors: Yokoyama Chie , Takayabu Yukari N.
Published: March 2012

Synoptic-scale westward-propagating disturbances over the eastern Pacific (EP) are analyzed in boreal autumn, utilizing spectral analysis, composite analysis, and energy budget analysis. The results are compared with those over the western Pacific (WP).

Spectral peaks of total precipitable water (TPW) and vertical velocity at 850 hPa (ω850), and outgoing longwave radiation (OLR) are detected at periods of ~3–7 days over the EP. Meanwhile over the WP, a spectral peak of OLR is pronounced, but peaks of TPW and ω850 are not detected. Composite analysis reveals that disturbances that have a coupled structure, with a vortex at its center near ~9°N and a mixed Rossby–gravity (MRG) wave–type disturbance, frequently exist over the EP. At the same time, the disturbances have a double-deck structure associated with divergence both in the upper and in the middle to lower troposphere. These disturbances are associated with both deep convection and congestus, which generate kinetic energy of the disturbance in the upper and in the lower troposphere, respectively.

Examining diabatic heating in relation to the coupled disturbances, deep heating with the peak at the height of ~7.5 km is greatest in the northeastern part of the vortex. The coupled MRG wave–type disturbance provides a relatively deep cross-equatorial southerly flow into the northeastern part of the vortex. It is suggested that deep rain is maintained with the existence of deep convergence produced by the coupled disturbances over the EP, where a very shallow convergence field exists on average.
Generating and Calibrating Probabilistic Quantitative Precipitation Forecasts from the High-Resolution NWP Model COSMO-DE
Authors: Bentzien Sabrina , Friederichs Petra
Published: March 2012

Statistical postprocessing is an integral part of an ensemble prediction system. This study compares methods used to derive probabilistic quantitative precipitation forecasts based on the high-resolution version of the German-focused Consortium for Small-Scale Modeling (COSMO-DE) time-lagged ensemble (COSMO-DE-TLE). The investigation covers the period from July 2008 to June 2011 for a region over northern Germany with rain gauge measurements from 445 stations. The investigated methods provide pointwise estimates of the predictive distribution using logistic and quantile regression, and full predictive distributions using parametric mixture models. All mixture models use a point mass at zero to represent the probability of precipitation. The amount of precipitation is modeled by either a gamma, lognormal, or inverse Gaussian distribution. Furthermore, an adaptive tail using a generalized Pareto distribution (GPD) accounts for a better representation of extreme precipitation. The predictive probabilities, quantiles, and distributions are evaluated using the Brier, the quantile verification, and the continuous ranked probability scores. Baseline predictions and covariates are based on first-guess estimates from the COSMO-DE-TLE. Predictive performance is largely improved by statistical postprocessing due to an increase in reliability and resolution. The mixture models show some deficiencies. The inverse Gaussian fails to provide calibrated predictive distributions, whereas the lognormal and gamma mixtures perform well within the bulk of the distribution. Both mixtures provide significantly less skill for the extremal quantiles (0.99–0.999). Their representation is largely improved by incorporating an adaptive GPD tail. Even more stable estimates are obtained if the annual cycle is included in the postprocessing and training is performed on almost 3 yr of data.
Internationalizing the curriculum: Pedagogy for social justice
Authors: Joseph Cynthia
Published: March 2012

This article examines the concept of internationalizing the curriculum in the context of Australian higher education. It draws on evidence from a research project driven by policy changes resulting from the diverse student demography. The article looks at the ways in which student diversity within the Australian higher education sector shapes academics’ pedagogical practices of internationalizing the curriculum (IoC). The author describes the process, findings and outcomes of a research project on IoC she was involved in. Interview narratives of a group of academics involved in this study are presented to highlight some of the cultural and pedagogical issues educators are engaging with in the process of knowledge production vis-a-vis IoC. Challenges of IoC and inclusive pedagogy for universities are also considered given the present market-driven goals of higher education.