bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Circulating miRNAs in a Mouse Model of Nerve Allograft Transplantation under FK506 Immunosuppression by Illumina Small RNA Deep Sequencing
Authors: Wu Shao-Chun , Rau Cheng-Shyuan , Yang Johnson Chia-Shen , Lu Tsu-Hsiang , Wu Yi-Chan , Chen Yi-Chun , Tzeng Siou-Ling , Wu Chia-Jung , Lin Chia-Wei , Hsieh Ching-Hua
Published: September 2015

Background. This study aimed to establish the expression profile of circulating microRNAs (miRNAs) during nerve allotransplantation in the presence and absence of FK506 immunosuppression.Methods. A 1 cm BALB/c donor sciatic nerve graft was transplanted into the sciatic nerve gaps created in recipient C57BL/6 mice with or without daily FK506 immunosuppression [1 mg/(kg·d)]. At 3, 7, and 14 d after nerve allotransplantation, serum samples were collected for miRNA expression analysis by Illumina small RNA deep sequencing.Results. Sequence analysis showed that the dominant size of circulating small RNAs after nerve allotransplantation was 22 nucleotides, followed by 23-nucleotide sequences. Nine upregulated circulating miRNAs (let-7e-5p, miR-101a-3p, miR-151-5p, miR-181a-5p, miR-204-5p, miR-340-5p, miR-381-3p, miR-411-5p, miR-9-5p, and miR-219-2-3p) were identified at 3 d, but none was identified at 7 or 14 d. Among them, miR-9-5p had the highest fold-change of >50-fold, followed by miR-340-5p with 38.8-fold. The presence of these nine miRNAs was not significant at 7 and 14 d after nerve allotransplantation with or without immunosuppression, showing that these miRNAs are not ideal biomarkers for monitoring rejection of deep-buried nerve allografts, a response usually observed later.Conclusions. We identified nine upregulated circulating miRNAs, which may have a biological function, particularly during the early stages after nerve allotransplantation under FK506 immunosuppression.
Optimal Vitamin D Supplementation Levels for Cardiovascular Disease Protection
Authors: Lugg Sebastian T. , Howells Phillip A. , Thickett David R.
Published: September 2015

First described in relation to musculoskeletal disease, there is accumulating data to suggest that vitamin D may play an important role in cardiovascular disease (CVD). In this review we aim to provide an overview of the role of vitamin D status as both a marker of and potentially causative agent of hypertension, coronary artery disease, heart failure, atrial fibrillation, stroke, and peripheral vascular disease. The role of vitamin D levels as a disease marker for all-cause mortality is also discussed. We review the current knowledge gathered from experimental studies, observational studies, randomised controlled trials, and subsequent systematic reviews in order to suggest the optimal vitamin D level for CVD protection.
Distributed Multiagent Control Approach for Multitarget Tracking
Authors: Ma Liang , Xue Kai , Wang Ping
Published: September 2015

In multiagent systems, tracking multiple targets is challenging for two reasons: firstly, it is nontrivial to dynamically deploy networked agents of different types for utility optimization; secondly, information fusion for multitarget tracking is difficult in the presence of uncertainties, such as data association, noise, and clutter. In this paper, we present a novel control approach in distributed manner for multitarget tracking. The control problem is modelled as a partially observed Markov decision process, which is a NP-hard combinatorial optimization problem, by seeking all possible combinations of control commands. To solve this problem efficiently, we assume that the measurement of each agent is independent of other agents’ behavior and provide a suboptimal multiagent control solution by maximizing the local Rényi divergence. In addition, we also provide the SMC implementation of the sequential multi-Bernoulli filter so that each agent can utilize the measurements from neighbouring agents to perform information fusion for accurate multitarget tracking. Numerical studies validate the effectiveness and efficiency of our multiagent control approach for multitarget tracking.
Persistent Notochord in a Fetus with COL2A1 Mutation
Authors: Codsi Elisabeth , Brost Brian C. , Faksh Arij , Volk Amber K. , Borowski Kristi S.
Published: September 2015

Multiple anomalies including micromelia, poor mineralization of the vertebrae, and a persistent notochord were identified on second trimester ultrasound in a fetus with aCOL2A1mutation. To our knowledge, this represents the first case of a persistent notochord associated with aCOL2A1mutation in humans. In this case report, we describe ultrasound and postmortem findings and review the pathogenesis associated with a persistent notochord.
PKCα Attenuates Jagged-1–Mediated Notch Signaling in ErbB-2–Positive Breast Cancer to Reverse Trastuzumab Resistance
Authors: Pandya Kinnari , Wyatt Debra , Gallagher Brian , Shah Deep , Baker Andrew , Bloodworth Jeffrey , Zlobin Andrei , Pannuti Antonio , Green Andrew , Ellis Ian O. , Filipovic Aleksandra , Sagert Jason , Rana Ajay , Albain Kathy S. , Miele Lucio , Denning Mitchell F. , Osipo Clodia
Published: September 2015

Purpose: Breast cancer is the second leading cause of cancer mortality among women worldwide. The major problem with current treatments is tumor resistance, recurrence, and disease progression. ErbB-2–positive breast tumors are aggressive and frequently become resistant to trastuzumab or lapatinib. We showed previously that Notch-1 is required for trastuzumab resistance in ErbB-2–positive breast cancer.

Experimental Design: Here, we sought to elucidate mechanisms by which ErbB-2 attenuates Notch signaling and how this is reversed by trastuzumab or lapatinib.

Results: The current study elucidates a novel Notch inhibitory mechanism by which PKCα downstream of ErbB-2 (i) restricts the availability of Jagged-1 at the cell surface to transactivate Notch, (ii) restricts the critical interaction between Jagged-1 and Mindbomb-1, an E3 ligase that is required for Jagged-1 ubiquitinylation and subsequent Notch activation, (iii) reverses trastuzumab resistance in vivo, and (iv) predicts better outcome in women with ErbB-2–positive breast cancer.

Conclusions: The clinical impact of these studies is PKCα is potentially a good prognostic marker for low Notch activity and increased trastuzumab sensitivity in ErbB-2–positive breast cancer. Moreover, women with ErbB-2–positive breast tumors expressing high Notch activation and low PKCα expression could be the best candidates for anti-Notch therapy. Clin Cancer Res; 22(1); 175–86. ©2015 AACR.
ROS-Induced CXCR4 Signaling Regulates Mantle Cell Lymphoma (MCL) Cell Survival and Drug Resistance in the Bone Marrow Microenvironment via Autophagy
Authors: Chen Zheng , Teo Albert E. , McCarty Nami
Published: September 2015

Purpose: Patients with advanced stages of mantle cell lymphoma (MCL) have a poor prognosis after standard therapies. MCL cells in those patients often spread into tissues other than lymph nodes, such as the bone marrow. Apart from directed migration and homing, there is little understanding of the function of the CXCR4/SDF-1 signaling axis in MCL. In this report, we aim to understand mechanisms of MCL cell survival in the bone marrow.

Experimental Design: For comprehensive analyses of MCL interactions with bone marrow stromal cells, we have generated gene knockout cells using CRISPR-CAS9 system and gene knockdown cells to reveal novel roles of the CXCR4/SDF-1 signaling.

Results: CXCR4 silencing in MCL cells led to a significant reduction in proliferation, cell adhesion to bone marrow stromal cells, and colony formation in PHA-LCM methylcellulose medium, which were reversed upon the addition of SDF-1–neutralizing antibodies. In addition, tracking MCL cell engraftment in vivo revealed that quiescent MCL cells are significantly reduced in the bone marrow upon CXCR4 silencing, indicating that CXCR4/SDF-1 signaling is required for the survival and maintenance of the quiescent MCL cells. Further analysis revealed novel mechanisms of ROS-induced CXCR4/SDF-1 signaling that stimulate autophagy formation in MCL cells for their survival.

Conclusions: Our data, for the first time, revealed new roles of the CXCR/SDF-1 signaling axis on autophagy formation in MCL, which further promoted their survival within the bone marrow microenvironment. Targeting the CXCR4/SDF-1/autophagy signaling axis may contribute to an enhanced efficacy of current therapies. Clin Cancer Res; 22(1); 187–99. ©2015 AACR.
Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies
Authors: Calpe Silvia , Wagner Koen , El Khattabi Mohamed , Rutten Lucy , Zimberlin Cheryl , Dolk Edward , Verrips C. Theo , Medema Jan Paul , Spits Hergen , Krishnadath Kausilia K.
Published: September 2015

Bone morphogenetic proteins (BMP) have important but distinct roles in tissue homeostasis and disease, including carcinogenesis and tumor progression. A large number of BMP inhibitors are available to study BMP function; however, as most of these antagonists are promiscuous, evaluating specific effects of individual BMPs is not feasible. Because the oncogenic role of the different BMPs varies for each neoplasm, highly selective BMP inhibitors are required. Here, we describe the generation of three types of llama-derived heavy chain variable domains (VHH) that selectively bind to either BMP4, to BMP2 and 4, or to BMP2, 4, 5, and 6. These generated VHHs have high affinity to their targets and are able to inhibit BMP signaling. Epitope binning and docking modeling have shed light into the basis for their BMP specificity. As opposed to the wide structural reach of natural inhibitors, these small molecules target the grooves and pockets of BMPs involved in receptor binding. In organoid experiments, specific inhibition of BMP4 does not affect the activation of normal stem cells. Furthermore, in vitro inhibition of cancer-derived BMP4 noncanonical signals results in an increase of chemosensitivity in a colorectal cancer cell line. Therefore, because of their high specificity and low off-target effects, these VHHs could represent a therapeutic alternative for BMP4+ malignancies. Mol Cancer Ther; 14(11); 2527–40. ©2015 AACR.
Collateral Circulation Predicts the Size of the Infarct Core and the Proportion of Salvageable Penumbra in Hyperacute Ischemic Stroke Patients Treated with Intravenous Thrombolysis
Authors: Rusanen Harri , Saarinen Jukka T. , Sillanpää Niko
Published: September 2015

Background: We studied the impact of collateral circulation on CT perfusion (CTP) parametric maps and the amount of salvaged brain tissue, the imaging and clinical outcome at 24 h and at 3 months in a retrospective acute (<3 h) stroke cohort (105 patients) with anterior circulation thrombus treated with intravenous thrombolysis. Methods: Baseline clinical and imaging information were collected and groups with different collateral scores (CS) were compared. Binary logistic regression analyses using good CS (CS ≥2) as the dependent variable were calculated. Results: CTP Alberta Stroke Program Early CT Score (ASPECTS) was successfully assessed in 58 cases. Thirty patients displayed good CS. Poor CS were associated with more severe strokes according to National Institutes of Health Stroke Scale (NIHSS) at arrival (15 vs. 7, p = 0.005) and at 24 h (10 vs. 3, p = 0.003) after intravenous thrombolysis. Good CS were associated with a longer mean onset-to-treatment time (141 vs. 121 min, p = 0.009) and time to CTP (102 vs. 87 min, p = 0.047), better cerebral blood volume (CBV) ASPECTS (9 vs. 6, p < 0.001), better mean transit time (MTT) ASPECTS (6 vs. 3, p < 0.001), better noncontrast CT (NCCT) ASPECTS (10 vs. 8, p < 0.001) at arrival and with favorable clinical outcome at 3 months (modified Rankin Scale ≤2, p = 0.002). The fraction of penumbra that was salvageable at arrival and salvaged at 24 h was higher with better CS (p < 0.001 and p = 0.035, respectively). In multivariate analysis, time from the onset of symptoms to imaging (p = 0.037, OR 1.04 per minute, 95% CI 1.00-1.08) and CBV ASPECTS (p = 0.001, OR 2.11 per ASPECTS point, 95% CI 1.33-3.34) predicted good CS. In similar multivariable models, MTT ASPECTS (p = 0.04, OR 1.46 per ASPECTS point, 95% CI 1.02-2.10) and NCCT ASPECTS predicted good CS (p = 0.003, OR 4.38 per CT ASPECTS point, 95% CI 1.66-11.55) along with longer time from the onset of symptoms to imaging (p = 0.045, OR 1.03 per minute, 95% CI 1.00-1.06 and p = 0.02, OR 1.05 per minute, 95% CI 1.00-1.09, respectively). CBV ASPECTS had a larger area under the receiver operating characteristic curve for good CS (0.837) than NCCT ASPECTS (0.802) or MTT ASPECTS (0.752) at arrival. Conclusions: Favorable CBV ASPECTS, NCCT ASPECTS and MTT ASPECTS are associated with good CS along with more salvageable tissue and longer time from the onset of symptoms to imaging in ischemic stroke patients treated with intravenous thrombolysis.
Cortical Superficial Siderosis and Risk of Bleeding after Thrombolysis for Ischemic Stroke
Authors: Gattringer Thomas , Eppinger Sebastian , Beitzke Markus , Wuensch Gerit , Niederkorn Kurt , Deutschmann Hannes , Fazekas Franz , Enzinger Christian
Published: September 2015

Background: Cortical superficial siderosis (CSS) is a neuroimaging marker of cerebral amyloid angiopathy and has been associated with a high risk for early subsequent major intracranial hemorrhage (ICH). Therefore, many experts recommend withholding of antithrombotic medication to patients with CSS. In this study, we sought to investigate the prevalence of CSS and the associated risk of ICH in the setting of intravenous thrombolysis (IVT) for ischemic stroke. Methods: We retrospectively searched the medical documentation system of our primary and tertiary care university clinic for all patients with ischemic stroke that received IVT from 2009 to December 2014. All available imaging data were reviewed in a standardized manner and blinded to any clinical data for the presence of CSS and ICH. CSS was defined as linear signal loss along the cerebral cortex on gradient echo T2*-weighted sequences. A stroke neurologist, who was blinded to the neuroimaging data, extracted the corresponding clinical data including follow-up information. Results: We identified 298 patients that received IVT and had undergone brain MRI (mean age 67.6 ± 12.6 years, 59.4% male). Cerebral MRI was performed in 116 patients (38.9%) before and in 182 patients (61.1%) after IVT (median time from stroke symptom onset to MRI: 1 day; range 0-7 days). Only 3 patients (2 females and 1 male aged 90, 76 and 73 years, respectively) had CSS (1%). All of them had a middle cerebral artery (MCA) stroke with a corresponding vessel occlusion. The 76-year-old female patient had extensive CSS and numerous cerebral microbleeds and received another IVT treatment for recurrent MCA stroke 8 months after the first event. After both IVTs, she had clinically asymptomatic small ICH outside the ischemic infarct and distant from CSS. The 2 other patients had only mild to moderate CSS and did not experience any ICH on postthrombolytic imaging. Conclusions: The prevalence of CSS in a clinical cohort of stroke patients that received IVT was low and thus does not appear to pose a substantial risk for symptomatic ICH although this may occur in individual patients. However, such analysis also needs to be extended to the very old stroke patients in whom IVT is increasingly used.
Impact of Bowel Preparation with Low-Volume (2-Liter) and Intermediate-Volume (3-Liter) Polyethylene Glycol on Colonoscopy Quality: A Prospective Observational Study
Authors: Cheng Chi-Liang , Kuo Yen-Lin , Liu Nai-Jen , Lin Cheng-Hui , Tang Jui-Hsiang , Tsui Yi-Ning , Lee Bai-Ping , Su Ming-Yao , Chiu Cheng-Tang
Published: September 2015

Background/Aims: Two-liter polyethylene glycol (PEG) is the most commonly used bowel-cleansing regimen in Taiwan, but its efficacy is unsatisfactory. The aim of this study was to compare 2-liter and 3-liter PEG in terms of their impact on colonoscopy quality among an average-risk population. Methods: Two-liter PEG was provided between August 2012 and May 2013, while 3-liter PEG was provided between June 2013 and March 2014. A split-dose regimen was provided for morning colonoscopy and a same-day regimen was provided for afternoon colonoscopy. The level of bowel cleansing was prospectively scored. Results: A total of 407 consecutive subjects completed the 2-liter regimen, and another 407 consecutive subjects completed the 3-liter regimen. The 3-liter group had a significantly higher rate of excellent or good preparations, equivalent to a Boston bowel preparation scale of ≥7, than the 2-liter group (90 vs. 73%, p < 0.0001). More subjects in the 3-liter preparation group compared with the 2-liter group had overall adenoma (70 vs. 54%, p < 0.0001), proximal adenoma (47 vs. 35%, p = 0.0006), sessile serrated adenoma (28 vs. 6%, p < 0.0001), and advanced adenoma (21 vs. 9%, p < 0.0001). Conclusions: Three-liter PEG provided better cleansing quality and higher adenoma detection rate than 2-liter PEG.
Determination of the Hypnotic Potency in Rats of the Novel Ketamine Ester Analogue SN 35210
Authors: Harvey Martyn , Sleigh James , Voss Logan , Pruijn Frederik , Jose Jiney , Gamage Swarma , Denny William
Published: September 2015

Background: Ketamine is a rapidly acting dissociative anaesthetic drug with additional sympathomimetic, analgesic, and antidepressant properties. Despite these advantages, clinical use is curtailed by prolonged psychomimetic effects apparent over the entire dose spectrum. In this study, we report on the hypnotic potency of SN 35210, the first ketamine ester-analogue designed for rapid offset via esterase-mediated hydrolysis. Methods: Thirty-three adult Sprague Dawley rats received intravenous racemic ketamine (n = 14), racemic SN 35210 (n = 19), S-enantiomer SN 35210 (n = 17), or R-enantiomer SN 35210 (n = 15), in crossover design. The ability to induce loss of righting reflex (LORR) at a given dose, the duration of righting reflex loss, and the time to return of normal behaviours were recorded. The ED50 for LORR was determined for all agents. Results: The ED50 for righting reflex loss was racemic ketamine 9.6 (95% CI 8.5-10.9) mg/kg, racemic SN 35210 10.4 (95% CI 9.5-11.5) mg/kg, S-enantiomer SN 35210 10.6 (95% CI 9.1-11.8), and R-enantiomer SN 35210 10.3 (95% CI 9.1-11.4) mg/kg. The duration of righting reflex loss and time to return to normal behaviours were approximately 5 times greater for racemic ketamine than all 3 SN 35210 ester analogues. Conclusions: Racemic, and R and S-enantiomer SN 35210, produced LORR in rats at similar doses to the parent compound ketamine. The duration of righting reflex loss, and duration of behavioural aberration, was significantly reduced for all SN 35210 analogues.
The Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) Classification System
Authors: Spatz Erica S. , Curry Leslie A. , Masoudi Frederick A. , Zhou Shengfan , Strait Kelly M. , Gross Cary P. , Curtis Jeptha P. , Lansky Alexandra J. , Soares Barreto-Filho Jose Augusto , Lampropulos Julianna F. , Bueno Hector , Chaudhry Sarwat I. , D’Onofrio Gail , Safdar Basmah , Dreyer Rachel P. , Murugiah Karthik , Spertus John A. , Krumholz Harlan M.
Published: September 2015

Background—

Current classification schemes for acute myocardial infarction (AMI) may not accommodate the breadth of clinical phenotypes in young women.

Methods and Results—

We developed a novel taxonomy among young adults (≤55 years) with AMI enrolled in the Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) study. We first classified a subset of patients (n=600) according to the Third Universal Definition of MI using a structured abstraction tool. There was heterogeneity within type 2 AMI, and 54 patients (9%; including 51 of 412 women) were unclassified. Using an inductive approach, we iteratively grouped patients with shared clinical characteristics, with the aims of developing a more inclusive taxonomy that could distinguish unique clinical phenotypes. The final VIRGO taxonomy classified 2802 study participants as follows: class 1, plaque-mediated culprit lesion (82.5% of women; 94.9% of men); class 2, obstructive coronary artery disease with supply-demand mismatch (2a: 1.4% women; 0.9% men) and without supply-demand mismatch (2b: 2.4% women; 1.1% men); class 3, nonobstructive coronary artery disease with supply-demand mismatch (3a: 4.3% women; 0.8% men) and without supply-demand mismatch (3b: 7.0% women; 1.9% men); class 4, other identifiable mechanism (spontaneous dissection, vasospasm, embolism; 1.5% women, 0.2% men); and class 5, undetermined classification (0.8% women, 0.2% men).

Conclusions—

Approximately 1 in 8 young women with AMI is unclassified by the Universal Definition of MI. We propose a more inclusive taxonomy that could serve as a framework for understanding biological disease mechanisms, therapeutic efficacy, and prognosis in this population.
Prevalence of Apparent Therapy-Resistant Hypertension and Its Effect on Outcome in Patients With Chronic Kidney Disease
Authors: de Beus Esther , Bots Michiel L. , van Zuilen Arjan D. , Wetzels Jack F.M. , Blankestijn Peter J.
Published: September 2015

New options recently became available for treatment of uncontrolled blood pressure. Information on the prevalence of therapy-resistant hypertension (TRH) in patients with chronic kidney disease and its consequences is relevant to balance risks and benefits of potential new therapies. Data of 788 patients with chronic kidney disease came from a multicenter study investigating the effect on outcome of an integrated multifactorial approach delivered by nurse practitioners added to usual care versus usual care alone. Blood pressure was measured at the office and during 30 minutes using an automated oscillometric device. Apparent TRH (aTRH) was defined as a blood pressure ≥130/80 mm Hg despite treatment with ≥3 antihypertensive drugs, including a diuretic or treatment with ≥4 antihypertensive drugs. Participants were followed up for the occurrence of myocardial infarction, stroke or cardiovascular mortality (composite cardiovascular end point) and end-stage renal disease. aTRH was present in 34% (office blood pressure) and in 32% (automated measurements). During 5.3 years of follow-up, 17% of patients with aTRH reached a cardiovascular end point and 27% reached end-stage renal disease. aTRH lead to a 1.5-fold higher risk (95% confidence interval, 0.8–3.0) of a cardiovascular end point compared with controlled hypertensives in multivariable-adjusted analysis. aTRH increased end-stage renal disease risk 2.3-fold (95% confidence interval, 1.4–3.7). During 4 years of follow-up, the prevalence of aTRH did not decline in either treatment group. The prevalence of aTRH is high in patients with chronic kidney disease even after optimization of nephrologist care. The presence of TRH is related to a substantially increased risk of renal and cardiovascular outcomes.
Pentaerythritol Tetranitrate Targeting Myocardial Reactive Oxygen Species Production Improves Left Ventricular Remodeling and Function in Rats With Ischemic Heart Failure
Authors: Fraccarollo Daniela , Galuppo Paolo , Neuser Jonas , Bauersachs Johann , Widder Julian D.
Published: September 2015

Reduced nitric oxide bioavailability contributes to progression of cardiac dysfunction and remodeling in ischemic heart failure. Clinical use of organic nitrates as nitric oxide donors is limited by development of nitrate tolerance and reactive oxygen species formation. We investigated the effects of long-term therapy with pentaerythritol tetranitrate (PETN), an organic nitrate devoid of tolerance, in rats with congestive heart failure after extensive myocardial infarction. Seven days after coronary artery ligation, rats were randomly allocated to treatment with PETN (80 mg/kg BID) or placebo for 9 weeks. Long-term PETN therapy prevented the progressive left ventricular dilatation and improved left ventricular contractile function and relaxation in rats with congestive heart failure. Mitochondrial superoxide anion production was markedly increased in the failing left ventricular myocardium and nearly normalized by PETN treatment. Gene set enrichment analysis revealed that PETN beneficially modulated the dysregulation of mitochondrial genes involved in energy metabolism, paralleled by prevention of uncoupling protein-3, thioredoxin-2, and superoxide dismutase-2 downregulation. Moreover, PETN provided a remarkable protective effect against reactive fibrosis in chronically failing hearts. Mechanistically, induction of heme oxygenase-1 by PETN prevented mitochondrial superoxide generation, NOX4 upregulation, and ensuing formation of extracellular matrix proteins in fibroblasts from failing hearts. In summary, PETN targeting reactive oxygen species generation prevented the changes of mitochondrial antioxidant enzymes and progressive fibrotic remodeling, leading to amelioration of cardiac functional performance. Therefore, PETN might be a promising therapeutic option in the treatment of ischemic heart diseases involving oxidative stress and impairment in nitric oxide bioactivity.
Different Somatic Mutations in Multinodular Adrenals With Aldosterone-Producing Adenoma
Authors: Fernandes-Rosa Fabio Luiz , Giscos-Douriez Isabelle , Amar Laurence , Gomez-Sanchez Celso E. , Meatchi Tchao , Boulkroun Sheerazed , Zennaro Maria-Christina
Published: September 2015

Primary aldosteronism is the most common form of secondary hypertension. Somatic mutations in
KCNJ5
,
ATP1A1
,
ATP2B3
, and
CACNA1D
are found in aldosterone-producing adenoma. In addition, adrenals with aldosterone-producing adenomas show cortical remodeling and frequently multiple secondary nodules. Our aim was to investigate whether different aldosterone-producing nodules from the same adrenal share the same mutational status. Aldosterone synthase expression was assessed in multinodular adrenals from 27 patients. DNA of 37 aldosterone-producing secondary nodules was extracted from formalin-fixed paraffin-embedded tissues and genotyped for
KCNJ5
,
ATP1A1
,
ATP2B3
, and
CACNA1D
mutations. Among 17 adrenals with a somatic mutation in the principal nodule, 4 showed the same mutation in a secondary nodule, whereas 10 had no mutation in any of the known genes. In 1 adrenal harboring the
KCNJ5
p.Gly151Arg mutation in the principal nodule, the same mutation was present in 2 secondary nodules, but no mutation was found in a third nodule. Finally, in 2 adrenals with a
CACNA1D
mutation in the principal nodule, a
KCNJ5
mutation was identified in the secondary nodule. Among 10 adrenals without mutations in the principal nodule, 1 carried a
KCNJ5
mutation in the secondary nodule. No mutations were detected in 7 aldosterone-producing cell clusters from 6 adrenals. No association was observed between the presence of mutations in secondary nodules and clinical parameters. In conclusion, different mutations are found in different aldosterone-producing nodules from the same adrenal, suggesting that somatic mutations are independent events triggered by mechanisms that remain to be identified.
Galectin-3 Participates in Cardiovascular Remodeling Associated With Obesity
Authors: Martínez-Martínez Ernesto , López-Ándres Natalia , Jurado-López Raquel , Rousseau Elodie , Bartolomé Mará Visitación , Fernández-Celis Amaya , Rossignol Patrick , Islas Fabian , Antequera Alfonso , Prieto Santiago , Luaces María , Cachofeiro Victoria
Published: September 2015

Remodeling, diastolic dysfunction, and arterial stiffness are some of the alterations through which obesity affects the cardiovascular system. Fibrosis and inflammation are important mechanisms underlying cardiovascular remodeling, although the precise promoters involved in these processes are still unclear. Galectin-3 (Gal-3) induces inflammation and fibrosis in the cardiovascular system. We have investigated the potential role of Gal-3 in cardiac damage in morbidly obese patients, and we have evaluated the protective effect of the Gal-3 inhibition in the occurrence of cardiovascular fibrosis and inflammation in an experimental model of obesity. Morbid obesity is associated with alterations in cardiac remodeling, mainly left ventricular hypertrophy and diastolic dysfunction. Obesity and hypertension are the main determinants of left ventricular hypertrophy. Insulin resistance, left ventricular hypertrophy, and circulating levels of C-reactive protein and Gal-3 are associated with a worsening of diastolic function in morbidly obese patients. Obesity upregulates Gal-3 production in the cardiovascular system in a normotensive animal model of diet-induced obesity by feeding for 6 weeks a high-fat diet (33.5% fat). Gal-3 inhibition with modified citrus pectin (100 mg/kg per day) reduced cardiovascular levels of Gal-3, total collagen, collagen I, transforming and connective growth factors, osteopontin, and monocyte chemoattractant protein-1 in the heart and aorta of obese animals without changes in body weight or blood pressure. In morbidly obese patients, Gal-3 levels are associated with diastolic dysfunction. In obese animals, Gal-3 blockade decreases cardiovascular fibrosis and inflammation. These data suggest that Gal-3 could be a novel therapeutic target in cardiac fibrosis and inflammation associated with obesity.
Mediators of the Age Effect in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)
Authors: Voeks Jenifer H. , Howard George , Roubin Gary , Farb Richard , Heck Donald , Logan William , Longbottom Mary , Sheffet Alice , Meschia James F. , Brott Thomas G.
Published: September 2015

Background and Purpose—

There is higher combined risk of stroke or death (S+D) at older ages with carotid stenting. We assess whether this can be attributed to patient or arterial characteristics that are in the pathway between older age and higher risk.

Methods—

Mediation analysis of selected patient (hypertension, diabetes mellitus, and dyslipidemia) and arterial characteristics assessed at the clinical sites and the core laboratory (plaque length, eccentric plaque, ulcerated plaque, percent stenosis, peak systolic velocity, and location) was performed in 1123 carotid artery stenting–treated patients in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST). We assessed the association of age with these characteristics, the association of these characteristics with stroke risk, and the amount of mediation of the association of age on the combined risk of periprocedural S+D with adjustment for these factors.

Results—

Only plaque length as measured at the sites increased with age, was associated with increased S+D risk and significantly mediated the association of age on S+D risk. However, adjustment for plaque length attenuated the increased risk per 10 years of age from 1.72 (95% confidence interval, 1.26–2.37) to 1.66 (95% confidence interval, 1.20–2.29), accounting for only 8% of the increased risk.

Conclusions—

Plaque length seems to be in the pathway between older age and higher risk of S+D among carotid artery stenting–treated patients, but it mediated only 8% of the age effect excess risk of carotid artery stenting in CREST. Other factors and mechanisms underlying the age effect need to be identified as plaque length will not identify elderly patients for whom stenting is safe relative to endarterectomy.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00004732.
Neural Correlates of Visual Short-term Memory Dissociate between Fragile and Working Memory Representations
Authors: Vandenbroucke Annelinde R. E. , Sligte Ilja G. , de Vries Jade G. , Cohen Michael X. , Lamme Victor A. F.
Published: September 2015

Evidence is accumulating that the classic two-stage model of visual STM (VSTM), comprising iconic memory (IM) and visual working memory (WM), is incomplete. A third memory stage, termed fragile VSTM (FM), seems to exist in between IM and WM [Vandenbroucke, A. R. E., Sligte, I. G., & Lamme, V. A. F. Manipulations of attention dissociate fragile visual STM from visual working memory. Neuropsychologia, 49, 1559–1568, 2011; Sligte, I. G., Scholte, H. S., & Lamme, V. A. F. Are there multiple visual STM stores? PLoS One, 3, e1699, 2008]. Although FM can be distinguished from IM using behavioral and fMRI methods, the question remains whether FM is a weak expression of WM or a separate form of memory with its own neural signature. Here, we tested whether FM and WM in humans are supported by dissociable time–frequency features of EEG recordings. Participants performed a partial-report change detection task, from which individual differences in FM and WM capacity were estimated. These individual FM and WM capacities were correlated with time–frequency characteristics of the EEG signal before and during encoding and maintenance of the memory display. FM capacity showed negative alpha correlations over peri-occipital electrodes, whereas WM capacity was positively related, suggesting increased visual processing (lower alpha) to be related to FM capacity. Furthermore, FM capacity correlated with an increase in theta power over central electrodes during preparation and processing of the memory display, whereas WM did not. In addition to a difference in visual processing characteristics, a positive relation between gamma power and FM capacity was observed during both preparation and maintenance periods of the task. On the other hand, we observed that theta–gamma coupling was negatively correlated with FM capacity, whereas it was slightly positively correlated with WM. These data show clear differences in the neural substrates of FM versus WM and suggest that FM depends more on visual processing mechanisms compared with WM. This study thus provides novel evidence for a dissociation between different stages in VSTM.
Shared and Distinct Neuroanatomic Regions Critical for Tool-related Action Production and Recognition: Evidence from 131 Left-hemisphere Stroke Patients
Authors: Tarhan Leyla Y. , Watson Christine E. , Buxbaum Laurel J.
Published: September 2015

The inferior frontal gyrus and inferior parietal lobe have been characterized as human homologues of the monkey “mirror neuron” system, critical for both action production (AP) and action recognition (AR). However, data from brain lesion patients with selective impairment on only one of these tasks provide evidence of neural and cognitive dissociations. We sought to clarify the relationship between AP and AR, and their critical neural substrates, by directly comparing performance of 131 chronic left-hemisphere stroke patients on both tasks—to our knowledge, the largest lesion-based experimental investigation of action cognition to date. Using voxel-based lesion-symptom mapping, we found that lesions to primary motor and somatosensory cortices and inferior parietal lobule were associated with disproportionately impaired performance on AP, whereas lesions to lateral temporo-occipital cortex were associated with a relatively rare pattern of disproportionately impaired performance on AR. In contrast, damage to posterior middle temporal gyrus was associated with impairment on both AP and AR. The distinction between lateral temporo-occipital cortex, critical for recognition, and posterior middle temporal gyrus, important for both tasks, suggests a rough gradient from modality-specific to abstract representations in posterior temporal cortex, the first lesion-based evidence for this phenomenon. Overall, the results of this large patient study help to bring closure to a long-standing debate by showing that tool-related AP and AR critically depend on both common and distinct left hemisphere neural substrates, most of which are external to putative human mirror regions.
Early Psychosocial Neglect Adversely Impacts Developmental Trajectories of Brain Oscillations and Their Interactions
Authors: Stamoulis Catherine , Vanderwert Ross E. , Zeanah Charles H. , Fox Nathan A. , Nelson Charles A.
Published: September 2015

Rhythmicity is a fundamental property of neural activity at multiple spatiotemporal scales, and associated oscillations represent a critical mechanism for communication and transmission of information across brain regions. During development, these oscillations evolve dynamically as a function of neural maturation and may be modulated by early experiences, positive and/or negative. This study investigated the impact of psychosocial deprivation associated with institutional rearing in early life and the effects of subsequent foster care intervention on developmental trajectories of neural oscillations and their cross-frequency correlations. Longitudinally acquired nontask EEGs from three cohorts of children from the Bucharest Early Intervention Project were analyzed. These included abandoned children initially reared in institutions and subsequently randomized to be placed in foster care or receive care as usual (prolonged institutional rearing) and a group of never-institutionalized children. Oscillation trajectories were estimated from 42 to 96 months, that is, 1–3 years after all children in the intervention arm of the study had been placed in foster care. Significant differences between groups were estimated for the amplitude trajectories of cognitive-related gamma, beta, alpha, and theta oscillations. Similar differences were identified as a function of time spent in institutions, suggesting that increased time spent in psychosocial neglect may have profound and widespread effects on brain activity. Significant group differences in cross-frequency coupling were estimated longitudinally between gamma and lower frequencies as well as alpha and lower frequencies. Lower cross-gamma coupling was estimated at 96 months in the group of children that remained in institutions at that age compared to the other two groups, suggesting potentially impaired communication between local and long-distance brain networks in these children. In contrast, higher cross-alpha coupling was estimated in this group compared to the other two groups at 96 months, suggesting impaired suppression of alpha–theta and alpha–delta activity, which has been associated with neuropsychiatric disorders. Age at foster care placement had a significant positive modulatory effect on alpha and beta trajectories and their mutual coupling, although by 96 months these trajectories remained distinct from those of never-institutionalized children. Overall, these findings suggest that early psychosocial neglect may profoundly impact neural maturation, particularly the evolution of neural oscillations and their interactions across a broad frequency range. These differences may result in widespread deficits across multiple cognitive domains.
The Backwash of Norenzayan’s Big Gods: A Post-Review Essay
Authors: Skjoldli Jane
Published: September 2015

This post-review discusses the reception of Ara Norenzayan’sBig Gods: How Religion Transformed Cooperation and Conflict(2013) by zooming in on two review symposia for the book — one inReligion(2014), the other inReligion, Brain and Behavior(2014). The symposia ran parallel to one another, and both have resulted in the publication of ten reviews plus one commentary. The post-review discusses a selection of topics raised, including some underlying key premises, similarities with the Supernatural Punishment Hypothesis, the evidence presented, its cultural evolution framework, its conceptualization of “religion,” prosociality versus obedience, and whether “Big Gods” are really just “Abrahamic gods” rewrapped.
Food consumption pattern in the snow crab Chionoecetes opilio (Fabricius, 1788) (Decapoda, Majoidea) megalopae under laboratory conditions
Authors: Yamamoto T. , Yamada T. , Fujimoto H. , Hamasaki K.
Published: September 2015

The food consumption pattern in megalopae of the snow crab Chionoecetes opilio (Fabricius, 1788) was investigated in the laboratory. Ten megalopae were individually cultured and given an excess of Artemia nauplii each day. All megalopae moulted into first-instar crabs 28-34 days after metamorphosis. The mean total number and total weight of Artemia consumed during the megalopal stage were 1920 individuals and 5.2 mg, respectively. Hence, the food requirement of snow crab megalopae was estimated as ∼190% of the dry body weight of the first-instar crab. Initially, the number of Artemia consumed was nearly constant or decreased only slightly but, later, Artemia consumption decreased with development days. Two-segmented regressions provided good fits to the relationship between the number of days after metamorphosis and the cumulative number of Artemia consumed by individual megalopae. The mean value of the time after metamorphosis of the breakpoint in the rate of food consumption was estimated as 69% of the stage duration, which corresponds to the intermediate of late premoult. Crab sizes (carapace width, wet and dry body weight) were not significantly dependent on the number of Artemia consumed during the entire megalopal period although a positive correlation between these variables was observed. These results provide useful information on the appropriate feeding schedule and management practice for culturing snow crab megalopae and contribute to the understanding of megalopal growth efficiency to the first-instar crab in their natural habitat.
Growth and moulting of wild-born immature snow crabs, Chionoecetes opilio (Fabricius, 1788) (Decapoda, Majoidea), in the laboratory
Authors: Yamamoto Takeo , Yamada Tatsuya , Kinoshita Takahiro , Ueda Yuji , Fujimoto Hiroshi , Yamasaki Atsushi , Hamasaki Katsuyuki
Published: September 2015

Growth and moulting of wild-born immature snow crabs (Chionoecetes opilio (Fabricius, 1788)) were investigated by laboratory culture experiments. Crabs with 16.2-42.9 mm carapace width caught from the Sea of Japan were cultured at a temperature of their natural habitat (approximately 1°C). The growth indices (size increments at moulting in mm and in % of premoult carapace width) and intermoult period were significantly affected by premoult carapace width, but sex did not affect these variables. Furthermore, we demonstrated that premoult carapace width and days after moulting significantly affected moulting probability and we developed a moulting probability model based on these variables. From this model, the number of days of intermoult periods when moults occurred in 50% of crabs of instars VI, VII and VIII was estimated at 234, 284 and 346 days, respectively.
Plasticity of external setae during claw transformation in the snapping shrimp, Alpheus angulosus McClure, 2002 (Decapoda, Caridea)
Authors: Akhter Erica T. , Pereira Ariane , Hughes Melissa , Korey Christopher A.
Published: September 2015

The snapping shrimp,Alpheus angulosusMcClure, 2002, is a small crustacean with bilaterally asymmetric claws that serve distinct behavioural and sensory functions. If the large claw is lost, the organism switches handedness, transforming its small pincer claw into a large snapping claw while simultaneously developing a small claw on the contralateral side. To better understand the mechanisms required to adapt to this radical change in body composition, we examined developmental plasticity by tracing changes in sensory setae distribution on the claws throughout transformation. We observed only two broad types of setae, simple and plumose. Quantitative analysis across molt stages revealed significant alterations in setae composition and numbers that occurred primarily on the edge of the propodus, where the most drastic morphological changes also occur. These results suggest that previous developmental mechanisms are re-engaged to support the proliferation and differentiation of new setae during transformation.
Seljuks on the Baltic: Polish-Lithuanian Muslim Pilgrims in the Court of Ottoman Sultan Süleyman i
Authors: Połczyński Michael
Published: September 2015

The unique authorship of the Risâle-i Tatar-i Leh, created in 1558 for Ottoman Grand Vezier Rüstem Pasha and Sultan Süleymân i by Polish-Lithuanian Muslim pilgrims and members of the Ottoman ulema, brings to light critical issues faced by one of early modern Christendom’s largest integrated Muslim populations. This document encourages further exploration of several aspects of the Muslim population of early modern Poland-Lithuania: the stratification of Muslim society, the ways in which both Ottoman and Polish-Lithuanian myths of origin and legitimizing narratives were combined to justify conflict between fellow Muslims and the loyalty of Muslim settlers to non-Muslim rulers, Polish-Lithuanian Muslims as a branch of the greater Islamic ecumene, the legal status and social hierarchies of Muslims in an emerging early modern republic, and the role of the Ottoman Sultan as the facilitator of the hajj and millenarian world-conqueror vis-á-vis Muslims residing outside of the dâr al-Islâm.
Las Lejeuneaceae (Hepaticae) de Misiones, Argentina II. Cololejeunea

Authors: Reiner-Drehwald M. Elena
Published: September 2015

The two species of Cololejeunea (Lejeuneaceae subfam. Cololejeuneoideae) found in Misiones, are described and illustrated. C. minutissima subsp. myriocarpa (Nees & Mont.) Schust. is registered for the first time for the provinces Misiones, Formosa and Corrientes in Argentina and for Paraguay; C. spegazzinii (C. Mass.) C. Mass., Lejeunea myriandroecia Spruce and C. myriantha (Herz.) S. Arnell are proposed as new synonyms of this subspecies. C. cardiocarpa (Mont.) Evans is registered for the first time for Argentina (provinces Misiones, Corrientes and Buenos Aires) and for Paraguay.
Ramalina subfraxinea Nyl. var. confirmata (Nyl.) N. Stevens (Ascomicete liquenizado, Ramalinaceae) en America
Authors: Marcano Antonio Morales Méndez y Vicente
Published: September 2015

Ramalina subfraxinea Nyl. var. confirmata (Nyl.) N. Stevens is reported as new to the New World from the Venezuelan Andes. Thus far this variety was known only from Australia, New Caledonia and the Indian Ocean. It has cryptochlorophaeic acid as chemical compound. Comments about ecology and morphology are given.
El género Radula Dum. (Radulaceae, Hepaticae) en el Noreste de Argentina

Authors: Reiner-Drehwald M. Elena
Published: September 2015

Eight species of Radula (R. macrostachya Lindenb. & Gott., R. episcia Spruce, R. kegelii Gott. ex Steph., R. ligula Steph., R. aurantii Spruce, R. montana Steph., R. quadrata Gott. and R. voluta Tayl.) are found in the province of Misiones, and two species (R. aurantii and R. kegelii) in Buenos Aires. These are described and illustrated, and habitat and geographic distribution of the species are indicated. Keys for the identification of these species and a synopsis with their systematic position are provided. R. ligula is transferred to the section Marginatae Castle ex Grolle. R. flaccida Lindenb. & Gott. is excluded from the study area.
 Notes on the Neckeraceae (Musci). 19. The identity of Porothamnium ceylonense

Authors: Enroth Johannes
Published: September 2015

Based on the gametophyte characters, Porothamnium ceylonense Fleisch. is transferred to Thamnobryum Nieuwl. and the combination T. ceylonense (Fleisch.) Enroth is made. The species is lectotypified and line drawings of it are provided.