bluuebunny/crossref_metadata_2025 huggingface dataset:
Long Noncoding RNA MALAT1 Promotes Aggressive Renal Cell Carcinoma through Ezh2 and Interacts with miR-205
Authors: Hirata Hiroshi , Hinoda Yuji , Shahryari Varahram , Deng Guoren , Nakajima Koichi , Tabatabai Z. Laura , Ishii Nobuhisa , Dahiya Rajvir
Published: January 2015

Recently, long noncoding RNAs (lncRNA) have emerged as new gene regulators and prognostic markers in several cancers, including renal cell carcinoma (RCC). In this study, we investigated the contributions of the lncRNA MALAT1 in RCC with a specific focus on its transcriptional regulation and its interactions with Ezh2 and miR-205. We found that MALAT1 expression was higher in human RCC tissues, where it was associated with reduced patient survival. MALAT1 silencing decreased RCC cell proliferation and invasion and increased apoptosis. Mechanistic investigations showed that MALAT1 was transcriptionally activated by c-Fos and that it interacted with Ezh2. After MALAT1 silencing, E-cadherin expression was increased, whereas β-catenin expression was decreased through Ezh2. Reciprocal interaction between MALAT1 and miR-205 was also observed. Lastly, MALAT1 bound Ezh2 and oncogenesis facilitated by MALAT1 was inhibited by Ezh2 depletion, thereby blocking epithelial–mesenchymal transition via E-cadherin recovery and β-catenin downregulation. Overall, our findings illuminate how overexpression of MALAT1 confers an oncogenic function in RCC that may offer a novel theranostic marker in this disease. Cancer Res; 75(7); 1322–31. ©2015 AACR.
FDA Approval: Siltuximab for the Treatment of Patients with Multicentric Castleman Disease
Authors: Deisseroth Albert , Ko Chia-Wen , Nie Lei , Zirkelbach Jeanne F. , Zhao Liang , Bullock Julie , Mehrotra Nitin , Del Valle Pedro , Saber Haleh , Sheth Christopher , Gehrke Brenda , Justice Robert , Farrell Ann , Pazdur Richard
Published: January 2015

On April 22, 2014, the FDA granted full approval to siltuximab (SYLVANT for injection; Janssen Biotech, Inc.), a chimeric human-mouse monoclonal antibody to IL6, for the treatment of patients with multicentric Castleman disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. The approval was primarily based on the results of a randomized, double-blind trial in which 79 symptomatic patients with MCD were allocated (2:1) to siltuximab plus best supportive care (BSC) or to placebo plus BSC. The primary efficacy endpoint was the proportion of patients in each arm achieving a durable tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure. Tumor response was based on independent review of CT scans using the revised Response Criteria for Malignant Lymphoma, and symptomatic response was defined as complete resolution or stabilization of 34 MCD-related signs and symptoms as reported by the investigator. Thirty-four percent of patients in the siltuximab arm and no patients in the placebo arm met the primary endpoint (P = 0.0012). The most common adverse reactions (>10% compared with placebo) during treatment with siltuximab were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infection. Clin Cancer Res; 21(5); 950–4. ©2015 AACR.
Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer
Authors: Gonzalez-Villasana Vianey , Fuentes-Mattei Enrique , Ivan Cristina , Dalton Heather J. , Rodriguez-Aguayo Cristian , Fernandez-de Thomas Ricardo J. , Aslan Burcu , del C. Monroig Paloma , Velazquez-Torres Guermarie , Previs Rebecca A. , Pradeep Sunila , Kahraman Nermin , Wang Huamin , Kanlikilicer Pinar , Ozpolat Bulent , Calin George , Sood Anil K. , Lopez-Berestein Gabriel
Published: January 2015

Purpose: Zoledronic acid is being increasingly recognized for its antitumor properties, but the underlying functions are not well understood. In this study, we hypothesized that zoledronic acid inhibits ovarian cancer angiogenesis preventing Rac1 activation.

Experimental Design: The biologic effects of zoledronic acid were examined using a series of in vitro [cell invasion, cytokine production, Rac1 activation, reverse-phase protein array, and in vivo (orthotopic mouse models)] experiments.

Results: There was significant inhibition of ovarian cancer (HeyA8-MDR and OVCAR-5) cell invasion as well as reduced production of proangiogenic cytokines in response to zoledronic acid treatment. Furthermore, zoledronic acid inactivated Rac1 and decreased the levels of Pak1/p38/matrix metalloproteinase-2 in ovarian cancer cells. In vivo, zoledronic acid reduced tumor growth, angiogenesis, and cell proliferation and inactivated Rac1 in both HeyA8-MDR and OVCAR-5 models. These in vivo antitumor effects were enhanced in both models when zoledronic acid was combined with nab-paclitaxel.

Conclusions: Zoledronic acid has robust antitumor and antiangiogenic activity and merits further clinical development as ovarian cancer treatment. Clin Cancer Res; 21(9); 2127–37. ©2015 AACR.
Fully Covered Self-Expandable Metal Stent in Tracheobronchial Disorders: Clinical Experience
Authors: Marchese Roberto , Poidomani Grazia , Paglino Giuseppe , Crimi Claudia , Lo Nigro Chiara , Argano Vincenzo
Published: January 2015

Background: The third-generation fully covered self-expandable metallic stent (SEMS) has been developed to solve the problems of difficult removal and in-stent granuloma formation related to the uncovered or partially covered type. There are few written reports about the performance of this type of stents with early encouraging results. Objectives: To report and analyse our experience with the Silmet® stent in the management of malignant and benign tracheobronchial disorders. Methods: We retrospectively reviewed medical records of patients who underwent fully covered SEMS Silmet placement at the Interventional Pulmonology Unit, La Maddalena Cancer Center, Palermo, Italy, between May 2010 and August 2013. Results: Stents were placed in 52 patients with malignant (n = 49) and benign airway obstruction (n = 2) and broncho-oesophageal fistula (n = 1). SEMSs were inserted into the trachea (n = 19), the main bronchi (n = 21) and the peripheral bronchi (n = 31). Besides 1 procedural dislocation, the deployment was successful in all patients with an immediate significant improvement of symptoms (Barthel Index p < 0.001; Medical Research Council score p < 0.001). A radiographic improvement was detected in 48% of patients. The mean follow-up duration was 119 ± 120 days (range 22-549 days). Complications observed were: migration (7.6%), tumour overgrowth (15%), infections (5.7%), granulation tissue formation (3.8%) and mucus plug (3.8%). Conclusions: The Silmet stent is effective, safe and simple to implant and remove. We suggest its use in cases of tight stenoses, in the treatment of small- to medium-caliber airways or in cases of tortuous airways.
Aerobic Physical Exercise Improved the Cognitive Function of Elderly Males but Did Not Modify Their Blood Homocysteine Levels
Authors: Antunes Hanna Karen M. , De Mello Marco Túlio , de Aquino Lemos Valdir , Santos-Galduróz Ruth Ferreira , Camargo Galdieri Luciano , Amodeo Bueno Orlando Francisco , Tufik Sergio , D'Almeida Vânia
Published: January 2015

Background: Physical exercise influences homocysteine (Hcy) concentrations, cognitive function and the metabolic profile. The purpose of this study was to investigate the influence of regular physical exercise on Hcy levels, the metabolic profile and cognitive function in healthy elderly males before and after an endurance exercise program. Methods: Forty-five healthy and sedentary volunteers were randomized into 2 groups: (1) a control group asked not to change their normal everyday activities and not to start any regular physical exercise program and (2) an experimental group trained at a heart rate intensity corresponding to ventilatory threshold 1 (VT-1) for 60 min/day 3 times weekly on alternate days for 6 months using a cycle ergometer. All volunteers underwent cognitive evaluations, blood sample analyses and ergospirometric assessments. Results: A significant improvement in cognitive function was observed in the experimental group compared with the control group (p < 0.05). No significant changes in Hcy levels were observed in the experimental group (p > 0.05), but there was a significant increase in peak oxygen consumption and workload at VT-1 as well as a significant improvement in cholesterol, triglycerides, HDL, glucose, alkaline phosphatase, urea, T3, T4 and prostate-specific antigen compared with the control group (p < 0.05). Conclusion: The data suggest that a physical exercise program does not reduce Hcy levels in healthy elderly males, although it improves the cardiovascular and metabolic profile as well as cognitive function.
Possible Introgression of B Chromosomes between Bee Species (Genus Partamona)
Authors: Tosta Vander C. , Marthe Jefferson B. , Tavares Mara G. , Fernandes-Salomão Tânia M. , Pompolo Silvia G. , Recco-Pimentel Shirlei M. , Perfectti Francisco , Campos Lucio A.O. , Camacho Juan Pedro M.
Published: January 2015

The origin of supernumerary (B) chromosomes is still a debated topic, with intra- and interspecific origins being the most plausible options. In the bee Partamona helleri, a sequence-characterized amplified region (SCAR) marker being specific to B chromosomes suggested the possibility of interspecific origin. Here, we search for this marker in 3 close relative species and perform DNA sequence comparison between species. The SCAR sequence does not show homology with other sequences in the databases, but does contain an open reading frame with sequence homology with a reverse transcriptase. Dot-blot hybridization using the SCAR marker as a probe confirmed that it is present in B-carrying, but not B-lacking larvae of P. helleri, and indicated its presence in adult individuals of P. cupira and P. criptica. Additionally, PCR amplification of the SCAR marker was successful on genomic DNA obtained from P. helleri and P. rustica larvae carrying B chromosomes, and on genomic DNA obtained from adult individuals of P. cupira, P. criptica and P. rustica. Finally, a comparison of the DNA sequence of the SCAR markers amplified from these 4 species showed very few nucleotide differences between the species. The complete association between B chromosome and SCAR presence and the scarce divergence observed for this DNA sequence between the 4 species analyzed suggest the possibility that this B chromosome has recently been transferred between species through several episodes of interspecific hybridization.
Development and Mapping of CL-Repeat Display Markers on the Maize B Chromosome
Authors: Chien Yu-Lun , Lin Chien-Yu , Lo Kuan-Lin , Cheng Ya-Ming
Published: January 2015

The CL-repeat is a repetitive sequence that is unique to the maize B chromosome, where it resides in the centromeric knob and the first 3 distal heterochromatic regions of the long arm. Given this organization, it would be desirable to identify molecular markers that are specifically distributed in the B chromosome. In this report, the CL-repeat has been used to develop a class of molecular markers for the maize B chromosome. To this end, a modified transposon display procedure designated as CL-repeat display was used to generate and display 26 genomic fragments that are specific to the B chromosome, all of which were cloned and sequenced. The sequences of 19 fragments were highly homologous to the 5′ or 3′ terminus of the CL-repeat. Five of these fragments also contained sequences that were homologous to sequences of the B chromosome centromere. Four of the other 7 fragments shared homology with B chromosome centromere sequences, and the remaining 3 were of unidentified sequences. Using 13 B-10L translocations with various breakpoints along the B chromosome long arm, the 26 CL-repeat display markers were mapped to definite regions of the B chromosome. This strategy should be feasible for the development of molecular markers for the B chromosome in maize and in other species where B chromosome-specific repeats have been identified.
Fractionating E-Wave Deceleration Time Into Its Stiffness and Relaxation Components Distinguishes Pseudonormal From Normal Filling
Authors: Mossahebi Sina , Zhu Simeng , Kovács Sándor J.
Published: January 2015

Background—

Pseudonormal Doppler E-wave filling patterns indicate diastolic dysfunction but are indistinguishable from the normal filling pattern. For accurate classification, maneuvers to alter load or to additionally measure peak
E
′ are required. E-wave deceleration time (DT) has been fractionated into its stiffness (DT
s
) and relaxation (DT
r
) components (DT=DT
s
+DT
r
) by analyzing E-waves via the parametrized diastolic filling formalism. The method has been validated with DT
s
and DT
r
correlating with simultaneous catheterization-derived stiffness (dP/dV) and relaxation (
τ
) with
r
=0.82 and
r
=0.94, respectively. We hypothesize that DT fractionation can (1) distinguish between unblinded (
E
′ known) normal versus pseudonormal age-matched groups with normal left ventricular ejection fraction, and (2) distinguish between blinded (
E
′ unknown) normal versus pseudonormal groups, based solely on E-wave analysis.

Methods and Results—

Data (763 E-waves) from 15 age-matched, pseudonormal (elevated
E
/
E
′) and 15 normal subjects were analyzed. Conventional echocardiographic and parametrized diastolic filling stiffness (
k
) and relaxation (
c
) parameters and DT
s
and DT
r
were compared. Conventional diastolic function parameters did not differentiate between unblinded groups, whereas
k
,
c
(
P
<0.001) and DT
s
, DT
r
(
P
<0.001) did. Independent, blinded (
E
′ not provided) analysis of 42 subjects (30 subjects from unblinded training set and 12 additional subjects from validation set, 581 E-waves) showed that
R
(=DT
r
/DT) had high sensitivity (0.90) and specificity (0.86) in differentiating pseudonormal from normal once
E
′ revealed actual classification.

Conclusions—

arametrized diastolic filling–based E-wave analysis (
k
,
c
or DT
s
and DT
r
) can differentiate normal versus pseudonormal filling patterns without requiring knowledge of
E
′.
Relative Flow Reserve Derived From Quantitative Perfusion Imaging May Not Outperform Stress Myocardial Blood Flow for Identification of Hemodynamically Significant Coronary Artery Disease
Authors: Stuijfzand Wijnand J. , Uusitalo Valtteri , Kero Tanja , Danad Ibrahim , Rijnierse Mischa T. , Saraste Antti , Raijmakers Pieter G. , Lammertsma Adriaan A. , Harms Hans J. , Heymans Martijn W. , Huisman Marc C. , Marques Koen M. , Kajander Sami A. , Pietilä Mikko , Sörensen Jens , Royen Niels van , Knuuti Juhani , Knaapen Paul
Published: January 2015

Background—

Quantitative myocardial perfusion imaging is increasingly used for the diagnosis of coronary artery disease. Quantitative perfusion imaging allows to noninvasively calculate fractional flow reserve (FFR). This so-called relative flow reserve (RFR) is defined as the ratio of hyperemic myocardial blood flow (MBF) in a stenotic area to hyperemic MBF in a normal perfused area. The aim of this study was to assess the value of RFR in the detection of significant coronary artery disease.

Methods and Results—

From a clinical population of patients with suspected coronary artery disease who underwent oxygen-15–labeled water cardiac positron emission tomography and invasive coronary angiography, 92 patients with single- or 2-vessel disease were included. Intermediate lesions (diameter stenosis, 30%–90%; n=75) were interrogated by FFR. Thirty-eight (41%) vessels were deemed hemodynamically significant (>90% stenosis or FFR ≤0.80). Hyperemic MBF, coronary flow reserve, and RFR were lower for vessels with a hemodynamically significant lesion (2.01±0.78 versus 2.90±1.16 mL·min
−1
·g
−1
;
P
<0.001, 2.27±1.03 versus 3.10±1.29;
P
<0.001, and 0.67±0.23 versus 0.93±0.15;
P
<0.001, respectively). The correlation between RFR and FFR was moderate (
r
=0.54;
P
<0.01). Receiver operator characteristic curve analysis showed an area under the curve of 0.82 for RFR, which was not significantly higher compared with that for hyperemic MBF and coronary flow reserve (0.76;
P
=0.32 and 0.72;
P
=0.08, respectively).

Conclusions—

Noninvasive estimation of FFR by quantitative perfusion positron emission tomography by calculating RFR is feasible, yet only a trend toward a slight improvement of diagnostic accuracy compared with hyperemic MBF assessment was determined.
Diagnostic Accuracy of Stress Myocardial Perfusion Imaging Compared to Invasive Coronary Angiography With Fractional Flow Reserve Meta-Analysis
Authors: Takx Richard A.P. , Blomberg Björn A. , Aidi Hamza El , Habets Jesse , de Jong Pim A. , Nagel Eike , Hoffmann Udo , Leiner Tim
Published: January 2015

Background—

Hemodynamically significant coronary artery disease is an important indication for revascularization. Stress myocardial perfusion imaging is a noninvasive alternative to invasive fractional flow reserve for evaluating hemodynamically significant coronary artery disease. The aim was to determine the diagnostic accuracy of myocardial perfusion imaging by single-photon emission computed tomography, echocardiography, MRI, positron emission tomography, and computed tomography compared with invasive coronary angiography with fractional flow reserve for the diagnosis of hemodynamically significant coronary artery disease.

Methods and Results—

The meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. PubMed, EMBASE, and Web of Science were searched until May 2014. Thirty-seven studies, reporting on 4721 vessels and 2048 patients, were included. Meta-analysis yielded pooled sensitivity, pooled specificity, pooled likelihood ratios (LR), pooled diagnostic odds ratio, and summary area under the receiver operating characteristic curve. The negative LR (NLR) was chosen as the primary outcome. At the vessel level, MRI (pooled NLR, 0.16; 95% confidence interval [CI], 0.13–0.21) was performed similar to computed tomography (pooled NLR, 0.22; 95% CI, 0.12–0.39) and positron emission tomography (pooled NLR, 0.15; 95% CI, 0.05–0.44), and better than single-photon emission computed tomography (pooled NLR, 0.47; 95% CI, 0.37–0.59). At the patient level, MRI (pooled NLR, 0.14; 95% CI, 0.10–0.18) performed similar to computed tomography (pooled NLR, 0.12; 95% CI, 0.04–0.33) and positron emission tomography (pooled NLR, 0.14; 95% CI, 0.02–0.87), and better than single-photon emission computed tomography (pooled NLR, 0.39; 95% CI, 0.27–0.55) and echocardiography (pooled NLR, 0.42; 95% CI, 0.30–0.59).

Conclusions—

Stress myocardial perfusion imaging with MRI, computed tomography, or positron emission tomography can accurately rule out hemodynamically significant coronary artery disease and can act as a gatekeeper for invasive revascularization. Single-photon emission computed tomography and echocardiography are less suited for this purpose.
Deficiency of Endothelium-Specific Transcription Factor
Sox17
Induces Intracranial Aneurysm
Authors: Lee Seungjoo , Kim Il-Kug , Ahn Jae Sung , Woo Dong-Cheol , Kim Sang-Tae , Song Sukhyun , Koh Gou Young , Kim Hyung-Seok , Jeon Byeong Hwa , Kim Injune
Published: January 2015

Background—

Intracranial aneurysm (IA) is a common vascular disorder that frequently leads to fatal vascular rupture. Although various acquired risk factors associated with IA have been identified, the hereditary basis of IA remains poorly understood. As a result, genetically modified animals accurately modeling IA and related pathogenesis have been lacking, and subsequent drug development has been delayed.

Methods and Results—

The transcription factor Sox17 is robustly expressed in endothelial cells of normal intracerebral arteries. The combination of
Sox17
deficiency and angiotensin II infusion in mice induces vascular abnormalities closely resembling the cardinal features of IA such as luminal dilation, wall thinning, tortuosity, and subarachnoid hemorrhages. This combination impairs junctional assembly, cell-matrix adhesion, regeneration capacity, and paracrine secretion in endothelial cells of intracerebral arteries, highlighting key endothelial dysfunctions that lead to IA pathogenesis. Moreover, human IA samples showed reduced Sox17 expression and impaired endothelial integrity, further strengthening the applicability of this animal model to clinical settings.

Conclusions—

Our findings demonstrate that
Sox17
deficiency in mouse can induce IA under hypertensive conditions, suggesting
Sox17
deficiency as a potential genetic factor for IA formation. The
Sox17
-deficient mouse model provides a novel platform to develop therapeutics for incurable IA.
Dabigatran and Rivaroxaban Use in Atrial Fibrillation Patients on Hemodialysis
Authors: Chan Kevin E. , Edelman Elazer R. , Wenger Julia B. , Thadhani Ravi I. , Maddux Franklin W.
Published: January 2015

Background—

Dabigatran and rivaroxaban are new oral anticoagulants that are eliminated through the kidneys. Their use in dialysis patients is discouraged because these drugs can bioaccumulate to precipitate inadvertent bleeding. We wanted to determine whether prescription of dabigatran or rivaroxaban was occurring in the dialysis population and whether these practices were safe.

Methods and Results—

Prevalence plots were used to describe the point prevalence (monthly) of dabigatran and rivaroxaban use among 29 977 hemodialysis patients with atrial fibrillation. Poisson regression compared the rate of bleeding, stroke, and arterial embolism in patients who started dabigatran, rivaroxaban, or warfarin. The first record of dabigatran prescription among hemodialysis patients occurred 45 days after the drug became available in the United States. Since then, dabigatran and rivaroxaban use in the atrial fibrillation–end-stage renal disease population has steadily risen where 5.9% of anticoagulated dialysis patients are started on dabigatrian or rivaroxaban. In covariate adjusted Poisson regression, dabigatran (rate ratio, 1.48; 95% confidence interval, 1.21–1.81;
P
=0.0001) and rivaroxaban (rate ratio, 1.38; 95% confidence interval, 1.03–1.83;
P
=0.04) associated with a higher risk of hospitalization or death from bleeding when compared with warfarin. The risk of hemorrhagic death was even larger with dabigatran (rate ratio, 1.78; 95% confidence interval, 1.18–2.68;
P
=0.006) and rivaroxaban (rate ratio, 1.71; 95% confidence interval, 0.94–3.12;
P
=0.07) relative to warfarin. There were too few events in the study to detect meaningful differences in stroke and arterial embolism between the drug groups.

Conclusions—

More dialysis patients are being started on dabigatran and rivaroxaban, even when their use is contraindicated and there are no studies to support that the benefits outweigh the risks of these drugs in end-stage renal disease.
Renal Transporter Activation During Angiotensin-II Hypertension is Blunted in Interferon-γ
−/−
and Interleukin-17A
−/−
Mice
Authors: Kamat Nikhil V. , Thabet Salim R. , Xiao Liang , Saleh Mohamed A. , Kirabo Annet , Madhur Meena S. , Delpire Eric , Harrison David G. , McDonough Alicia A.
Published: January 2015

Ample genetic and physiological evidence establishes that renal salt handling is a critical regulator of blood pressure. Studies also establish a role for the immune system, T-cell infiltration, and immune cytokines in hypertension. This study aimed to connect immune cytokines, specifically interferon-γ (IFN-γ) and interleukin-17A (IL-17A), to sodium transporter regulation in the kidney during angiotensin-II (Ang-II) hypertension. C57BL/6J (wild-type) mice responded to Ang-II infusion (490 ng/kg per minute, 2 weeks) with a rise in blood pressure (170 mm Hg) and a significant decrease in the rate of excretion of a saline challenge. In comparison, mice that lacked the ability to produce either IFN-γ (IFN-γ
−/−
) or IL-17A (IL-17A
−/−
) exhibited a blunted rise in blood pressure (<150 mm Hg), and both the genotypes maintained baseline diuretic and natriuretic responses to a saline challenge. Along the distal nephron, Ang-II infusion increased abundance of the phosphorylated forms of the Na-K-2Cl cotransporter, Na-Cl cotransporter, and Ste20/SPS-1–related proline-alanine–rich kinase, in both the wild-type and the IL-17A
−/−
but not in IFN-γ
−/−
mice; epithelial Na channel abundance increased similarly in all the 3 genotypes. In the proximal nephron, Ang-II infusion significantly decreased abundance of Na/H-exchanger isoform 3 and the motor myosin VI in IL-17A
−/−
and IFN-γ
−/−
, but not in wild-type; the Na-phosphate cotransporter decreased in all the 3 genotypes. Our results suggest that during Ang-II hypertension both IFN-γ and IL-17A production interfere with the pressure natriuretic decrease in proximal tubule sodium transport and that IFN-γ production is necessary to activate distal sodium reabsorption.
Weight Loss, Saline Loading, and the Natriuretic Peptide System
Authors: Arora Pankaj , Reingold Jason , Baggish Aaron , Guanaga Derek P. , Wu Connie , Ghorbani Anahita , Song Yanna , Chen‐Tournaux Annabel , Khan Abigail May , Tainsh Laurel T. , Buys Emmanuel S. , Williams Jonathan S. , Heublein Denise M. , Burnett John C. , Semigran Marc J. , Bloch Kenneth D. , Scherrer‐Crosbie Marielle , Newton‐Cheh Christopher , Kaplan Lee M. , Wang Thomas J.
Published: January 2015

Background

In epidemiologic studies, obesity has been associated with reduced natriuretic peptide (
NP
) concentrations. Reduced
NP
production could impair the ability of obese individuals to respond to salt loads, increasing the risk of hypertension and other disorders. We hypothesized that weight loss enhances
NP
production before and after salt loading.

Methods and Results

We enrolled 15 obese individuals (mean
BMI
45±5.4 kg/m
2
) undergoing gastric bypass surgery. Before and 6 months after surgery, subjects were admitted to the clinical research center and administered a large‐volume intravenous saline challenge. Echocardiography and serial blood sampling were performed. From the pre‐operative visit to 6 months after surgery, subjects had a mean
BMI
decrease of 27%. At the 6‐month visit, N‐terminal pro‐atrial
NP
(Nt‐pro
ANP
) levels were 40% higher before, during, and after the saline infusion, compared with levels measured at the same time points during the pre‐operative visit (
P
<0.001). The rise in Nt‐pro‐
ANP
induced by the saline infusion (≈50%) was similar both before and after surgery (saline,
P
<0.001; interaction,
P
=0.2). Similar results were obtained for
BNP
and Nt‐pro
BNP
; resting concentrations increased by 50% and 31%, respectively, after gastric bypass surgery. The increase in
NP
concentrations after surgery was accompanied by significant decreases in mean arterial pressure (
P
=0.004) and heart rate (
P
<0.001), and an increase in mitral annular diastolic velocity (
P
=0.02).

Conclusion

In obese individuals, weight loss is associated with a substantial increase in the “setpoint” of circulating
NP
concentrations. Higher
NP
concentrations could contribute to an enhanced ability to handle salt loads after weight loss.
Fast Learning of Simple Perceptual Discriminations Reduces Brain Activation in Working Memory and in High-level Auditory Regions
Authors: Daikhin Luba , Ahissar Merav
Published: January 2015

Introducing simple stimulus regularities facilitates learning of both simple and complex tasks. This facilitation may reflect an implicit change in the strategies used to solve the task when successful predictions regarding incoming stimuli can be formed. We studied the modifications in brain activity associated with fast perceptual learning based on regularity detection. We administered a two-tone frequency discrimination task and measured brain activation (fMRI) under two conditions: with and without a repeated reference tone. Although participants could not explicitly tell the difference between these two conditions, the introduced regularity affected both performance and the pattern of brain activation. The “No-Reference” condition induced a larger activation in frontoparietal areas known to be part of the working memory network. However, only the condition with a reference showed fast learning, which was accompanied by a reduction of activity in two regions: the left intraparietal area, involved in stimulus retention, and the posterior superior-temporal area, involved in representing auditory regularities. We propose that this joint reduction reflects a reduction in the need for online storage of the compared tones. We further suggest that this change reflects an implicit strategic shift “backwards” from reliance mainly on working memory networks in the “No-Reference” condition to increased reliance on detected regularities stored in high-level auditory networks.
On Firing Rate Estimation for Dependent Interspike Intervals
Authors: Benedetto Elisa , Polito Federico , Sacerdote Laura
Published: January 2015

If interspike intervals are dependent, the instantaneous firing rate does not catch important features of spike trains. In this case, the conditional instantaneous rate plays the role of the instantaneous firing rate for the case of samples of independent interspike intervals. If the conditional distribution of the interspikes intervals (ISIs) is unknown, it becomes difficult to evaluate the conditional firing rate. We propose a nonparametric estimator for the conditional instantaneous firing rate for Markov, stationary, and ergodic ISIs. An algorithm to check the reliability of the proposed estimator is introduced, and its consistency properties are proved. The method is applied to data obtained from a stochastic two-compartment model and to in vitro experimental data.
The Development of the Albanian Prison System in the Light of International Standards
Authors: Papavangjeli Edlira
Published: January 2015

The article focuses on the main developments in the Albanian prison system mainly during the last 24 years of democratic transformation. In more concrete terms, the article provides an insight into the legislative, institutional and infrastructural reforms of the Albanian prison system. Special attention is given to the rights and treatment of prisoners seen from a human rights perspective and principles of proper treatment. Furthermore, the article highlights the worrying issues that the prison system faces and concrete suggestions are provided from the perspective of international standards. The impact of international and national monitoring mechanisms on the Albanian prison system reforms also forms part of the analysis.
Effect on Laryngeal Adductor Function of Vincristine Block of Posterior Cricoarytenoid Muscle 3 to 5 Months After Recurrent Laryngeal Nerve Injury
Authors: Paniello Randal C. , Park Andrea
Published: January 2015

Objectives:

It has been shown in a canine model that a single injection of vincristine into the posterior cricoarytenoid (PCA) muscle at the time of recurrent laryngeal nerve (RLN) injury effectively blocks its reinnervation and results in improved adductor strength. But clinically, such injuries are usually diagnosed weeks or months after onset. Vincristine injection does not affect a muscle that is already innervated; thus, there is a limited time frame following RLN injury during which a vincristine injection could effectively improve ultimate laryngeal adductor functional recovery. A series of delayed injections was performed in a canine model and results assessed.

Study Design:

Animal (canine) experiment.

Methods:

The RLN was transected and repaired, and vincristine (0.4 mg) was injected into the PCA muscle at the time of injury (n = 12) or 3, 4, and 5 months later (n = 8 each study group). Six months after RLN injury, laryngeal adductor function was measured. Results of vincristine injection without RLN injury (n = 6) and longer-term (12 months) follow-up for time zero injections (n = 4) are also reported.

Results:

The animals injected at time zero had better adductor function than non-injected controls, as reported previously, and this result was further increased at 12 months. The 3-month delay gave results similar to the time zero group. The 5-month delay group showed no vincristine benefit, and the 4-month delay group gave an intermediate result. Vincristine to the PCA had no effect on adductor function when the RLN was left intact. Plasma levels showed 19% of injected vincristine reached systemic circulation, which was cleared within 69 hours.

Conclusions:

Vincristine injection of the PCA muscle after RLN injury, which blocks this antagonist muscle from synkinetic reinnervation, leads to improved laryngeal adductor functional recovery. The window of opportunity to apply this treatment closes by 4 months after RLN injury in the canine model. Human RLN recovery follows a similar time course and can reasonably be expected to have a similar therapeutic window.
The reform of New Public Management and the creation of public values: compatible processes? An empirical analysis of public water utilities
Authors: Colon Marine , Guérin-Schneider Lætitia
Published: January 2015

How compatible are the reform of New Public Management (NPM) reforms and the creation of public values in practice? This issue is addressed in the light of the reforms of two public water utilities. Building on Moore’s (1995) strategic triangle, we have analysed the process of value creation associated with measures inspired by NPM. These reforms were first intended to secure financial resources. Certain public values were subsequently created, either under the influence of a leader, or through formalized NPM management tools. Under certain conditions, the implementation of an NPM reform thus proves compatible with the introduction of processes that sustain public values. However, an undemocratic context necessarily limits these processes.

Points for practitioners

This article encourages public managers to think about the values they uphold when implementing a public policy and the terms and conditions of this implementation. The water sector in developing countries, reformed in line with the principles of NPM, offers two distinct illustrations. The cases of the NWSC in Uganda and of the PPWSA in Cambodia allow the question to be studied in contexts where the public service mission entails strong societal challenges that cannot be reduced to efficiency alone.
The impact of temperature and humidity on bonded repairs performed in the field
Authors: Charles Andrew DM , Wang John , Stoyanovski Ivan
Published: January 2015

In this investigation, sandwich and laminate single lap-shear specimens were manufactured in cold, ambient and hot environments using five typical adhesives commonly used for bonded repairs conducted in the field. The use of these adhesives in these environments, and resulting mechanical strength of repair were evaluated. The results indicate that in most instances, the hot environment proved favourable for adhesive handling and application, but dramatically reduced adhesive gel time and the effectiveness of surface treatment procedures. Flatwise tension strength of the sandwich specimens was not affected, and single lap-shear strength performance varied for each of the adhesives. In the cold environment, adhesive handling and application was relatively difficult, whilst the single lap-shear strength was found to improve, likely resulting from improved effectiveness of surface preparation procedures in this environment.
Mechanical, thermal, and viscoelastic properties of polypropylene/glass hybrid composites reinforced with multiwalled carbon nanotubes
Authors: Taraghi Iman , Fereidoon Abdolhossein , Zamani Mahdieh M , Mohyeddin Ali
Published: January 2015

This experimental study is conducted to investigate the mechanical, thermal, and viscoelastic properties of isotactic polypropylene reinforced with short glass fibers and multiwalled carbon nanotubes. The study of morphological properties shows that multiwalled carbon nanotubes were completely mixed with neat polypropylene at low contents of multiwalled carbon nanotube, whereas some part of agglomeration was observed for 1.5 wt.%. Optimum tensile and flexural properties were achieved by adding 1 wt.% multiwalled carbon nanotube and 20 wt.% short glass fibers to polypropylene matrix. Dynamic mechanical thermal analysis results demonstrated improvements in the storage and loss modulus by increasing multiwalled carbon nanotube content up to an optimum value due to higher degrees of stress transfer from the matrix to the filler. Also, a reduction in loss factor was observed because of the interfacial bonding improvement between the constituents. Differential scanning calorimetry results revealed increasing of the crystallization peak temperature and the degree of crystallinity in the presence of multiwalled carbon nanotubes.
Stress model and strain energy release rate of a prescribed crack in scarf joint/repair of composite panels
Authors: Yang Chihdar , Tomblin John S , Salah Lamia
Published: January 2015

An analytical model for stress distribution was derived and an analytical model for determining the strain energy release rate of a prescribed crack in a scarf joint or a bonded scarf repair of a composite panel was developed. The crack closure method was used to calculate the strain energy release rate at the crack tip after a prescribed crack was inserted at high adhesive stress locations. In the stress model, the first-order laminated plate theory was applied to the composite panels, including the following: (1) scarfed parent substrate and corresponding repair panel for a bonded scarf repair or (2) both adherend panels for a scarf joint, assuming a linear elastic adhesive. The bondline was presumed to be thin, so the adhesive stresses were presumed to be uniform through the thickness. The coupled second-order differential equations obtained via kinematics and force equilibrium were solved semi-numerically using the symbolic computational tool Maple. Finite element analyses using the commercial software ABAQUS™ were conducted for comparison purposes, and results correlated well with the developed analytical model. Experimental strain data of the bonded scarf repairs was also used to verify the developed model. It can be seen that the highest adhesive stresses occur at locations where high-stiffness plies are discontinued. The obtained strain energy release rate can be used for failure analysis if appropriate critical energy release rates in conjunction with proper mode mixture rule are used.
Hypotonic Stress Induces RANKL via Transient Receptor Potential Melastatin 3 (TRPM3) and Vaniloid 4 (TRPV4) in Human PDL Cells
Authors: Son G.Y. , Yang Y.M. , Park W.S. , Chang I. , Shin D.M.
Published: January 2015

Bone remodeling occurs in response to various types of mechanical stress. The periodontal ligament (PDL) plays an important role in mechanical stress–mediated alveolar bone remodeling. However, the underlying mechanism at the cellular level has not been extensively studied. In this study, we investigated the effect of shear stress on the expression of bone remodeling factors, including receptor activator of nuclear factor–kappa B (NF-κB) ligand (RANKL) and osteoprotegerin (OPG), as well as its upstream signaling pathway in primary human PDL cells. We applied hypotonic stress to reproduce shear stress to PDL cells. Hypotonic stress induced the messenger RNA (mRNA) and protein expression of RANKL but not OPG. It also increased intracellular Ca2+ concentration ([Ca2+]i). Extracellular Ca2+ depletion and nonspecific plasma membrane Ca2+ channel blockers completely inhibited the increase in both [Ca2+]i and RANKL mRNA expression. We identified the expression and activation of transient receptor potential melastatin 3 (TRPM3) and vaniloid 4 (TRPV4) channels in PDL cells. Pregnenolone sulfate (PS) and 4α-phorbol 12, 13-didecanoate (4α-PDD), which are agonists of TRPM3 and TRPV4, augmented Ca2+ influx and RANKL mRNA expression. Both pharmacological (2-aminoethoxydiphenyl borate [2-APB], ruthenium red [RR], ononetin [Ono], and HC 067047 [HC]) and genetic (small interfering RNA [siRNA]) inhibitors of TRPM3 and TRPV4 reduced the hypotonic stress–mediated increase in [Ca2+]i and RANKL mRNA expression. Our study shows that hypotonic stress induced RANKL mRNA expression via TRPM3- and TRPV4-mediated extracellular Ca2+ influx and RANKL expression. This signaling pathway in PDL cells may play a critical role in mechanical stress–mediated alveolar bone remodeling.
Wntless Regulates Dentin Apposition and Root Elongation in the Mandibular Molar
Authors: Bae C.H. , Kim T.H. , Ko S.O. , Lee J.C. , Yang X. , Cho E.S.
Published: January 2015

Wnt signaling plays an essential role in the dental epithelium and mesenchyme during tooth morphogenesis. However, it remains unclear if Wnt ligands, produced from dental mesenchyme, are necessary for odontoblast differentiation and dentin formation. Here, we show that odontoblast-specific disruption of Wntless (Wls), a chaperon protein that regulates Wnt sorting and secretion, leads to severe defects in dentin formation and root elongation. Dentin thickness decreased remarkably and pulp chambers enlarged in the mandibular molars of OC-Cre;WlsCO/CO mice. Although the initial odontoblast differentiation was normal in the mutant crown, odontoblasts became cuboidal and dentin thickness was reduced. In immunohistochemistry, Wnt10a, β-catenin, type I collagen, and dentin sialoprotein were significantly down-regulated in the odontoblasts of mutant crown. In addition, roots were short and root canals were widened. Cell proliferation was reduced in the developing root apex of mutant molars. Furthermore, Wnt10a and Axin2 expression was remarkably decreased in the odontoblasts of mutant roots. Deletion of the Wls gene in odontoblasts appears to reduce canonical Wnt activity, leading to inhibition of odontoblast maturation and root elongation.
Non-judgemental Discourse in the Development of Critical Capacity for Language Teachers
Authors: Edge Julian
Published: January 2015

A major structural problem in the teaching of English worldwide is to be found in the arthritic power relationships that continue to limit the continuing professional development of its practitioners. The acceptance of the superior status of ‘theory’ and ‘theorists’, and the consequent subordination of teachers as the ‘appliers’ of such theory, in alliance with the continuing acceptance of the primacy of monolingually-derived approaches to the exploration of language learning and teaching, express the constraints of hegemony rather than the needs of the profession. Against this background, the disciplined use of non-judgemental discourse, here formalized in an approach called cooperative development, offers one way forward in the attempt to encourage the bottom-up theorization of experience that can reflexively encourage and be nourished by the growth of critical capacity.
A Multilevel Higher Order Item Response Theory Model for Measuring Latent Growth in Longitudinal Data
Authors: Huang Hung-Yu
Published: January 2015

In educational and psychological testing, individuals are often repeatedly measured to assess the changes in their abilities over time or their latent trait growth. If a test consists of several subtests, the latent traits may have a higher order structure, and traditional item response theory (IRT) models for longitudinal data are no longer applicable. In this study, various multilevel higher order item response theory (ML-HIRT) models for simultaneously measuring growth in the second- and first-order latent traits of dichotomous and polytomous items are proposed. A series of simulations conducted using the WinBUGS software with Markov chain Monte Carlo (MCMC) methods reveal that the parameters could be recovered satisfactorily and that latent trait estimation was reliable across measurement times. The application of the ML-HIRT model to longitudinal data sets is illustrated with two empirical examples.
A Descriptive Study of the Risk Factors Associated With Catheter‐Related Bloodstream Infections in the Home Parenteral Nutrition Population
Authors: Durkin Michael J. , Dukes Jonathan L. , Reeds Dominic N. , Mazuski John E. , Camins Bernard C.
Published: January 2015

Background: Home parenteral nutrition (HPN) is increasingly used for nutrition support after patients are discharged from the hospital. Catheter‐related bloodstream infections (CR‐BSI) are a common and potentially fatal complication of HPN. The risk factors for development of CR‐BSI in the outpatient setting are poorly understood. Methods: We conducted an observational, retrospective study of 225 patients discharged from Barnes‐Jewish Hospital on HPN between January 1, 2007, and December 31, 2009. HPN complications were defined as any cause that led to either premature discontinuation of HPN therapy or catheter replacement. CR‐BSI events were identified by provider documentation. We calculated the overall complication rate and the complication rate specifically due to CR‐BSI. Backward stepwise Cox regression analyses were used to assess for independent predictors of catheter‐related complications. Results: In total, 111 of 225 patients (49%) developed complications while receiving HPN (incidence = 5.06 episodes/1000 catheter days). Sixty‐eight of 225 patients (30%) required catheter removal for CR‐BSI (incidence = 3.10 episodes/1000 catheter days). Independent predictors of line removal specifically due to infection included anticoagulant use, ulcer or open wound, and Medicare or Medicaid insurance. The following risk factors were associated with catheter‐associated complications and/or CR‐BSI: the presence of ulcers, the use of systemic anticoagulants, public insurance (Medicare or Medicaid), and patient age. Independent predictors of line removal for any complication included age and anticoagulant use. Conclusion: Catheter‐related complications were extremely common in patients receiving HPN. Healthcare providers caring for individuals who require HPN should be aware of risk factors for complications.
Vitamin E in New‐Generation Lipid Emulsions Protects Against Parenteral Nutrition–Associated Liver Disease in Parenteral Nutrition–Fed Preterm Pigs
Authors: Ng Kenneth , Stoll Barbara , Chacko Shaji , Saenz de Pipaon Miguel , Lauridsen Charlotte , Gray Matthew , Squires E. James , Marini Juan , Zamora Irving J. , Olutoye Oluyinka O. , Burrin Douglas G.
Published: January 2015

Introduction: Parenteral nutrition (PN) in preterm infants leads to PN‐associated liver disease (PNALD). PNALD has been linked to serum accumulation of phytosterols that are abundant in plant oil but absent in fish oil emulsions. Hypothesis: Whether modifying the phytosterol and vitamin E composition of soy and fish oil lipid emulsions affects development of PNALD in preterm pigs. Methods: We measured markers of PNALD in preterm pigs that received 14 days of PN that included 1 of the following: (1) Intralipid (IL, 100% soybean oil), (2) Intralipid + vitamin E (ILE, d‐α‐tocopherol), (3) Omegaven (OV, 100% fish oil), or (4) Omegaven + phytosterols (PS, β‐sitosterol, campesterol, and stigmasterol). Results: Serum levels of direct bilirubin, gamma glutamyl transferase, serum triglyceride, low‐density lipoprotein, and hepatic triglyceride content were significantly lower (P < .05) in the ILE, OV, and PS compared to IL. Hepatic cholesterol 7‐hydroxylase and organic solute transporter–α expression was lower (P < .05) and portal plasma FGF19 higher in the ILE, OV, and PS vs IL. Hepatic expression of mitochondrial carnitine palmitoyltransferase 1A and microsomal cytochrome P450 2E1 fatty acid oxidation genes was higher in ILE, OV, and PS vs IL. In vivo 13C‐CDCA clearance and expression of pregnane X receptor target genes, cytochrome P450 3A29 and multidrug resistance‐associated protein 2, were higher in ILE, OV, and PS vs IL. Conclusions: α‐tocopherol in Omegaven and added to Intralipid prevented serum and liver increases in biliary and lipidemic markers of PNALD in preterm piglets. The addition of phytosterols to Omegaven did not produce evidence of PNALD.