bluuebunny/crossref_metadata_2025_split huggingface dataset:
Operant conditioning of the motor-evoked potential and locomotion in people with and without chronic incomplete spinal cord injury
Authors: Thompson Aiko K. , Fiorenza Gina , Smyth Lindsay , Favale Briana , Brangaccio Jodi , Sniffen Janice 
Published: January 2019

Foot drop is very common among people with chronic incomplete spinal cord injury (SCI) and likely stems from SCI that disturbs the corticospinal activation of the ankle dorsiflexor tibialis anterior (TA). Thus, if one can recover or increase the corticospinal excitability reduced by SCI, motor function recovery may be facilitated. Here, we hypothesized that in people suffering from weak dorsiflexion due to chronic incomplete SCI, increasing the TA motor-evoked potential (MEP) through operant up-conditioning can improve dorsiflexion during locomotion, while in people without any injuries, it would have little impact on already normal locomotion. Before and after 24 MEP conditioning or control sessions, locomotor electromyography (EMG) and kinematics were measured. This study reports the results of these locomotor assessments. In participants without SCI, locomotor EMG activity, soleus Hoffmann reflex modulation, and joint kinematics did not change, indicating that MEP up-conditioning or repeated single-pulse transcranial magnetic stimulation (i.e., control protocol) does not influence normal locomotion. In participants with SCI, MEP up-conditioning increased TA activity during the swing-to-swing stance transition phases and ankle joint motion during locomotion in the conditioned leg and increased walking speed consistently. In addition, the swing-phase TA activity and ankle joint motion also improved in the contralateral leg. The results are consistent with our hypothesis. Together with the previous operant conditioning studies in humans and rats, the present study suggests that operant conditioning can be a useful therapeutic tool for enhancing motor function recovery in people with SCI and other central nervous system disorders. NEW & NOTEWORTHY This study examined the functional impact of operant conditioning of motor-evoked potential (MEP) to transcranial magnetic stimulation that aimed to increase corticospinal excitability for the ankle dorsiflexor tibialis anterior (TA). In people with chronic incomplete spinal cord injury (SCI), MEP up-conditioning increased TA activity and improved dorsiflexion during locomotion, while in people without injuries, it had little impact on already normal locomotion. MEP conditioning may potentially be used to enhance motor function recovery after SCI.
Anterior cingulate cortex encoding of effortful behavior
Authors: Porter Blake S. , Hillman Kristin L. , Bilkey David K. 
Published: January 2019

An animal’s ability to assess the value of their behaviors to minimize energy use while maximizing goal achievement is critical to its survival. The anterior cingulate cortex (ACC) has been previously shown to play a critical role in this behavioral optimization process, especially when animals are faced with effortful behaviors. In the present study, we designed a novel task to investigate the role of the ACC in evaluating behaviors that varied in effort but all resulted in the same outcome. We recorded single unit activity from the ACC as rats ran back and forth in a shuttle box that could be tilted to different tilt angles (0, 15, and 25°) to manipulate effort. Overall, a majority of ACC neurons showed selective firing to specific effort conditions. During effort expenditure, ACC units showed a consistent firing rate bias toward the downhill route compared with the more difficult uphill route, regardless of the tilt angle of the apparatus. Once rats completed a run and received their fixed reward, ACC units also showed a clear firing rate preference for the single condition with the highest relative value (25° downhill). To assess effort preferences, we used a choice version of our task and confirmed that rats prefer downhill routes to uphill routes when given the choice. Overall, these results help to elucidate the functional role of the ACC in monitoring and evaluating effortful behaviors that may then bias decision-making toward behaviors with the highest utility. NEW & NOTEWORTHY We developed a novel effort paradigm to investigate how the anterior cingulate cortex (ACC) responds to behaviors with varied degrees of physical effort and how changes in effort influence the ACC’s evaluation of behavioral outcomes. Our results provide evidence for a wider role of the ACC in its ability to motivate effortful behaviors and evaluate the outcome of multiple behaviors within an environment.
Mechanochemical Disruption Suppresses Metastatic Phenotype and Pushes Prostate Cancer Cells toward Apoptosis
Authors: Murad Hakm Y. , Yu Heng , Luo Daishen , Bortz Emma P. , Halliburton Gray M. , Sholl Andrew B. , Khismatullin Damir B. 
Published: January 2019

AbstractChemical-based medicine that targets specific oncogenes or proteins often leads to cancer recurrence due to tumor heterogeneity and development of chemoresistance. This challenge can be overcome by mechanochemical disruption of cancer cells via focused ultrasound (FUS) and sensitizing chemical agents such as ethanol. We demonstrate that this disruptive therapy decreases the viability, proliferation rate, tumorigenicity, endothelial adhesion, and migratory ability of prostate cancer cells in vitro. It sensitized the cells to TNFR1-- and Fas--mediated apoptosis and reduced the expression of metastatic markers CD44 and CD29. Using a prostate cancer xenograft model, we observed that the mechanochemical disruption led to complete tumor regression in vivo. This switch to a nonaggressive cell phenotype was caused by ROS and Hsp70 overproduction and subsequent impairment of NFκB signaling. FUS induces mechanical perturbations of diverse cancer cell populations, and its combination with agents that amplify and guide remedial cellular responses can stop lethal cancer progression.Implications:Mechanochemical disruption therapy in which FUS is combined with ethanol can be curative for locally aggressive and castration-resistant prostate cancer.
Intravenous Misuse of Methadone, Buprenorphine and Buprenorphine-Naloxone in Patients Under Opioid Maintenance Treatment: A Cross-Sectional Multicentre Study
Authors: Lugoboni Fabio , Zamboni Lorenzo , Cibin Mauro , Tamburin Stefano ,   Gruppo InterSERT di Collaborazione Scientifica (GICS)
Published: January 2019

<b><i>Background:</i></b> The act of intravenous misuse is common in patients under opioid maintenance treatment (OMT), but information on associated factors is still limited. <b><i>Objectives:</i></b> To explore factors associated with (a) intravenous OMT misuse, (b) repeated misuse, (c) emergency room (ER) admission, (d) misuse of different OMT types and (e) concurrent benzodiazepine misuse. <b><i>Methods:</i></b> We recruited 3,620 patients in 27 addiction units in Italy and collected data on the self-reported rate of intravenous injection of methadone (MET), buprenorphine (BUP), BUP-naloxone (NLX), OMT dosage and type, experience of and reason for misuse, concurrent intravenous benzodiazepine misuse, pattern of ­misuse in relation to admission to the addiction unit and ER ­admissions because of misuse. According to inclusion/exclusion criteria, 2,585 patients were included. <b><i>Results:</i></b> Intravenous misuse of OMT substances was found in 28% of patients with no difference between OMT types and was associated with gender, age, type of previous opioid abuse and intravenous benzodiazepine misuse. Repeated OMT misuse was reported by 20% (i.e., 71% of misusers) of patients and was associated with positive OMT misuse experience and intravenous benzodiazepine misuse. Admission to the ER because of misuse complications was reported by 34% of patients, this outcome being associated with gender, employment, type of previous opioid abuse and intravenous benzodiazepine misuse. OMT dosage was lower than the recommended maintenance dosage. <b><i>Conclusions:</i></b> We offered new information on factors associated with intravenous OMT misuse, repeated misuse and ER admission in Italian patients under OMT. Our data indicate that BUP-NLX misuse is not different from that of BUP or MET. Choosing the more expensive BUP-NLX over MET will likely not lead to the expected reduction of the risk of injection misuse of the OMT. Instead of prescribing new and expensive OMT formulations, addiction unit physicians and medical personnel should better focus on patient’s features that are associated with a higher likelihood of misuse. Care should be paid to concurrent benzodiazepine and OMT misuse.
Ablation of Myeloid ADK (Adenosine Kinase) Epigenetically Suppresses Atherosclerosis in ApoE
−/−
(Apolipoprotein E Deficient) Mice
Authors: Zhang Min , Zeng Xianqiu , Yang Qiuhua , Xu Jiean , Liu Zhiping , Zhou Yaqi , Cao Yapeng , Zhang Xiaoyu , An Xiaofei , Xu Yiming , Huang Lei , Han Zhen , Wang Tao , Wu Chaodong , Fulton David J. , Weintraub Neal L. , Hong Mei , Huo Yuqing 
Published: January 2019

Objective—
Monocyte-derived foam cells are one of the key players in the formation of atherosclerotic plaques. Adenosine receptors and extracellular adenosine have been demonstrated to modulate foam cell formation. ADK (adenosine kinase) is a major enzyme regulating intracellular adenosine levels, but its functional role in myeloid cells remains poorly understood. To enhance intracellular adenosine levels in myeloid cells, ADK was selectively deleted in novel transgenic mice using Cre-LoxP technology, and foam cell formation and the development of atherosclerotic lesions were determined.

Approach and Results—

ADK was upregulated in macrophages on ox-LDL (oxidized low-density lipoprotein) treatment in vitro and was highly expressed in foam cells in atherosclerotic plaques. Atherosclerotic mice deficient in ADK in myeloid cells were generated by breeding floxed ADK (ADK
F/F
) mice with LysM-Cre (myeloid-specific Cre recombinase expressing) mice and ApoE
−/−
(apolipoprotein E deficient) mice. Mice absent ADK in myeloid cells exhibited much smaller atherosclerotic plaques compared with controls. In vitro assays showed that ADK deletion or inhibition resulted in increased intracellular adenosine and reduced DNA methylation of the
ABCG1
(ATP-binding cassette transporter G1) gene. Loss of methylation was associated with ABCG1 upregulation, enhanced cholesterol efflux, and eventually decreased foam cell formation.

Conclusions—

Augmentation of intracellular adenosine levels through ADK knockout in myeloid cells protects ApoE
−/−
mice against atherosclerosis by reducing foam cell formation via the epigenetic regulation of cholesterol trafficking. ADK inhibition is a promising approach for the treatment of atherosclerotic diseases.
Left Atrial Reservoir Function and Outcome in Heart Failure With Reduced Ejection Fraction
Authors: Carluccio Erberto , Biagioli Paolo , Mengoni Anna , Francesca Cerasa Maria , Lauciello Rosanna , Zuchi Cinzia , Bardelli Giuliana , Alunni Gianfranco , Coiro Stefano , Gronda Edoardo G. , Ambrosio Giuseppe 
Published: January 2019

Background
Left atrial (LA) volume is a marker of cardiac remodeling and prognosis in heart failure (HF) with reduced ejection fraction (EF), but LA function is rarely measured or characterized. We investigated determinants and prognostic impact of LA reservoir function in patients with HF with reduced EF.

Methods and Results

In 405 patients with stable HF with reduced EF (EF, ≤40%) in sinus rhythm, we assessed LA reservoir function by both LA total EF (by phasic volume changes) and peak atrial longitudinal strain (PALS; by speckle tracking echocardiography); LA functional index was also calculated. During follow-up (median, 30 months; Q1–Q3, 13–52), 139 patients (34%) reached the composite end point (all-cause death/HF hospitalization). Median PALS was 15.5% (interquartile range, 11.2–20.6). By univariable analysis, all LA function parameters significantly predicted outcome (
P
<0.01 for all), with PALS showing the highest predictive accuracy (area under the curve, 0.75; sensitivity, 73%; specificity, 70%). Impaired PALS was associated with greater left ventricular and LA volumes, worse left ventricular EF, left ventricular global longitudinal strain, right ventricular systolic function, and more severe diastolic dysfunction. After multivariable adjustment (including LA volume and left ventricular global longitudinal strain), PALS, but not LA total EF or LA functional index, remained significantly associated with outcome (hazard ratio per 1-SD decrease, 1.38; 95% CI, 1.05–1.84;
P
=0.030). Adding PALS to a base model, including age, sex, LA volume, EF, E/E′ ratio, and global longitudinal strain, provided incremental predictive value (continuous net reclassification improvement, 0.449;
P
=0.0009).

Conclusions
In HF with reduced EF, assessment of LA reservoir function by PALS allows powerful prognostication, independently of LA volume and left ventricular longitudinal contraction.
Analysis of Cell Type-Specific Effects of MicroRNA-92a Provides Novel Insights Into Target Regulation and Mechanism of Action
Authors: Rogg Eva-Maria , Abplanalp Wesley T. , Bischof Corinne , John David , Schulz Marcel H. , Krishnan Jaya , Fischer Ariane , Poluzzi Chiara , Schaefer Liliana , Bonauer Angelika , Zeiher Andreas M. , Dimmeler Stefanie 
Published: January 2019

Background:
MicroRNAs (miRs) regulate nearly all biological pathways. Because the dysregulation of miRs can lead to disease progression, they are being explored as novel therapeutic targets. However, the cell type-specific effects of miRs in the heart are poorly understood. Thus, we assessed miR target regulation using miR-92a-3p as an example. Inhibition of miR-92a is known to improve endothelial cell function and recovery after acute myocardial infarction.

Methods:

miR-92a-3p was inhibited by locked nucleic acid (LNA)-based antimiR (LNA-92a) in mice after myocardial infarction. Expression of regulated genes was evaluated 3 days after myocardial infarction by RNA sequencing of isolated endothelial cells, cardiomyocytes, fibroblasts, and CD45
+
hematopoietic cells.

Results:
LNA-92a depleted miR-92a-3p expression in all cell types and derepressed predicted miR-92a-3p targets in a cell type-specific manner. RNAseq showed endothelial cell-specific regulation of autophagy-related genes. Imaging confirmed increased endothelial cell autophagy in LNA-92a treated relative to control animals. In vitro inhibition of miR-92a-3p augmented EC autophagy, derepressed autophagy-related gene 4a, and increased luciferase activity in autophagy-related gene 4a 3’UTR containing reporters, whereas miR-92a-3p overexpression had the opposite effect. In cardiomyocytes, LNA-92a derepressed metabolism-related genes, notably, the high-density lipoprotein transporter Abca8b. LNA-92a further increased fatty acid uptake and mitochondrial function in cardiomyocytes in vitro.

Conclusions:
Our data show that miRs have cell type-specific effects in vivo. Analysis of miR targets in cell subsets disclosed a novel function of miR-92a-3p in endothelial cell autophagy and cardiomyocyte metabolism. Because autophagy is upregulated during ischemia to supply nutrients and cardiomyocyte metabolic-switching improves available substrate utilization, these prosurvival mechanisms may diminish tissue damage.
Inflammation and NLRP3 Inflammasome Activation Initiated in Response to Pressure Overload by Ca
2+
/Calmodulin-Dependent Protein Kinase II δ Signaling in Cardiomyocytes Are Essential for Adverse Cardiac Remodeling
Authors: Suetomi Takeshi , Willeford Andrew , Brand Cameron S. , Cho Yoshitake , Ross Robert S. , Miyamoto Shigeki , Brown Joan Heller 
Published: January 2019

Background:

Inflammation is associated with cardiac remodeling and heart failure, but how it is initiated in response to nonischemic interventions in the absence of cell death is not known. We tested the hypothesis that activation of Ca
2+
/calmodulin-dependent protein kinase II δ (CaMKIIδ) in cardiomyocytes (CMs) in response to pressure overload elicits inflammatory responses leading to adverse remodeling.

Methods:
Mice in which CaMKIIδ was selectively deleted from CMs (cardiac-specific knockout [CKO]) and floxed control mice were subjected to transverse aortic constriction (TAC). The effects of CM-specific CaMKIIδ deletion on inflammatory gene expression, inflammasome activation, macrophage accumulation, and fibrosis were assessed by quantitative polymerase chain reaction, histochemistry, and ventricular remodeling by echocardiography.

Results:
TAC induced increases in cardiac mRNA levels for proinflammatory chemokines and cytokines in ≤3 days, and these responses were significantly blunted when CM CaMKIIδ was deleted. Apoptotic and necrotic cell death were absent at this time. CMs isolated from TAC hearts mirrored these robust increases in gene expression, which were markedly attenuated in CKO. Priming and activation of the NOD-like receptor pyrin domain-containing protein 3 inflammasome, assessed by measuring interleukin-1β and NOD-like receptor pyrin domain-containing protein 3 mRNA levels, caspase-1 activity, and interleukin-18 cleavage, were increased at day 3 after TAC in control hearts and in CMs isolated from these hearts. These responses were dependent on CaMKIIδ and associated with activation of Nuclear Factor-kappa B and reactive oxygen species. Accumulation of macrophages observed at days 7 to 14 after TAC was diminished in CKO and, by blocking Monocyte Chemotactic Protein-1 signaling, deletion of CM Monocyte Chemotactic Protein-1 or inhibition of inflammasome activation. Fibrosis was also attenuated by these interventions and in the CKO heart. Ventricular dilation and contractile dysfunction observed at day 42 after TAC were diminished in the CKO. Inhibition of CaMKII, Nuclear Factor-kappa B, inflammasome, or Monocyte Chemotactic Protein-1 signaling in the first 1 or 2 weeks after TAC decreased remodeling, but inhibition of CaMKII after 2 weeks did not.

Conclusions:
Activation of CaMKIIδ in response to pressure overload triggers inflammatory gene expression and activation of the NOD-like receptor pyrin domain-containing protein 3 inflammasome in CMs. These responses provide signals for macrophage recruitment, fibrosis, and myocardial dysfunction in the heart. Our work suggests the importance of targeting early inflammatory responses induced by CM CaMKIIδ signaling to prevent progression to heart failure.
Metabolomic Consequences of Genetic Inhibition of PCSK9 Compared With Statin Treatment
Authors: Sliz Eeva , Kettunen Johannes , Holmes Michael V. , Williams Clare Oliver , Boachie Charles , Wang Qin , Männikkö Minna , Sebert Sylvain , Walters Robin , Lin Kuang , Millwood Iona Y. , Clarke Robert , Li Liming , Rankin Naomi , Welsh Paul , Delles Christian , Jukema J. Wouter , Trompet Stella , Ford Ian , Perola Markus , Salomaa Veikko , Järvelin Marjo-Riitta , Chen Zhengming , Lawlor Debbie A. , Ala-Korpela Mika , Danesh John , Davey Smith George , Sattar Naveed , Butterworth Adam , Würtz Peter 
Published: January 2019

Background:
Both statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower blood low-density lipoprotein cholesterol levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these 2 lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial.

Methods:

Two hundred twenty-eight circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5359 individuals (2659 on treatment) in the PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) trial at 6 months postrandomization. The corresponding metabolic measures were analyzed in 8 population cohorts (N=72 185) using
PCSK9
rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors.

Results:

Scaled to an equivalent lowering of low-density lipoprotein cholesterol, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (
R
2
=0.88). Alterations in lipoprotein lipid composition and fatty acid distribution were similar. However, discrepancies were observed for very-low-density lipoprotein lipid measures. For instance, genetic inhibition of PCSK9 had weaker effects on lowering of very-low-density lipoprotein cholesterol compared with statin therapy (54% versus 77% reduction, relative to the lowering effect on low-density lipoprotein cholesterol;
P
=2×10
-7
for heterogeneity). Genetic inhibition of PCSK9 showed no significant effects on amino acids, ketones, or a marker of inflammation (GlycA), whereas statin treatment weakly lowered GlycA levels.

Conclusions:
Genetic inhibition of PCSK9 had similar metabolic effects to statin therapy on detailed lipid and metabolite profiles. However, PCSK9 inhibitors are predicted to have weaker effects on very-low-density lipoprotein lipids compared with statins for an equivalent lowering of low-density lipoprotein cholesterol, which potentially translate into smaller reductions in cardiovascular disease risk.
Refining Prediction of Atrial Fibrillation–Related Stroke Using the P
2
-CHA
2
DS
2
-VASc Score
Authors: Maheshwari Ankit , Norby Faye L. , Roetker Nicholas S. , Soliman Elsayed Z. , Koene Ryan J. , Rooney Mary R. , O’Neal Wesley T. , Shah Amil M. , Claggett Brian L. , Solomon Scott D. , Alonso Alvaro , Gottesman Rebecca F. , Heckbert Susan R. , Chen Lin Y. 
Published: January 2019

Background:

In people with atrial fibrillation (AF), periods of sinus rhythm present an opportunity to detect prothrombotic atrial remodeling through measurement of P-wave indices (PWIs)—prolonged P-wave duration, abnormal P-wave axis, advanced interatrial block, and abnormal P-wave terminal force in lead V1. We hypothesized that the addition of PWIs to the CHA
2
DS
2
-VASc score would improve its ability to predict AF-related ischemic stroke.

Methods:
We included 2229 participants from the ARIC study (Atherosclerosis Risk in Communities) and 700 participants from MESA (Multi-Ethnic Study of Atherosclerosis) with incident AF who were not on anticoagulants within 1 year of AF diagnosis. PWIs were obtained from study visit ECGs before development of AF. AF was ascertained using study visit ECGs and hospital records. Ischemic stroke cases were based on physician adjudication of hospital records. We used Cox proportional hazards models to estimate hazard ratios and 95% CIs of PWIs for ischemic stroke. Improvement in 1-year stroke prediction was assessed by C-statistic, categorical net reclassification improvement, and relative integrated discrimination improvement.

Results:

Abnormal P-wave axis was the only PWI associated with increased ischemic stroke risk (hazard ratio, 1.84; 95% CI, 1.33–2.55) independent of CHA
2
DS
2
-VASc variables, and that resulted in meaningful improvement in stroke prediction. The β estimate was approximately twice that of the CHA
2
DS
2
-VASc variables, and thus abnormal P-wave axis was assigned 2 points to create the P
2
-CHA
2
DS
2
-VASc score. This improved the C-statistic (95% CI) from 0.60 (0.51–0.69) to 0.67 (0.60–0.75) in ARIC and 0.68 (0.52–0.84) to 0.75 (0.60–0.91) in MESA (validation cohort). In ARIC and MESA, the categorical net reclassification improvements (95% CI) were 0.25 (0.13–0.39) and 0.51 (0.18–0.86), respectively, and the relative integrated discrimination improvement (95% CI) were 1.19 (0.96–1.44) and 0.82 (0.36–1.39), respectively.

Conclusions:

Abnormal P-wave axis—an ECG correlate of left atrial abnormality— improves ischemic stroke prediction in AF. Compared with CHA
2
DS
2
-VASc, the P
2
-CHA
2
DS
2
-VASc is a better prediction tool for AF-related ischemic stroke.