bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelial cells downregulate apolipoprotein D expression in mural cells through paracrine secretion and Notch signaling
Authors: Pajaniappan Mohanasundari , Glober Nancy K. , Kennard Simone , Liu Hua , Zhao Ning , Lilly Brenda
Published: June 2011

Endothelial and mural cell interactions are vitally important for proper formation and function of blood vessels. These two cell types communicate to regulate multiple aspects of vessel function. In studying genes regulated by this interaction, we identified apolipoprotein D (APOD) as one gene that is downregulated in mural cells by coculture with endothelial cells. APOD is a secreted glycoprotein that has been implicated in governing stress response, lipid metabolism, and aging. Moreover, APOD is known to regulate smooth muscle cells and is found in abundance within atherosclerotic lesions. Our data show that the regulation of APOD in mural cells is bimodal. Paracrine secretion by endothelial cells causes partial downregulation of APOD expression. Additionally, cell contact-dependent Notch signaling plays a role. NOTCH3 on mural cells promotes the downregulation of APOD, possibly through interaction with the JAGGED-1 ligand on endothelial cells. Our results show that NOTCH3 contributes to the downregulation of APOD and by itself is sufficient to attenuate APOD transcript expression. In examining the consequence of decreased APOD expression in mural cells, we show that APOD negatively regulates cell adhesion. APOD attenuates adhesion by reducing focal contacts; however, it has no effect on stress fiber formation. These data reveal a novel mechanism in which endothelial cells control neighboring mural cells through the downregulation of APOD, which, in turn, influences mural cell function by modulating adhesion.
Discovery of shear- and side-specific mRNAs and miRNAs in human aortic valvular endothelial cells
Authors: Holliday Casey J. , Ankeny Randall F. , Jo Hanjoong , Nerem Robert M.
Published: June 2011

The role of endothelial cells (ECs) in aortic valve (AV) disease remains relatively unknown; however, disease preferentially occurs in the fibrosa. We hypothesized oscillatory shear (OS) present on the fibrosa stimulates ECs to modify mRNAs and microRNAs (miRNAs) inducing disease. Our goal was to identify mRNAs and miRNAs differentially regulated by OS and laminar shear (LS) in human AVECs (HAVECs) from the fibrosa (fHAVECs) and ventricularis (vHAVECs). HAVECs expressed EC markers as well as some smooth muscle cell markers and functionally aligned with the flow. HAVECs were exposed to OS and LS for 24 h, and total RNA was analyzed by mRNA and miRNA microarrays. We found over 700 and 300 mRNAs down- and upregulated, respectively, by OS; however, there was no side dependency. mRNA microarray results were validated for 26 of 28 tested genes. Ingenuity Pathway Analysis revealed thrombospondin 1 ( Thbs1) and NF-κB inhibitor-α ( Nfkbia) as highly connected, shear-sensitive genes. miRNA array analysis yielded 30 shear-sensitive miRNAs and 3 side-specific miRNAs. miRNA validation confirmed 4 of 17 shear-sensitive miRNAs and 1 of 3 side-dependent miRNAs. Using miRWalk and several filtering steps, we identified shear-sensitive mRNAs potentially targeted by shear-sensitive miRNAs. These genes and signaling pathways could act as therapeutic targets of AV disease.
Temperature effects on morphological integrity and Ca2+signaling in freshly isolated murine feed artery endothelial cell tubes
Authors: Socha Matthew J. , Hakim Chady H. , Jackson William F. , Segal Steven S.
Published: June 2011

To study Ca2+signaling in the endothelium of murine feed arteries, we determined the in vitro stability of endothelial cell (EC) tubes freshly isolated from abdominal muscle feed arteries of male and female C57BL/6 mice (5–9 mo, 25–35 g). We tested the hypothesis that intracellular Ca2+concentration ([Ca2+]i) responses to muscarinic receptor activation would increase with temperature. Intact EC tubes (length: 1–2 mm, width: 65–80 μm) were isolated using gentle enzymatic digestion with trituration to remove smooth muscle cells. A freshly isolated EC tube was secured in a chamber and superfused at 24 (room temperature), 32, or 37°C. Using fura-2 dye, [Ca2+]iwas monitored (ratio of fluorescence at 340- to 380-nm wavelength) at rest and in response to bolus doses of ACh (20 nmol to 200 μmol). The morphological integrity of EC tubes was preserved at 24 and 32°C. Based on the Ca2+Kdvalues we determined for fura-2 (174 nM at 24°C and 146 nM at 32°C), resting [Ca2+]iremained stable for 180 min at both 24 and 32°C (27 ± 4 and 34 ± 2 nM, respectively), with peak responses to ACh (20 μmol) increasing from ∼220 nM at 24°C to ∼500 nM at 32°C ( P < 0.05). There was no difference in responses to ACh between EC tubes from male versus female mice. When EC tubes were maintained at 37°C (typical in vivo temperature), resting [Ca2+]iincreased by ∼30% within 15 min, and gaps formed between individual ECs as they retracted and extruded dye, precluding further study. We conclude that EC tubes enable Ca2+signaling to be evaluated in the freshly isolated endothelium of murine feed arteries. While Ca2+responses are enhanced by approximately twofold at 32 versus 24°C, the instability of EC tubes at 37°C precludes their study at typical body temperature.
In vivo assessment of neurocardiovascular regulation in the mouse: principles, progress, and prospects
Authors: Young Colin N. , Davisson Robin L.
Published: June 2011

A growing body of evidence indicates that a number of common complex diseases, including hypertension, heart failure, and obesity, are characterized by alterations in central neurocardiovascular regulation. However, our understanding of how changes within the central nervous system contribute to the development and progression of these and other diseases remains unclear. As with many areas of cardiovascular research, the mouse has emerged as a key species for investigations of neuroregulatory processes because of its amenability to highly specific genetic manipulations. In parallel with the development of increasingly sophisticated murine models has come the miniaturization and advancement in methodologies for in vivo assessment of neurocardiovascular end points in the mouse. The following brief review will focus on a number of key direct and indirect experimental approaches currently in use, including measurement of arterial blood pressure, assessment of cardiovascular autonomic control, and evaluation of arterial baroreflex function. The advantages and limitations of each methodology are highlighted to allow for a critical evaluation by the reader when considering these approaches.
Stiffness and heterogeneity of the pulmonary endothelial glycocalyx measured by atomic force microscopy
Authors: O'Callaghan Ryan , Job Kathleen M. , Dull Randal O. , Hlady Vladimir
Published: June 2011

The mechanical properties of endothelial glycocalyx were studied using atomic force microscopy with a silica bead (diameter ∼18 μm) serving as an indenter. Even at indentations of several hundred nanometers, the bead exerted very low compressive pressures on the bovine lung microvascular endothelial cell (BLMVEC) glycocalyx and allowed for an averaging of stiffness in the bead-cell contact area. The elastic modulus of BLMVEC glycocalyx was determined as a pointwise function of the indentation depth before and after enzymatic degradation of specific glycocalyx components. The modulus-indentation depth profiles showed the cells becoming progressively stiffer with increased indentation. Three different enzymes were used: heparinases III and I and hyaluronidase. The main effects of heparinase III and hyaluronidase enzymes were that the elastic modulus in the cell junction regions increased more rapidly with the indentation than in BLMVEC controls, and that the effective thickness of glycocalyx was reduced. Cytochalasin D abolished the modulus increase with the indentation. The confocal profiling of heparan sulfate and hyaluronan with atomic force microscopy indentation data demonstrated marked heterogeneity of the glycocalyx composition between cell junctions and nuclear regions.
Alterations of GABAergic Signaling in Autism Spectrum Disorders
Authors: Pizzarelli Rocco , Cherubini Enrico
Published: June 2011

Autism spectrum disorders (ASDs) comprise a heterogeneous group of pathological conditions, mainly of genetic origin, characterized by stereotyped behavior, marked impairment in verbal and nonverbal communication, social skills, and cognition. Interestingly, in a small number of cases, ASDs are associated with single mutations in genes encoding for neuroligin-neurexin families. These are adhesion molecules which, by regulating transsynaptic signaling, contribute to maintain a proper excitatory/inhibitory (E/I) balance at the network level. Furthermore, GABA, the main inhibitory neurotransmitter in adult life, at late embryonic/early postnatal stages has been shown to depolarize and excite targeted cell through an outwardly directed flux of chloride. The depolarizing action of GABA and associated calcium influx regulate a variety of developmental processes from cell migration and differentiation to synapse formation. Here, we summarize recent data concerning the functional role of GABA in building up and refining neuronal circuits early in development and the molecular mechanisms regulating the E/I balance. A dysfunction of the GABAergic signaling early in development leads to a severe E/I unbalance in neuronal circuits, a condition that may account for some of the behavioral deficits observed in ASD patients.
Polonium and Lung Cancer
Authors: Zagà Vincenzo , Lygidakis Charilaos , Chaouachi Kamal , Gattavecchia Enrico
Published: June 2011

The alpha-radioactive polonium 210 (Po-210) is one of the most powerful carcinogenic agents of tobacco smoke and is responsible for the histotype shift of lung cancer from squamous cell type to adenocarcinoma. According to several studies, the principal source of Po-210 is the fertilizers used in tobacco plants, which are rich in polyphosphates containing radio (Ra-226) and its decay products, lead 210 (Pb-210) and Po-210. Tobacco leaves accumulate Pb-210 and Po-210 through their trichomes, and Pb-210 decays into Po-210 over time. With the combustion of the cigarette smoke becomes radioactive and Pb-210 and Po-210 reach the bronchopulmonary apparatus, especially in bifurcations of segmental bronchi. In this place, combined with other agents, it will manifest its carcinogenic activity, especially in patients with compromised mucous-ciliary clearance. Various studies have confirmed that the radiological risk from Po-210 in a smoker of 20 cigarettes per day for a year is equivalent to the one deriving from 300 chest X-rays, with an autonomous oncogenic capability of 4 lung cancers per 10000 smokers. Po-210 can also be found in passive smoke, since part of Po-210 spreads in the surrounding environment during tobacco combustion. Tobacco manufacturers have been aware of the alpha-radioactivity presence in tobacco smoke since the sixties.
Potential Prostate Cancer Drug Target: Bioactivation of Androstanediol by Conversion to Dihydrotestosterone
Authors: Mohler James L. , Titus Mark A. , Wilson Elizabeth M.
Published: June 2011

High-affinity binding of dihydrotestosterone (DHT) to the androgen receptor (AR) initiates androgen-dependent gene activation, required for normal male sex development in utero, and contributes to prostate cancer development and progression in men. Under normal physiologic conditions, DHT is synthesized predominantly by 5α-reduction of testosterone, the major circulating androgen produced by the testis. During androgen deprivation therapy, intratumoral androgen production is sufficient for AR activation and prostate cancer growth, even though circulating testicular androgen levels are low. Recent studies indicate that the metabolism of 5α-androstane-3α, 17β-diol by 17β-hydroxysteroid dehydrogenase 6 in benign prostate and prostate cancer cells is a major biosynthetic pathway for intratumoral synthesis of DHT, which binds AR and initiates transactivation to promote prostate cancer growth during androgen deprivation therapy. Drugs that target the so-called backdoor pathway of DHT synthesis provide an opportunity to enhance clinical response to luteinizing-hormone–releasing hormone (LHRH) agonists or antagonists, AR antagonists, and inhibitors of 5α-reductase enzymes (finasteride or dutasteride), and other steroid metabolism enzyme inhibitors (ketoconazole or the recently available abiraterone acetate). Clin Cancer Res; 17(18); 5844–9. ©2011 AACR.
Resveratrol Selectively Induces DNA Damage, Independent of Smad4 Expression, in Its Efficacy against Human Head and Neck Squamous Cell Carcinoma
Authors: Tyagi Alpna , Gu Mallikarjuna , Takahata Takenori , Frederick Barbara , Agarwal Chapla , Siriwardana Sunitha , Agarwal Rajesh , Sclafani Robert A.
Published: June 2011

Purpose: Alterations in Smad4 signaling and its loss cause genomic instability and head and neck squamous cell carcinoma (HNSCC), suggesting that agents that target both Smad4-dependent and -independent pathways could control HNSCC.

Experimental Design: Resveratrol efficacy was evaluated against the HNSCC cells FaDu, Cal27, Det562, and Cal27-Smad4 for viability, DNA damage, cell-cycle progression, and apoptosis, as well as γ-H2AX expression, and focus formation (γ-H2AX and Brca1). Resveratrol efficacy was also examined in nude mice for FaDu xenograft growth. Xenografts were analyzed for γ-H2AX and cleaved caspase-3.

Results: Resveratrol (5–50 μmol/L) suppressed viability and induced DNA damage in FaDu and Cal27 cells but not in normal human epidermal keratinocytes and human foreskin fibroblasts, showing its selectivity toward HNSCC cells; however, Det562 cells were resistant to resveratrol even at 100 μmol/L. Cal27 cells stably transfected with Smad4 showed similar resveratrol effects as parental Cal27, indicating that a lack of resveratrol effect in Det562 cells was independent of Smad4 status in these cells. Furthermore, resveratrol caused S-phase arrest and apoptotic death of FaDu and Cal27 cells together with induction of Brca1 and γ-H2AX foci. Resveratrol (50 mg/kg body weight) treatment also inhibited FaDu tumor growth in nude mice, and γ-H2AX and cleaved caspase-3 were strongly increased in xenografts from resveratrol-treated mice compared with controls.

Conclusion: Our findings for the first time showed antiproliferative, DNA damaging, and apoptotic effects of resveratrol in HNSCC cells independent of Smad4 status, both in vitro and in vivo, suggesting that more studies are needed to establish its potential usefulness against HNSCC. Clin Cancer Res; 17(16); 5402–11. ©2011 AACR.
Functional Neuroimaging in Obsessive-Compulsive Disorder
Authors: Del Casale A. , Kotzalidis G.D. , Rapinesi C. , Serata D. , Ambrosi E. , Simonetti A. , Pompili M. , Ferracuti S. , Tatarelli R. , Girardi P.
Published: June 2011

Background and Aim: Obsessive-compulsive disorder (OCD) is a severe, highly prevalent and chronically disabling psychiatric disorder that usually emerges during childhood or adolescence. This paper aims to review the literature on functional neuroimaging in OCD, analysing the reported dysfunctional connectivity in the corticostriatothalamocortical circuitry. Method: This study included papers published in peer-reviewed journals dealing with functional imaging in OCD. Results: Striatal dysfunction, mainly of the caudate nucleus, leads to inefficient thalamic gating, resulting in hyperactivity within the orbitofrontal cortex (intrusive thoughts) and the anterior cingulate cortex (non-specific anxiety). Compulsions consist of ritualistic behaviours performed to recruit the inefficient striatum and neutralise unwanted thoughts and anxiety. Functional neuroimaging findings are discussed against the background of specific cognitive impairments, mainly regarding visuospatial processing, executive functioning and motor speed. Cognitive deficits are partial and specific, matching imaging data. Conclusions: Several studies have targeted brain regions hypothesised to be involved in the pathogenesis of OCD, showing the existence of dysfunctional connectivity in the corticostriatothalamocortical circuitry. Improvements in spatial resolution of neuroimaging techniques may contribute to a better understanding of the neurocircuitry of OCD and other anxiety disorders.
Growth Factors, Stem Cells and Bronchopulmonary Dysplasia
Authors: Alphonse Rajesh S. , Thébaud Bernard
Published: June 2011

Bronchopulmonary dysplasia (BPD) is the chronic lung disease of prematurity mainly affecting preterm infants that are born at 24–28 weeks of gestation. Surfactant therapy, antenatal steroids and incremental improvements in perinatal care have modified the pattern of injury and allowed survival of ever more immature infants, but there is still no specific treatment for BPD. As a consequence, this disorder remains the most common complication of extreme prematurity. Arrested alveolar growth and disrupted vasculogenesis, the histological hallmarks of BPD, may persist beyond childhood and lead to chronic lung diseases in adults. Recent advances in our understanding of stem cells and their potential to repair damaged organs offer the possibility for cell-based treatment for intractable diseases. This review summarizes basic concepts of stem cell biology and discusses the recent advances and challenges of stem cell-based therapies for lung diseases, with a particular focus on BPD.
Tailoring Oxygen Needs of Extremely Low Birth Weight Infants in the Delivery Room
Authors: Vento Máximo
Published: June 2011

Fetal to neonatal transition poses an extraordinary challenge for the extremely low birth weight (ELBW) neonate. Indeed a significant number of ELBW neonates will need proactive resuscitation to achieve postnatal stabilization. Positive pressure ventilation and oxygenation are the most relevant interventions in the delivery room (DR). Oxygen needs during resuscitation still represent a conundrum for neonatologists. While hyperoxemia favors oxidative stress and subsequent organ injury, hypoxemia is associated with long-term neurodevelopmental impairment. It has been shown that ELBW neonates can be successfully resuscitated with lower concentrations of oxygen as had been done traditionally. Moreover, reducing oxygen load has resulted in achievement of arterial partial pressures of oxygen at admission closer to the physiologic range, less oxidative stress and less inflammation. The availability of reference ranges for arterial oxygen saturation (SpO2) for ELBW neonates in the first 10 min after birth has been an extraordinary step forward in our ability to individually titrate oxygen needs thus avoiding the risks of both hypo- and hyperoxemia. The optimal fraction of inspired oxygen (FiO2) to initiate resuscitation and the safest SpO2 percentiles for ELBW neonates during the first minutes of life are still unknown and will need further research in the future. Until then, optimal ventilation at birth and individually tailoring FiO2 according to the nomogram seem to be the most reasonable and safe approach.
Prognostic Factors in Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib: A Retrospective Comparison with Previously Known Prognostic Models
Authors: Baek Kyung Kee , Kim Jung-Hoon , Uhm Ji Eun , Park Se Hoon , Lee Jeeyun , Park Joon Oh , Park Young Suk , Kang Won Ki , Lim Ho Yeong
Published: June 2011

Background: Sorafenib, a multitargeted tyrosine kinase inhibitor, is now the treatment of choice for systemic therapy of patients with advanced hepatocellular carcinoma (HCC). Herein, we present the clinical characteristics and outcomes of patients with advanced HCC who were treated with sorafenib. Methods: Data of 201 sorafenib-treated, metastatic HCC patients were collected from a single institution tumor registry. The primary and secondary endpoints were overall survival (OS) and failure-free survival (FFS). Results: Chronic hepatitis B was the predominant cause of HCC (84%). Of 162 evaluable patients, 4 partial responses were recorded. With a median follow-up of 15.7 months, the median FFS and OS were 2.5 months (95% CI 2.3–2.7) and 5.3 months (95% CI 4.4–6.3), respectively. In multivariate analysis, the prognostic factors associated with FFS were the presence of ascites, portal venous thrombosis, serum α-fetoprotein ≧400 ng/ml, albumin, bilirubin, tumor size and number, and performance status. Likewise, the presence of ascites, portal venous thrombosis, tumor size and number, performance status and baseline levels of α-fetoprotein, albumin and bilirubin were significantly related with OS. After adjusting for performance status, the Cancer of the Liver Italian Program scoring system and Okuda stages can better predict the hazard of failure or death than the Child-Pugh classification. Conclusions: Our results suggest that Cancer of the Liver Italian Program scores or Okuda stages, along with performance status, can be useful in stratifying patients with advanced HCC treated with sorafenib.
A High Proliferative Index of Recurrent Melanoma Is Associated with Worse Survival
Authors: Tu Ting J. , Ma Michelle W. , Monni Stefano , Rose Amy E. , Yee Herman , Darvishian Farbod , Polsky David , Berman Russell S. , Shapiro Richard L. , Pavlick Anna C. , Mazumdar Madhu , Osman Iman
Published: June 2011

Objective: Previous melanoma studies evaluating prognostic factors of survival at recurrence have focused on primary tumor characteristics and clinical variables at first recurrence. We examined the prognostic relevance of recurrent tumor proliferation. Methods: 114 melanoma patients with available recurrent tissues who were prospectively enrolled at New York University Medical Center were studied. Standard of care prognostic variables (e.g. stage at initial diagnosis and lactate dehydrogenase level) and recurrent tissue expression of proliferative marker Ki-67 were evaluated for their association with overall survival. Results: High Ki-67 expression was observed in 57 (50%) of the 114 recurrent melanomas. On univariate analysis, the median overall survival of patients whose recurrent tumors overexpressed Ki-67 was significantly shorter than that of patients whose recurrent tumors had low Ki-67 expression (3.6 vs. 9.5 years, p = 0.03). On multivariate analysis, a high proliferative index of the recurrent melanoma remained an independent predictor of worse overall survival, controlling for stage at initial diagnosis, disease-free survival, and stage at first recurrence [HR = 2.09 (95% CI 1.24–3.54), p = 0.006]. Conclusions: Our results demonstrate the prognostic relevance of tumor proliferation in recurrent melanoma patients. Data also support restratification of risk assessment upon recurrence that considers tumor biology in addition to clinical variables evaluated as part of the standard of care.
Cardiospecific microRNA Plasma Levels Correlate with Troponin and Cardiac Function in Patients with ST Elevation Myocardial Infarction, Are Selectively Dependent on Renal Elimination, and Can Be Detected in Urine Samples
Authors: Gidlöf Olof , Andersson Patrik , van der Pals Jesper , Götberg Matthias , Erlinge David
Published: June 2011

Objectives: Circulating microRNAs (miRNAs) are promising as biomarkers for various diseases. We examined the release patterns of cardiospecific miRNAs in a closed-chest, large animal ischemia-reperfusion model and in patients with ST elevation myocardial infarction (STEMI). Methods: Six anesthetized pigs were subjected to coronary occlusion-reperfusion. Plasma, urine, and clinical parameters were collected from 25 STEMI patients undergoing primary percutaneous coronary intervention. miRNA was extracted and measured with qPCR. Results: In the pig reperfusion model miR-1, miR-133a, and miR-208b increased rapidly in plasma with a peak at 120 min, while miR-499-5p remained elevated longer. In patients with STEMI all 4 miRNAs increased abruptly from 70-fold to 3,000-fold in plasma, with a peak within 12 h (p < 0.01). miR-1 and miR-133a both correlated strongly with the glomerular filtration rate (GFR), indicating renal elimination. This was confirmed by detection of miR-1 and miR-133a, but not miR-208b or miR-499-5p, in urine. Peak values of miR-208b correlated with peak troponin and the ejection fraction. Conclusion: We demonstrate a distinct and rapid increase in levels of cardiospecific miRNA in the circulation after myocardial infarction. Release of miRNAs correlated with cardiomyocyte necrosis markers, the ejection fraction, and the GFR, indicating a possible role for these molecules as biomarkers for the diagnosis of STEMI as well as the prediction of long-term complications.
Drug and Device Effects on Peak Oxygen Consumption, 6-Minute Walk Distance, and Natriuretic Peptides as Predictors of Therapeutic Effects on Mortality in Patients With Heart Failure and Reduced Ejection Fraction
Authors: Wessler Benjamin S. , Kramer Daniel G. , Kelly Jessica L. , Trikalinos Thomas A. , Kent David M. , Konstam Marvin A. , Udelson James E.
Published: June 2011

Background—

Although peak oxygen consumption (peak V
o
2
), 6-minute walk distance (6MW), and natriuretic peptides (BNP and NT-proBNP) are predictors of mortality in heart failure (HF) patients, it is not known whether therapy-induced changes in these measures can predict therapeutic effect on mortality. The objective of this analysis is to quantitatively assess the relationship between therapeutic effects on commonly proposed short-term markers in HF trials and therapeutic effects on long-term outcome in patients with HF and left ventricular dysfunction.

Methods and Results—

We identified drug or device therapies for which there exists at least 1 randomized, controlled trial (RCT) assessing mortality over at least 6 months in at least 500 patients. For each of these therapies, we identified RCTs assessing the short-term changes in V
o
2
, 6MW, BNP, and NT-proBNP (few of the mortality RCTs assessed the short-term changes in markers). For each intervention, we calculated the odds ratio for mortality (using random effect meta-analysis when necessary), as well as the trial level average drug- or device-induced change in the markers. We assessed the correlation between the odds ratio for death with the placebo-corrected change in the functional parameter or biomarker across the interventions. We identified mortality RCTs of 27 distinct therapies (n=73 267 patients) with a median follow-up of 19 months, that directed the search for RCTs of the effect of those interventions on the functional markers and biomarkers. There were 54 peak V
o
2
trials (n=4646 patients), 34 6MW trials (n=6995 patients), 15 BNP trials (n=7233), and 6 NT-proBNP trials (n=1946) included in this analysis. There was no significant correlation between the average therapy-induced placebo-corrected change in peak V
o
2
and the odds ratio for mortality (
r
=0.158,
P
=0.26). Increased drug or device-induced average change in 6MW was correlated with increased odds ratio for mortality (
r
=0.373,
P
=0.036). There was no significant correlation between the average therapy-induced, placebo-corrected change in the natriuretic peptides and the odds ratio for mortality (BNP:
r
=−0.065,
P
=0.82, NT-proBNP:
r
=−0.667,
P
=0.15). There was no apparent relation between change in the functional parameter or biomarker and categorical effect on mortality.

Conclusions—

This analysis, limited to trial level data from different therapeutic eras, suggests that drug- or device-induced effects on peak V
o
2
, 6MW, and natriuretic peptides found in short-term trials do not predict the corresponding average long-term therapeutic effects on mortality for patients with HF and left ventricular dysfunction.
Disease Pathways and Novel Therapeutic Targets in Hypertrophic Cardiomyopathy
Authors: Ashrafian Houman , McKenna William J. , Watkins Hugh
Published: June 2011

As described in earlier reviews in this series on the molecular basis of hypertrophic cardiomyopathy (HCM), HCM is one of the archetypal monogenic cardiovascular disorders to be understood at the molecular level. Twenty years after the discovery of the first HCM disease gene, genetic studies still confirm that HCM is principally a disease of the sarcomere. At the biophysical level, myofilament mutations generally enhance Ca
2+
sensitivity, maximal force production, and ATPase activity. These defects ultimately appear to converge on energy deficiency and altered Ca
2+
handling as major common paths leading to the anatomic (hypertrophy, myofiber disarray, and fibrosis) and functional features (pathological signaling and diastolic dysfunction) characteristic of HCM. In this review, we provide an account of the consequences of HCM mutations and describe how specifically targeting these molecular features has already yielded early promise for novel therapies for HCM. Although substantial efforts are still required to understand the molecular link between HCM mutations and their clinical consequences, HCM endures as an exemplar of how novel insights derived from molecular characterization of Mendelian disorders can inform the understanding of biological processes and translate into rational therapies.
Delayed Paraplegia After Spinal Cord Ischemic Injury Requires Caspase-3 Activation in Mice
Authors: Kakinohana Manabu , Kida Kotaro , Minamishima Shizuka , Atochin Dmitriy N. , Huang Paul L. , Kaneki Masao , Ichinose Fumito
Published: June 2011

Background and Purpose—

Delayed paraplegia remains a devastating complication after ischemic spinal cord injury associated with aortic surgery and trauma. Although apoptosis has been implicated in the pathogenesis of delayed neurodegeneration, mechanisms responsible for the delayed paraplegia remain incompletely understood. The aim of this study was to elucidate the role of apoptosis in delayed motor neuron degeneration after spinal cord ischemia.

Methods—

Mice were subjected to spinal cord ischemia induced by occlusion of the aortic arch and left subclavian artery for 5 or 9 minutes. Motor function in the hind limb was evaluated up to 72 hours after spinal cord ischemia. Histological studies were performed to detect caspase-3 activation, glial activation, and motor neuron survival in the serial spinal cord sections. To investigate the impact of caspase-3 activation on spinal cord ischemia, outcome of the spinal cord ischemia was examined in mice deficient for caspase-3.

Results—

In wild-type mice, 9 minutes of spinal cord ischemia caused immediate paraplegia, whereas 5 minutes of ischemia caused delayed paraplegia. Delayed paraplegia after 5 minutes of spinal cord ischemia was associated with histological evidence of caspase-3 activation, reactive astrogliosis, microglial activation, and motor neuron loss starting at approximately 24 to 48 hours after spinal cord ischemia. Caspase-3 deficiency prevented delayed paraplegia and motor neuron loss after 5 minutes of spinal cord ischemia, but not immediate paraplegia after 9 minutes of ischemia.

Conclusions—

The present results suggest that caspase-3 activation is required for delayed paraplegia and motor neuron degeneration after spinal cord ischemia.
A Systematic Review of Stenting and Angioplasty of Symptomatic Extracranial Vertebral Artery Stenosis
Authors: Stayman Aaron N. , Nogueira Raul G. , Gupta Rishi
Published: June 2011

Background and Purpose—

Extracranial vertebral artery stenosis (ECVAS) is common among patients with ischemic stroke. Despite the limited knowledge of the natural history of patients with symptomatic vertebral disease, endovascular revascularization techniques are now utilized in clinical practice. We sought to determine the risk of endovascular treatment for ECVAS with a systematic review of the literature.

Methods—

A search strategy was used using the terms “stenting,” “vertebral,” “ostium,” “origin,” and “extracranial” through Medline. All articles were reviewed along with their references to determine the risk and durability of endovascular treatment.

Results—

A total of 27 articles were identified that met inclusion criterion, with a total of 980 of 993 patients treated with stents. The majority of patients (56%) were noted to have contralateral vertebral artery stenosis or occlusion and 92% were symptomatic at the time of treatment. A total of 11 patients (1.1%) experienced a stroke and 8 (0.8%) experienced a transient ischemic attack within 30 days of the procedure. Drug-eluting stents were associated with lower restenosis rates (11%) compared to bare metal stents (30%) at a mean of 24 months of follow-up.

Conclusions—

Stenting and angioplasty of ECVAS appear to have a low rate of periprocedural stroke or transient ischemic attack and restenosis rates that may not be as high as suspected. Given the frequency of ECVAS as an etiology for ischemic stroke, future studies aimed at determining efficacy of this treatment modality relative to medical therapy would be of benefit to clinicians caring for these patients.
Oxidative Damage in Ischemic Stroke Revealed Using Multiple Biomarkers
Authors: Seet Raymond C.S. , Lee Chung-Yung J. , Chan Bernard P.L. , Sharma Vijay K. , Teoh Hock-Luen , Venketasubramanian Narayanaswamy , Lim Erle C.H. , Chong Wan-Ling , Looi Woan-Foon , Huang Shan-Hong , Ong Benjamin K.C. , Halliwell Barry
Published: June 2011

Background and Purpose—

We investigated changes in oxidative damage after ischemic stroke using multiple biomarkers.

Methods—

Serial blood and urine samples of ischemic stroke subjects and age-matched control subjects were assayed for F
2
-isoprostanes, hydroxyeicosatetraenoic acid products, F
4
-neuroprostanes, 24-hydroxycholesterol, allantoin, and urate.

Results—

Sixty-six stroke subjects (mean age, 65 years; median National Institutes of Health Stroke Scale 17) and 132 control subjects were recruited. A bimodal pattern of change was observed in plasma and urinary F
2
-isoprostanes and plasma 24-hydroxycholesterol. The rise in plasma hydroxyeicosatetraenoic acid products, F
4
-neuroprostanes, and allantoin was highest 6 to 12 hours after stroke onset, whereas plasma urate was significantly lower than controls on Days 1 to 3. After adjusting for age and baseline National Institutes of Health Stroke Scale, baseline plasma esterified hydroxyeicosatetraenoic acid products (OR, 1.01; 95% CI, 1.01 to 1.02), plasma urate (1.01; 1.00 to 1.01), and plasma free F
4
-neuroprostanes (2.73; 1.76 to 3.93) were associated with 90-day good functional recovery (modified Rankin Scale ≤1).

Conclusions—

Multiple markers of oxidative damage are increased immediately after stroke and remain elevated for several days. Recognition of these temporal changes may help design better antioxidant treatment trials for acute ischemic stroke.
Transition Towards a Knowledge-Based Society in Post-Communist Kazakhstan: Does Good Governance Matter?
Authors: Bhuiyan Shahjahan H
Published: June 2011

This article analyses and reviews the progress made by Kazakhstan, a post-communist country in Central Asia, towards its journey to become a knowledge-based society. An attempt has been made to examine how and to what extent good governance plays a critical role in building a knowledge-based society. Available evidence suggests that Kazakhstan made considerable advancement, in the midst of profound transitional challenges, to move to transform itself into a knowledge society. The article argues that, while improving governmental quality, good governance will have a solid impact on transforming Kazakhstan to a knowledge-based society in order to achieve the ‘Kazakhstan 2030’ policy strategy.
Fuzzy-integrative judgment on the end-use performance of knitted fabrics made with polytrimethylene terephthalate blended yarns
Authors: Li Zhao  , Hong Hu  , Wang Shao-hui
Published: June 2011

Polytrimethylene terephthalate (PTT) fiber is a new kind of synthetic fiber that has outstanding thermal, chemical, and mechanical properties and has widely been used in leisure wear, underwear, sportswear, and other textile products in the recent years. In this study, five different PTT blended yarns were used for the development of weft knitted fabrics for sweaters, which are traditionally produced with wool and acrylic fiber yarns. Three fuzzy-integrative judgment methods, that is, the fuzzy Borda method, osculating value method, and fuzzy clustering analysis, were used to evaluate the end-use performance of these fabrics. The results have shown that the fuzzy-integrative judgment is an effective way for the evaluation of this kind of fabric product and that the fabrics with the best end-use performance among the five fabrics developed are those knitted with PTT/wool/Tencel and PTT/bamboo blended yarns. These results can be used to help knitting companies for the development of new products using PTT material.
Verification of an Electromagnetic Placement Device Compared With Abdominal Radiograph to Predict Accuracy of Feeding Tube Placement
Authors: Powers Jan , Luebbehusen Michael , Spitzer Tracy , Coddington Anthony , Beeson Terri , Brown Jamie , Jones Diana
Published: June 2011

Background: Use of an electromagnetic placement device (EMPD) facilitates placement of feeding tubes at the bedside. Standard practice for verification of feeding tube placement is via radiographic confirmation. The purpose of this research study was to assess the accuracy of placement of small‐bore feeding tubes (SBFTs) as determined by EMPD interpretation compared with that of abdominal radiograph verification by a radiologist. Methods: This multicenter prospective study enrolled patients requiring bedside feeding tube placement. SBFTs were placed by an experienced investigator using the EMPD. Two abdominal radiographs were then obtained: one after initial SBFT placement and an additional radiograph after injection of contrast. Documentation of location based on clinician interpretation using the EMPD was then compared with radiologist interpretation. Results: The final sample size was 194 patients, including 18 pediatric patients. Patient age ranged from 12 days to 102 years. Median time for tube placement was 12 minutes. Of the 194 patients, only 1 patient had data showing discrepancies between the original EMPD verification and the final abdominal radiograph interpretation, providing a 99.5% agreement. No patient experienced complications during SBFT placement, and 15 patients had inadvertent airway placement that was avoided with the use of the EMPD. Conclusions: There was a high percentage of agreement between EMPD and radiologic interpretation after contrast injection. The EMPD aided in avoiding inadvertent airway placement, with no patient complications. This device can be used safely at the bedside to facilitate placement of feeding tubes, leading to the delivery of early enteral nutrition.
Arthroscopic Management of Chronic Patellar Tendinopathy
Authors: Pascarella Antonio , Alam Mahbub , Pascarella Fabio , Latte Carmine , Di Salvatore Mariano Giuseppe , Maffulli Nicola
Published: June 2011

Background: In patients with patellar tendinopathy in whom nonoperative management is unsuccessful, surgery is an option to return to high levels of physical activity. Although open surgery is traditionally advocated, an arthroscopic approach may be safe and effective.

Purpose: This study was undertaken to analyze medium- and long-term outcome of 64 patients undergoing arthroscopic surgery for the management of patellar tendinopathy after failing nonoperative treatment.

Study Design: Case series; Level of evidence, 4.

Methods: A total of 64 patients (73 knees), 27 of whom were professional athletes, with patellar tendinopathy refractory to nonoperative management underwent arthroscopic debridement of the adipose tissue of the Hoffa’s body posterior to the patellar tendon, debridement of abnormal patellar tendon, and excision of the lower pole of the patella. Preoperative and postoperative evaluation was undertaken using the International Knee Documentation Committee (IKDC), Lysholm knee scale, and Victorian Institute of Sport Assessment–Patella (VISA-P) scores for all patients at 1 and 3 years. No patients were lost to follow-up. Forty-three and 29 patients were similarly assessed at 5 and 10 years, respectively, after surgery. Return to sports and rehabilitation was also assessed.

Results: The IKDC, Lysholm, and VISA-P scores all significantly improved at 1 and 3 years’ follow-up. The average preoperative IKDC score of 51.6 improved to 86.4 at both the 1- and 3-year stage. The average preoperative Lysholm score of 52.3 improved to 94.7 at 1-year follow-up and was 95.5 at 3-year follow-up. The average preoperative VISA-P score of 35.3 improved to 69.8 at the 1-year stage and was 70.7 at the 3-year follow-up. These scores remained significantly better for the patients assessed at 5 and 10 years’ follow-up. There were no postoperative complications. Nineteen of the 27 professional athletes returned to sports at the same level. Seven patients developed pain after sports within 3 years after the operation, a failure rate of 7 of 73 knees (9.6%). All patients were able to return to sports by 3 months.

Conclusion: Arthroscopic surgery for patients with patellar tendinopathy, refractory to nonoperative management, appears to provide significant improvements in symptoms and function, with improvements maintained for at least 3 years. These results suggest that some patients may not be able to achieve their presymptom sporting level; or if they do, they may participate in sports with some degree of residual symptoms. Limited data show that these improvements are maintained for up to 10 years. Early return to sports may also be achieved.
Issues in Nonprofit Finance Research
Authors: Bowman Woods , Tuckman Howard P. , Young Dennis R.
Published: June 2011

As the first systematic attempt to identify the issues involved in the use of large data sets to examine nonprofit surpluses and endowments, this paper provides suggestions for how best to ensure that the data are consistent and useful. We introduce five definitions of nonprofit surplus (the analogue of profit) and identify when researchers should use one in preference to the other. The distinctions are especially important when analyzing endowed organizations because surpluses affect the amount and rate of accumulation of endowment assets. Conversely, an endowment affects how managers and analysts should calculate surplus. Information on IRS 990 reports is incomplete, so we explain how to construct a pro forma endowment portfolio and endowment spending from available data for the purpose of calculating operating surplus of endowed organizations. We argue that researchers doing statistical analyses with large data bases should distinguish between endowed organizations and those without endowments because their financial behavior may differ. To lump them together is likely to distort statistical results. Finally, we discuss practical issues of data cleaning when using data from IRS 990 reports.
Feature extraction for engine fault diagnosis utilizing the generalized S-transform and non-negative tensor factorization
Authors: Li B , Zhang P-L , Liang S-B , Zhang Y-T , Fan H-B
Published: June 2011

In this study, a novel feature extraction scheme was proposed for engine fault diagnosis utilizing the generalized S-transform combined with the non-negative tensor factorization (NTF). To represent the information of the non-stationary vibration signals acquired from engine, the generalized S-transform was used to get a time–frequency distribution with enhanced energy concentration. Meanwhile, a newly developed technique called NTF, which can preserve more structure information hiding in original two-dimensional matrices compared to the non-negative matrix factorization (NMF), was adopted to extract more informative features from the time–frequency matrices. Five operating states of engine were tested in an experiment for evaluating the proposed feature extraction scheme. Four different types of learning algorithms were employed to conduct the fault classification task. The NMF technique was also used for feature extraction and compared with the NTF approach. The experimental results have demonstrated that the proposed feature extraction scheme can achieve a satisfactory performance when applied to diagnose the engine faults.
Culturally Divergent Responses to Mortality Salience
Authors: Ma-Kellams Christine , Blascovich Jim
Published: June 2011

Two experiments compared the effects of death thoughts, or mortality salience, on European and Asian Americans. Research on terror management theory has demonstrated that in Western cultural groups, individuals typically employ self-protective strategies in the face of death-related thoughts. Given fundamental East-West differences in self-construal (i.e., the independent vs. interdependent self), we predicted that members of Eastern cultural groups would affirm other people, rather than defend and affirm the self, after encountering conditions of mortality salience. We primed European Americans and Asian Americans with either a death or a control prime and examined the effect of this manipulation on attitudes about a person who violates cultural norms (Study 1) and on attributions about the plight of an innocent victim (Study 2). Mortality salience promoted culturally divergent responses, leading European Americans to defend the self and Asian Americans to defend other people.
The Development and Evaluation of a Measure Assessing School Nurses' Perceived Barriers to Addressing Pediatric Obesity
Authors: Wu Yelena P. , Steele Ric G.
Published: June 2011

School nurses represent an important resource for addressing pediatric obesity and weight-related health. However, school nurses perceive numerous barriers that prevent them from addressing the weight-related health of students. The current study developed and tested a new, comprehensive measure of nurses' perceptions of 10 types of barriers to addressing pediatric weight in a nationally representative sample of 214 school nurses. The measure was developed in the context of Bronfenbrenner’s (1979) ecological systems theory and includes subscales assessing nurses' perceptions of skills-based, job-related, and societal barriers. Confirmatory factor analyses (CFAs) provided evidence for the validity of the measure, including the three barrier subscales. In addition, the subscales demonstrated adequate internal consistencies. Results indicate that school nurses perceive barriers to addressing weight-related health on multiple ecological levels, which may inform intervention or continuing education efforts. Future pediatric weight programs that involve school nurses might consider using the measure to assess nurses' perceptions of barriers.
From ‘placement’ to ‘a child on the move’: Methodological strategies to give children a more central position in Child Welfare Service
Authors: Andenæs Agnes
Published: June 2011

Within both politics and research children have been increasingly depicted as autonomous individuals with a right to be heard and have a say. Children's Welfare Services has been criticized for neglecting to view children as knowledgeable actors in their own cases. In referring to a national Norwegian study with 109 children aged 6–12 years who were placed out-of-home by Children's Welfare Services, this article proposes strategies to make children more visible in practice as well as within research related to Children's Welfare Services. By conceptualizing such placement as a change of residency, or, more colloquially, the ‘child on the move’, new sources of knowledge appear to be relevant; namely studies about children's everyday life, even encompassing knowledge about ordinary moves in ordinary families. The article concludes that importing methodological approaches and substantial knowledge from research on the everyday lives of unremarkable children to the field of Child Welfare Service may help establish children as key agents in their own cases, and even reduce the process of ‘othering’ welfare clients.