bluuebunny/crossref_metadata_2025 huggingface dataset:
Thrombosis and systemic and cardiac oxidative stress and DNA damage induced by pulmonary exposure to diesel exhaust particles and the effect of nootkatone thereon
Authors: Nemmar Abderrahim , Al-Salam Suhail , Beegam Sumaya , Yuvaraju Priya , Ali Badreldin H.
Published: January 2018

Adverse cardiovascular effects of particulate air pollution persist even at lower concentrations than those of the current air quality limit. Therefore, identification of safe and effective measures against particle-induced cardiovascular toxicity is needed. Nootkatone is a sesquiterpenoid in grapefruit with diverse bioactivities including anti-inflammatory and antioxidant effects. However, its protective effect on the cardiovascular injury induced by diesel exhaust particles (DEPs) has not been studied before. We assessed the possible protective effect of nootkatone (90 mg/kg) administered by gavage 1 h before intratracheal instillation of DEPs (30 μg/mouse). Twenty-four hours after the intratracheal administration of DEPs, various thrombotic and cardiac parameters were assessed. Nootkatone inhibited the prothrombotic effect induced by DEPs in pial arterioles and venules in vivo and platelet aggregation in whole blood in vitro. Also, nootkatone prevented the shortening of activated partial thromboplastin time and prothrombin time induced by DEPs. Nootkatone inhibited the increase of plasma concentration of fibrinogen, plasminogen activator inhibitor-1, interleukin-6, and lipid peroxidation induced by DEPs. Immunohistochemically, hearts showed an analogous increase in glutathione and nuclear factor erythroid-derived 2-like 2 expression by cardiac myocytes and endothelial cells after DEP exposure, and these effects were enhanced in mice treated with nootkatone + DEPs. Likewise, heme oxygenase-1 was increased in mice treated with nootkatone + DEPs compared with those treated with DEPs or nootkatone + saline. The DNA damage caused by DEPs was prevented by nootkatoone pretreatment. In conclusion, nootkatoone alleviates DEP-induced thrombogenicity and systemic and cardiac oxidative stress and DNA damage, at least partly, through nuclear factor erythroid-derived 2-like 2 and heme oxygenase-1 activation.

NEW & NOTEWORTHY Nootkatoone, a sesquiterpenoid found in grapefruit, alleviates the thrombogenicity and systemic and cardiac oxidative stress and DNA damage in mice exposed to diesel exhaust particles. Nootkatone-induced boosting of nuclear factor erythroid-derived 2-like 2 and heme oxygenase-1 levels in the heart of mice exposed to diesel exhaust particles suggests that its protective effect is, at least partly, mediated through nuclear factor erythroid-derived 2-like 2 and heme oxygenase-1 activation.
Guidelines for measuring cardiac physiology in mice
Authors: Lindsey Merry L. , Kassiri Zamaneh , Virag Jitka A. I. , de Castro Brás Lisandra E. , Scherrer-Crosbie Marielle
Published: January 2018

Cardiovascular disease is a leading cause of death, and translational research is needed to understand better mechanisms whereby the left ventricle responds to injury. Mouse models of heart disease have provided valuable insights into mechanisms that occur during cardiac aging and in response to a variety of pathologies. The assessment of cardiovascular physiological responses to injury or insult is an important and necessary component of this research. With increasing consideration for rigor and reproducibility, the goal of this guidelines review is to provide best-practice information regarding how to measure accurately cardiac physiology in animal models. In this article, we define guidelines for the measurement of cardiac physiology in mice, as the most commonly used animal model in cardiovascular research.

Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/guidelines-for-measuring-cardiac-physiology-in-mice/ .
Important role of endothelium-dependent hyperpolarization in the pulmonary microcirculation in male mice: implications for hypoxia-induced pulmonary hypertension
Authors: Tanaka Shuhei , Shiroto Takashi , Godo Shigeo , Saito Hiroki , Ikumi Yosuke , Ito Akiyo , Kajitani Shoko , Sato Saori , Shimokawa Hiroaki
Published: January 2018

Endothelium-dependent hyperpolarization (EDH) plays important roles in the systemic circulation, whereas its role in the pulmonary circulation remains largely unknown. Furthermore, the underlying mechanisms of pulmonary hypertension (PH) also remain to be elucidated. We thus aimed to elucidate the role of EDH in pulmonary circulation in general and in PH in particular. In isolated perfused lung and using male wild-type mice, endothelium-dependent relaxation to bradykinin (BK) was significantly reduced in the presence of Nω-nitro-l-arginine by ~50% compared with those in the presence of indomethacin, and the combination of apamin plus charybdotoxin abolished the residual relaxation, showing the comparable contributions of nitric oxide (NO) and EDH in the pulmonary microcirculation under physiological conditions. Catalase markedly inhibited EDH-mediated relaxation, indicating the predominant contribution of endothelium-derived H2O2. BK-mediated relaxation was significantly reduced at day 1 of hypoxia, whereas it thereafter remained unchanged until day 28. EDH-mediated relaxation was diminished at day 2 of hypoxia, indicating a transition from EDH to NO in BK-mediated relaxation before the development of hypoxia-induced PH. Mechanistically, chronic hypoxia enhanced endothelial NO synthase expression and activity associated with downregulation of caveolin-1. Nitrotyrosine levels were significantly higher in vascular smooth muscle of pulmonary microvessels under chronic hypoxia than under normoxia. A similar transition of the mediators in BK-mediated relaxation was also noted in the Sugen hypoxia mouse model. These results indicate that EDH plays important roles in the pulmonary microcirculation in addition to NO under normoxic conditions and that impaired EDH-mediated relaxation and subsequent nitrosative stress may be potential triggers of the onset of PH.

NEW & NOTEWORTHY This study provides novel evidence that both endothelium-dependent hyperpolarization and nitric oxide play important roles in endothelium-dependent relaxation in the pulmonary microcirculation under physiological conditions in mice and that hypoxia first impairs endothelium-dependent hyperpolarization-mediated relaxation, with compensatory upregulation of nitric oxide, before the development of hypoxia-induced pulmonary hypertension.
Differences in L-type Ca2+ channel activity partially underlie the regional dichotomy in pumping behavior by murine peripheral and visceral lymphatic vessels
Authors: Zawieja Scott D. , Castorena-Gonzalez Jorge A. , Scallan Joshua P. , Davis Michael J.
Published: January 2018

We identified a regional dichotomy in murine lymphatic contractile function with regard to vessel location within the periphery or visceral cavity. All vessels isolated from peripheral regions [cervical, popliteal, inguinal, axillary, and internodal inguinal axillary (Ing-Ax)] developed robust contractions with maximal ejection fractions (EFs) of 50–80% in our ex vivo isobaric myograph experiments. Conversely, vessels isolated from the visceral cavity (mesenteric, thoracic duct, and iliac) demonstrated maximal EFs of ≤10%. Using pressure myography, sharp electrode membrane potential recordings, and Ca2+ imaging, we assessed the role of L-type Ca2+ channels in this contractile dichotomy. Ing-Ax membrane potential revealed a ~2-s action potential (AP) cycle (resting −35 mV, spike −5 mV, and plateau −11 mV) with a plateau phase that was significantly lengthened by the L-type Ca2+ channel agonist Bay K8644 (BayK; 100 nM). APs recorded from mesenteric vessels, however, displayed a slower upstroke and an elongated time over threshold. BayK (100 nM) increased the mesenteric AP upstroke velocity and plateau duration but also significantly hyperpolarized the vessel. Contractions of vessels from both regions were preceded by Ca2+ flashes, detected with a smooth muscle-specific endogenous Ca2+ reporter, that typically were coordinated over the length of the vessel. Similar to the membrane potential recordings, Ca2+ flashes in mesenteric vessels were weaker and had a slower rise time but were longer lasting than those in Ing-Ax vessels. BayK (100 nM) significantly increased the Ca2+ transient amplitude and duration in both vessels and decreased time to peak Ca2+ in mesenteric vessels. However, a higher concentration (1 μM) of BayK was required to produce even a modest increase in EF in visceral lymphatics, which remained at <20%.

NEW & NOTEWORTHY Lymphatic collecting vessels isolated from murine peripheral tissues, but not from the visceral cavities, display robust contractile behavior similar to lymphatic vessels from other animal models and humans. These differences are partially explained by L-type Ca2+ channel activity as revealed by the first measurements of murine lymphatic action potentials and contraction-associated Ca2+ transients.
Guidelines for authors and reviewers on antibody use in physiology studies
Authors: Brooks Heddwen L. , Lindsey Merry L.
Published: January 2018

Antibody use is a critical component of cardiovascular physiology research, and antibodies are used to monitor protein abundance (immunoblot analysis) and protein expression and localization (in tissue by immunohistochemistry and in cells by immunocytochemistry). With ongoing discussions on how to improve reproducibility and rigor, the goal of this review is to provide best practice guidelines regarding how to optimize antibody use for increased rigor and reproducibility in both immunoblot analysis and immunohistochemistry approaches.

Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/guidelines-on-antibody-use-in-physiology-studies/ .
Exercise training induces eNOS coupling and restores relaxation in coronary arteries of heart failure rats
Authors: Couto Gisele K. , Paula Suliana M. , Gomes-Santos Igor L. , Negrão Carlos Eduardo , Rossoni Luciana V.
Published: January 2018

Exercise training (ET) has emerged as a nonpharmacological therapy for cardiovascular diseases because of its helpful milieu for improving vascular function. The aim of the present study was to assess whether ET reverses the alterations in vascular reactivity observed in heart failure (HF)-related coronary arteries and to elucidate the molecular mechanisms involved in these adjustments. Male Wistar rats were subjected to either coronary artery ligation or sham operation. Four weeks after the surgery, rats were divided into two groups: untrained HF (UHF) and exercise-trained HF (THF). ET was conducted on a treadmill for 8 wk. An untrained SO group was included in the study as a normal control. ET restored the impaired acetylcholine (ACh)- and sodium nitroprusside-induced relaxation in coronary arteries to levels of the control. Oxidative stress and reduced nitric oxide (NO) production were observed in UHF, whereas ET restored both parameters to the levels of the control. Expression levels of endothelial NO synthase (eNOS) and soluble guanylyl cyclase subunits were increased in coronary arteries of UHF rats but reduced in THF rats. Tetrahydrobiopterin restored ACh-induced NO production in the UHF group, indicating that eNOS was uncoupled. ET increased the eNOS dimer-to-monomer ratio and expression of GTP cyclohydrolase 1, thus increasing NO bioavailability. Taken together, these findings demonstrate that ET reverses the dysfunction of the NO/soluble guanylyl cyclase pathway present in coronary arteries of HF rats. These effects of ET are associated with increased GTP cyclohydrolase 1 expression, restoration of NO bioavailability, and reduced oxidative stress through eNOS coupling.

NEW & NOTEWORTHY The present study provides a molecular basis for the exercise-induced improvement in coronary arteries function in heart failure. Increasing the expression of GTP cyclohydrolase 1, the rate-limiting enzyme in the de novo biosynthesis of tetrahydrobiopterin, exercise training couples endothelial nitric oxide synthase, reduces oxidative stress, and increases nitric oxide bioavailability and sensitivity in coronary arteries of heart failure rats.
Effects of cigarette smoke on pulmonary endothelial cells
Authors: Lu Qing , Gottlieb Eric , Rounds Sharon
Published: January 2018

Cigarette smoking is the leading cause of preventable disease and death in the United States. Cardiovascular comorbidities associated with both active and secondhand cigarette smoking indicate the vascular toxicity of smoke exposure. Growing evidence supports the injurious effect of cigarette smoke on pulmonary endothelial cells and the roles of endothelial cell injury in development of acute respiratory distress syndrome (ARDS), emphysema, and pulmonary hypertension. This review summarizes results from studies of humans, preclinical animal models, and cultured endothelial cells that document toxicities of cigarette smoke exposure on pulmonary endothelial cell functions, including barrier dysfunction, endothelial activation and inflammation, apoptosis, and vasoactive mediator production. The discussion is focused on effects of cigarette smoke-induced endothelial injury in the development of ARDS, emphysema, and vascular remodeling in chronic obstructive pulmonary disease.
Metabolic reprogramming in the pathogenesis of chronic lung diseases, including BPD, COPD, and pulmonary fibrosis
Authors: Zhao Haifeng , Dennery Phyllis A. , Yao Hongwei
Published: January 2018

The metabolism of nutrient substrates, including glucose, glutamine, and fatty acids, provides acetyl-CoA for the tricarboxylic acid cycle to generate energy, as well as metabolites for the biosynthesis of biomolecules, including nucleotides, proteins, and lipids. It has been shown that metabolism of glucose, fatty acid, and glutamine plays important roles in modulating cellular proliferation, differentiation, apoptosis, autophagy, senescence, and inflammatory responses. All of these cellular processes contribute to the pathogenesis of chronic lung diseases, including bronchopulmonary dysplasia, chronic obstructive pulmonary disease, and pulmonary fibrosis. Recent studies demonstrate that metabolic reprogramming occurs in patients with and animal models of chronic lung diseases, suggesting that metabolic dysregulation may participate in the pathogenesis and progression of these diseases. In this review, we briefly discuss the catabolic pathways for glucose, glutamine, and fatty acids, and focus on how metabolic reprogramming of these pathways impacts cellular functions and leads to the development of these chronic lung diseases. We also highlight how targeting metabolic pathways can be utilized in the prevention and treatment of these diseases.
Increased insulin clearance in mice with double deletion of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors
Authors: Tura Andrea , Bizzotto Roberto , Yamada Yuchiro , Seino Yutaka , Pacini Giovanni , Ahrén Bo
Published: January 2018

To establish whether incretin hormones affect insulin clearance, the aim of this study was to assess insulin clearance in mice with genetic deletion of receptors for both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), so called double incretin receptor knockout mice (DIRKO). DIRKO ( n = 31) and wild-type (WT) C57BL6J mice ( n = 45) were intravenously injected with d-glucose (0.35 g/kg). Blood was sampled for 50 min and assayed for glucose, insulin, and C-peptide. Data were modeled to calculate insulin clearance; C-peptide kinetics was established after human C-peptide injection. Assessment of C-peptide kinetics revealed that C-peptide clearance was 1.66 ± 0.10 10−3 1/min. After intravenous glucose administration, insulin clearance during first phase insulin secretion was markedly higher in DIRKO than in WT mice (0.68 ± 0.06 10−3 l/min in DIRKO mice vs. 0.54 ± 0.03 10−3 1/min in WT mice, P = 0.02). In contrast, there was no difference between the two groups in insulin clearance during second phase insulin secretion ( P = 0.18). In conclusion, this study evaluated C-peptide kinetics in the mouse and exploited a mathematical model to estimate insulin clearance. Results showed that DIRKO mice have higher insulin clearance than WT mice, following intravenous injection of glucose. This suggests that incretin hormones reduce insulin clearance at physiological, nonstimulated levels.
Evolution of ventricular hypertrophy and myocardial mechanics in physiological and pathological hypertrophy
Authors: Yalçin Fatih , Kucukler Nagehan , Cingolani Oscar , Mbiyangandu Blaid , Sorensen Lars , Pinherio Aurelio , Abraham M. Roselle , Abraham Theodore P.
Published: January 2018

Left ventricular hypertrophy (LVH) is an adaptive response to physiological or pathological stimuli, and distinguishing between the two has obvious clinical implications. However, asymmetric septal hypertrophy and preserved cardiac function are noted in early stages in both cases. We characterized the early anatomic and functional changes in a mouse model of physiological and pathological stress using serial echocardiography-based morphometry and tissue velocity imaging. Weight-matched CF-1 male mice were separated into Controls ( n = 10), treadmill Exercise 1 h daily for 5 days/wk ( n = 7), and transverse aortic constriction (TAC, n = 7). Hypertrophy was noted first in the left ventricle basal septum compared with other segments in Exercise (0.84 ± 0.02 vs. 0.79 ± 0.03 mm, P = 0.03) and TAC (0.86 ± 0.05 vs. 0.77 ± 0.04 mm, P = 0.02) at 4 and 3 wk, respectively. At 8 wk, eccentric LVH was noted in Exercise and concentric LVH in TAC. Septal E/E′ ratio increased in TAC (32.6 ± 3.7 vs. 37 ± 6.2, P = 0.002) compared with the Controls and Exercise (32.3 ± 5.2 vs. 32.8 ± 3.8 and 31.2 ± 4.9 vs. 28.2 ± 5.0, respectively, nonsignificant for both). Septal s′ decreased in TAC (21 ± 3.6 vs. 17 ± 4.2 mm/s, P = 0.04) but increased in Exercise (19.6 ± 4.1 vs. 29.2 ± 2.3 mm/s, P = 0.001) and was unchanged in Controls (20.1 ± 4.2 vs. 20.9 ± 5.1 mm/s, nonsignificant). With similar asymmetric septal hypertrophy and normal global function during the first 4–8 wk of pathological and physiological stress, there is an early marginal increase with subsequent decrease in systolic tissue velocity in pathological but early and progressive increase in physiological hypertrophy. Tissue velocities may help adjudicate between these two states when there are no overt anatomic or functional differences.

NEW & NOTEWORTHY Pathological and physiological stress-induced ventricular hypertrophy have different clinical connotations but present with asymmetric septal hypertrophy and normal global function in their early stages. We observed a marginal but statistically significant decrease in systolic tissue velocity in pathological but progressive increase in velocity in physiological hypertrophy. Tissue velocity imaging could be an important tool in the management of asymmetric septal hypertrophy by adjudicating between these two etiologies when there are no overt anatomic or functional differences.
Roller massage decreases spinal excitability to the soleus
Authors: Young James D. , Spence Alyssa-Joy , Behm David G.
Published: January 2018

Roller massage (RM) interventions have shown acute increases in range of motion (ROM) and pain pressure threshold (PPT). It is unclear whether the RM-induced increases can be attributed to changes in neural or muscle responses. The purpose of this study was to evaluate the effect of altered afferent input via application of RM on spinal excitability, as measured with the Hoffmann (H-) reflex. A randomized within-subjects design was used. Three 30-s bouts of RM were implemented on a rested, nonexercised, injury-free muscle with 30 s of rest between bouts. The researcher applied RM to the plantar flexors at three intensities of pain: high, moderate, and sham. Measures included normalized M-wave and H-reflex peak-to-peak amplitudes before, during, and up to 3 min postintervention. M-wave and H-reflex measures were highly reliable. RM resulted in significant decreases in soleus H-reflex amplitudes. High-intensity, moderate-intensity, and sham conditions decreased soleus H-reflex amplitudes by 58%, 43%, and 19%, respectively. H-reflexes induced with high-intensity rolling discomfort or pain were significantly lower than moderate and sham conditions. The effects were transient in nature, with an immediate return to baseline following RM. This is the first evidence of RM-induced modulation of spinal excitability. The intensity-dependent response observed indicates that rolling pressure or pain perception may play a role in modulation of the inhibition. Roller massage-induced neural modulation of spinal excitability may explain previously reported increases in ROM and PPT.

NEW & NOTEWORTHY Recent evidence indicates that the benefits of foam rolling and roller massage are primarily accrued through neural mechanisms. The present study attempts to determine the neuromuscular response to roller massage interventions. We provide strong evidence of roller massage-induced neural modulation of spinal excitability to the soleus. It is plausible that reflex inhibition may explain subsequent increases in pain pressure threshold.
The partial pressure of carbon monoxide in human tissues calculated using a parallel capillary-tissue cylinder model
Authors: Coburn Ronald F.
Published: January 2018

Tissue PCOvalues have not been previously estimated under conditions where the blood carboxyhemoglobin % saturation ([COHb]) is at a normal level or increased. Tissue PCOvalues are not known for conditions when [COHb] is increased during CO therapy or during CO poisoning. Using a modified Krogh parallel capillary-tissue model, mean tissue PCOwas calculated for when [COHb] was 1, 5, 10, and 15% saturation, relevant to CO therapy, and 20, 30, and 40% saturation, relevant to CO poisoning. Calculations were made for the time during which CO was being inhaled, after cessation of CO uptake, and for different O2extractions from blood flowing in the model capillary. The T1/2of relevant CO reactions was used in these calculations. When the [COHb] increased to 5 to 10% saturation, mean tissue PCOvalues increased to 500 to 1,100% of values when the [COHb] was 1% saturation. When the [COHb] increased to 20 to 40% saturation, mean tissue PCOvalues increased to 2,300 to 5,700% of the 1% saturation value. Results indicate the utility of the modified Krogh model in furthering understanding the physiology of determinants of tissue PCOand should facilitate future studies of in vivo CO binding to different extravascular heme proteins during CO therapy and during CO poisoning.

NEW & NOTEWORTHY Tissue PCOlevels resulting from carboxyhemoglobin concentrations achieved during CO therapy or during CO poisoning have not been previously estimated. Results published here show that at carboxyhemoglobin levels achieved during CO therapy there are 500 to 1,100% increases in mean tissue PCOvalues. With carboxyhemoglobin increases associated with toxic effects, there are 2,300 to 5,700% increases in the mean tissue PCO. These differences suggest a basis for understanding the therapeutic and toxic effects of CO.
Chronic low-intensity exercise attenuates cardiomyocyte contractile dysfunction and impaired adrenergic responsiveness in aortic-banded mini-swine
Authors: Hiemstra Jessica A. , Veteto Adam B. , Lambert Michelle D. , Olver T. Dylan , Ferguson Brian S. , McDonald Kerry S. , Emter Craig A. , Domeier Timothy L.
Published: January 2018

Exercise improves clinical outcomes in patients diagnosed with heart failure with reduced ejection fraction (HFrEF), in part via beneficial effects on cardiomyocyte Ca2+ cycling during excitation-contraction coupling (ECC). However, limited data exist regarding the effects of exercise training on cardiomyocyte function in patients diagnosed with heart failure with preserved ejection fraction (HFpEF). The purpose of this study was to investigate cardiomyocyte Ca2+ handling and contractile function following chronic low-intensity exercise training in aortic-banded miniature swine and test the hypothesis that low-intensity exercise improves cardiomyocyte function in a large animal model of pressure overload. Animals were divided into control (CON), aortic-banded sedentary (AB), and aortic-banded low-intensity trained (AB-LIT) groups. Left ventricular cardiomyocytes were electrically stimulated (0.5 Hz) to assess Ca2+ homeostasis (fura-2-AM) and unloaded shortening during ECC under conditions of baseline pacing and pacing with adrenergic stimulation using dobutamine (1 μM). Cardiomyocytes in AB animals exhibited depressed Ca2+ transient amplitude and cardiomyocyte shortening vs. CON under both conditions. Exercise training attenuated AB-induced decreases in cardiomyocyte Ca2+ transient amplitude but did not prevent impaired shortening vs. CON. With dobutamine, AB-LIT exhibited both Ca2+ transient and shortening amplitude similar to CON. Adrenergic sensitivity, assessed as the time to maximum inotropic response following dobutamine treatment, was depressed in the AB group but normal in AB-LIT animals. Taken together, our data suggest exercise training is beneficial for cardiomyocyte function via the effects on Ca2+ homeostasis and adrenergic sensitivity in a large animal model of pressure overload-induced heart failure.

NEW & NOTEWORTHY Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Our findings show chronic low-intensity exercise training can prevent cardiomyocyte dysfunction and impaired adrenergic responsiveness in a translational large animal model of chronic pressure overload-induced heart failure with relevance to human HFpEF.
Involvement of hypoglossal and recurrent laryngeal nerves on swallowing pressure
Authors: Tsujimura Takanori , Suzuki Taku , Yoshihara Midori , Sakai Shogo , Koshi Naomi , Ashiga Hirokazu , Shiraishi Naru , Tsuji Kojun , Magara Jin , Inoue Makoto
Published: January 2018

Swallowing pressure generation is important to ensure safe transport of an ingested bolus without aspiration or leaving residue in the pharynx. To clarify the mechanism, we measured swallowing pressure at the oropharynx (OP), upper esophageal sphincter (UES), and cervical esophagus (CE) using a specially designed manometric catheter in anesthetized rats. A swallow, evoked by punctate mechanical stimulation to the larynx, was identified by recording activation of the suprahyoid and thyrohyoid muscles using electromyography (EMG). Areas under the curve of the swallowing pressure at the OP, UES, and CE from two trials indicated high intrasubject reproducibility. Effects of transecting the hypoglossal nerve (12N) and recurrent laryngeal nerve (RLN) on swallowing were investigated. Following bilateral hypoglossal nerve transection (Bi-12Nx), OP pressure was significantly decreased, and time intervals between peaks of thyrohyoid EMG bursts and OP pressure were significantly shorter. Decreased OP pressure and shortened times between peaks of thyrohyoid EMG bursts and OP pressure following Bi-12Nx were significantly increased and longer, respectively, after covering the hard and soft palates with acrylic material. UES pressure was significantly decreased after bilateral RLN transection compared with that before transection. These results suggest that the 12N and RLN play crucial roles in OP and UES pressure during swallowing, respectively. We speculate that covering the palates with a palatal augmentation prosthesis may reverse the reduced swallowing pressure in patients with 12N or tongue damage by the changes of the sensory information and of the contact between the tongue and a palates.

NEW & NOTEWORTHY Hypoglossal nerve transection reduced swallowing pressure at the oropharynx. Covering the hard and soft palates with acrylic material may reverse the reduced swallowing function caused by hypoglossal nerve damage. Recurrent laryngeal nerve transection reduced upper esophageal sphincter negative pressure during swallowing.
Diaphragm muscle activity across respiratory motor behaviors in awake and lightly anesthetized rats
Authors: Jimenez-Ruiz Federico , Khurram Obaid U. , Zhan Wen-Zhi , Gransee Heather M. , Sieck Gary C. , Mantilla Carlos B.
Published: January 2018

Respiratory muscles such as the diaphragm are active across a range of behaviors including ventilation and higher-force behaviors necessary for maintenance of airway patency, and minimal information is available regarding anesthetic effects on the capacity of respiratory muscles to generate higher forces. The purpose of the present study was to determine whether diaphragm EMG activity during lower-force behaviors, such as eupnea and hypoxia-hypercapnia, is differentially affected compared with higher-force behaviors, such as a sigh, in lightly anesthetized animals. In adult male rats, chronically implanted diaphragm EMG electrodes were used to measure the effects of low-dose ketamine (30 mg/kg) and xylazine (3 mg/kg) on root mean square (RMS) EMG amplitude across a range of motor behaviors. A mixed linear model was used to evaluate the effects of ketamine-xylazine anesthesia on peak RMS EMG and ventilatory parameters, with condition (awake vs. anesthetized), behavior (eupnea, hypoxia-hypercapnia, sigh), side (left or right hemidiaphragm), and their interactions as fixed effects and animal as a random effect. Compared with the awake recordings, there was an overall reduction of peak diaphragm RMS EMG across behaviors during anesthesia, but this reduction was more pronounced during spontaneous sighs (which require ~60% of maximal diaphragm force). Respiratory rates and duty cycle during eupnea and hypoxia-hypercapnia were higher in awake compared with anesthetized conditions. These results highlight the importance of identifying anesthetic effects on a range of respiratory motor behaviors, including sighs necessary for maintaining airway patency.

NEW & NOTEWORTHY Respiratory muscles accomplish a range of motor behaviors, with forces generated for ventilatory behaviors comprising only a small fraction of their maximal force generating capacity. Induction of anesthesia exerts more robust effects on the higher-force diaphragm motor behaviors such as sighs compared with eupnea. This novel information on effects of low, sedative doses of a commonly used anesthetic combination (ketamine-xylazine) highlights the importance of identifying anesthetic effects on a range of respiratory motor behaviors.
Motor unit discharge characteristics and walking performance of individuals with multiple sclerosis
Authors: Almuklass Awad M. , Davis Leah , Hamilton Landon D. , Vieira Taian M. , Botter Alberto , Enoka Roger M.
Published: January 2018

Walking performance of persons with multiple sclerosis (MS) is strongly influenced by the activation signals received by lower leg muscles. We examined the associations between force steadiness and motor unit discharge characteristics of lower leg muscles during submaximal isometric contractions with tests of walking performance and disability status in individuals who self-reported walking difficulties due to MS. We expected that worse walking performance would be associated with weaker plantar flexor muscles, worse force steadiness, and slower motor unit discharge times. Twenty-three individuals with relapsing-remitting MS (56 ± 7 yr) participated in the study. Participants completed one to three evaluation sessions that involved two walking tests (25-ft walk and 6-min walk), a manual dexterity test (grooved pegboard), health-related questionnaires, and measurement of strength, force steadiness, and motor unit discharge characteristics of lower leg muscles. Multiple regression analyses were used to construct models to explain the variance in measures of walking performance. There were statistically significant differences (effect sizes: 0.21–0.60) between the three muscles in mean interspike interval (ISI) and ISI distributions during steady submaximal contractions with the plantar flexor and dorsiflexor muscles. The regression models explained 40% of the variance in 6-min walk distance and 47% of the variance in 25-ft walk time with two or three variables that included mean ISI for one of the plantar flexor muscles, dorsiflexor strength, and force steadiness. Walking speed and endurance in persons with relapsing-remitting MS were reduced in individuals with longer ISIs, weaker dorsiflexors, and worse plantar flexor force steadiness.

NEW & NOTEWORTHY The walking endurance and gait speed of persons with relapsing-remitting multiple sclerosis (MS) were worse in individuals who had weaker dorsiflexor muscles and greater force fluctuations and longer times between action potentials discharged by motor units in plantar flexor muscles during steady isometric contractions. These findings indicate that the control of motor unit activity in lower leg muscles of individuals with MS is associated with their walking ability.
Corticospinal gating during action preparation and movement in the primate motor cortex
Authors: Soteropoulos Demetris S.
Published: January 2018

During everyday actions there is a need to be able to withhold movements until the most appropriate time. This motor inhibition is likely to rely on multiple cortical and subcortical areas, but the primary motor cortex (M1) is a critical component of this process. However, the mechanisms behind this inhibition are unclear, particularly the role of the corticospinal system, which is most often associated with driving muscles and movement. To address this, recordings were made from identified corticospinal (PTN, n = 94) and corticomotoneuronal (CM, n = 16) cells from M1 during an instructed delay reach-to-grasp task. The task involved the animals withholding action for ~2 s until a GO cue, after which they were allowed to reach and perform the task for a food reward. Analysis of the firing of cells in M1 during the delay period revealed that, as a population, non-CM PTNs showed significant suppression in their activity during the cue and instructed delay periods, while CM cells instead showed a facilitation during the preparatory delay. Analysis of cell activity during movement also revealed that a substantial minority of PTNs (27%) showed suppressed activity during movement, a response pattern more suited to cells involved in withholding rather than driving movement. These results demonstrate the potential contributions of the M1 corticospinal system to withholding of actions and highlight that suppression of activity in M1 during movement preparation is not evenly distributed across different neural populations.

NEW & NOTEWORTHY Recordings were made from identified corticospinal (PTN) and corticomotoneuronal (CM) cells during an instructed delay task. Activity of PTNs as a population was suppressed during the delay, in contrast to CM cells, which were facilitated. A minority of PTNs showed a rate profile that might be expected from inhibitory cells and could suggest that they play an active role in action suppression, most likely through downstream inhibitory circuits.
The rhythmic nature of visual perception
Authors: Helfrich Randolph F.
Published: January 2018

Our continuous perception of the world could be the result of discrete sampling, where individual snapshots are seamlessly fused into a coherent stream. It has been argued that endogenous oscillatory brain activity could provide the functional substrate of cortical rhythmic sampling. A new study demonstrates that cortical rhythmic sampling is tightly linked to the oculomotor system, thus providing a novel perspective on the neural network underlying top-down guided visual perception.
Antigen-Specific Antitumor Responses Induced by OX40 Agonist Are Enhanced by the IDO Inhibitor Indoximod
Authors: Berrong Zuzana , Mkrtichyan Mikayel , Ahmad Shamim , Webb Mason , Mohamed Eslam , Okoev Grigori , Matevosyan Adelaida , Shrimali Rajeev , Eid Rasha Abu , Hammond Scott , Janik John E. , Khleif Samir N.
Published: January 2018

Although an immune response to tumors may be generated using vaccines, so far, this approach has only shown minimal clinical success. This is attributed to the tendency of cancer to escape immune surveillance via multiple immune suppressive mechanisms. Successful cancer immunotherapy requires targeting these inhibitory mechanisms along with enhancement of antigen-specific immune responses to promote sustained tumor-specific immunity. Here, we evaluated the effect of indoximod, an inhibitor of the immunosuppressive indoleamine-(2,3)-dioxygenase (IDO) pathway, on antitumor efficacy of anti-OX40 agonist in the context of vaccine in the IDO− TC-1 tumor model. We demonstrate that although the addition of anti-OX40 to the vaccine moderately enhances therapeutic efficacy, incorporation of indoximod into this treatment leads to enhanced tumor regression and cure of established tumors in 60% of treated mice. We show that the mechanisms by which the IDO inhibitor leads to this therapeutic potency include (i) an increment of vaccine-induced tumor-infiltrating effector T cells that is facilitated by anti-OX40 and (ii) a decrease of IDO enzyme activity produced by nontumor cells within the tumor microenvironment that results in enhancement of the specificity and the functionality of vaccine-induced effector T cells. Our findings suggest a translatable strategy to enhance the overall efficacy of cancer immunotherapy. Cancer Immunol Res; 6(2); 201–8. ©2018 AACR.
Soluble SLAMF6 Receptor Induces Strong CD8+ T-cell Effector Function and Improves Anti-Melanoma Activity In Vivo
Authors: Eisenberg Galit , Engelstein Roni , Geiger-Maor Anat , Hajaj Emma , Merims Sharon , Frankenburg Shoshana , Uzana Ronny , Rutenberg Abraham , Machlenkin Arthur , Frei Gabi , Peretz Tamar , Lotem Michal
Published: January 2018

SLAMF6, a member of the SLAM (signaling lymphocyte activation molecules) family, is a homotypic-binding immune receptor expressed on NK, T, and B lymphocytes. Phosphorylation variance between T-cell subclones prompted us to explore its role in anti melanoma immunity. Using a 203-amino acid sequence of the human SLAMF6 (seSLAMF6) ectodomain, we found that seSLAMF6 reduced activation-induced cell death and had an antiapoptotic effect on tumor-infiltrating lymphocytes. CD8+ T cells costimulated with seSLAMF6 secreted more IFNγ and displayed augmented cytolytic activity. The systemic administration of seSLAMF6 to mice sustained adoptively transferred transgenic CD8+ T cells in comparable numbers to high doses of IL2. In a therapeutic model, lymphocytes activated by seSLAMF6 delayed tumor growth, and when further supported in vivo with seSLAMF6, induced complete tumor clearance. The ectodomain expedites the loss of phosphorylation on SLAMF6 that occurs in response to T-cell receptor triggering. Our findings suggest that seSLAMF6 is a costimulator that could be used in melanoma immunotherapy. Cancer Immunol Res; 6(2); 127–38. ©2018 AACR.
Maintenance of Ideal Cardiovascular Health and Coronary Artery Calcium Progression in Low-Risk Men and Women in the Framingham Heart Study
Authors: Hwang Shih-Jen , Onuma Oyere , Massaro Joseph M. , Zhang Xiaoling , Fu Yi-Ping , Hoffmann Udo , Fox Caroline S. , O’Donnell Christopher J.
Published: January 2018

Background—

Ideal cardiovascular health (CVH) is associated with a lower risk of cardiovascular disease and freedom from coronary artery calcium (CAC). Prospective data on the association between maintenance of optimal CVH and the progression of subclinical coronary atherosclerosis are limited. We assessed the influence of unfavorable versus favorable CVH on the incidence of CAC progression.

Methods and Results—

The study population consisted of 1119 FHS (Framingham Heart Study) participants who attended the serial FHS MDCT I and MDCT II study (Multi-Detector Computed Tomography) and had a zero Agatston CAC score at baseline. CVH status was defined using 6 CVH metrics from the American Heart Association definition. CAC progression was defined by an increase in Agatston CAC score to ≥3.4. Generalized estimating equations were applied to identify significant associations of CAC progression with both the baseline measurement of CVH and the longitudinal maintenance of CVH. After follow-up (mean, 6.1 years), we observed CAC progression in 191 participants (17.1%). Participants with unfavorable CVH at baseline had a greater risk of CAC progression (odds ratio, 2.43; 95% confidence interval, 1.40–4.23;
P
=0.0017). In addition, each unit decrease in ideal CVH metric was associated with an increase in CAC progression (odds ratio, 1.15; 95% confidence interval, 0.99–1.34;
P
=0.067), after adjustment for baseline ideal CVH metrics.

Conclusions—

Significant associations between an unfavorable CVH profile and CAC progression support public health measures that seek to prevent cardiovascular disease by promoting favorable CVH profiles in persons free of clinical and subclinical cardiovascular disease.
Computed Tomographic Coronary Angiography–Derived Plaque Characteristics Predict Major Adverse Cardiovascular Events
Authors: Nerlekar Nitesh , Ha Francis J. , Cheshire Caitlin , Rashid Hashrul , Cameron James D. , Wong Dennis T. , Seneviratne Sujith , Brown Adam J.
Published: January 2018

Background—

Computed tomographic coronary angiography is a noninvasive imaging modality that permits identification and characterization of coronary plaques. Despite consensus statements supporting routine reporting of computed tomographic coronary angiography plaque characteristics, there remains uncertainty whether these data convey prognostic information. We performed a systematic review and meta-analysis assessing the strength of association between computed tomographic coronary angiography–derived plaque characterization and major adverse cardiovascular events (MACE).

Methods and Results—

Electronic databases were searched for studies reporting computed tomographic coronary angiography plaque characterization and MACE. Data were gathered on plaque morphology (noncalcified, partially calcified, and calcified) and high-risk plaque (HRP) features, including low-attenuation plaque, napkin-ring sign, spotty calcification, and positive remodeling. Of 5496 citations, 13 studies met inclusion criteria. Five hundred fifty-two (3.9%) MACE occurred in 13 977 patients with mean follow-up ranging between 1.3 and 8.2 years. In terms of plaque morphology, the strongest association was observed for noncalcified plaque (hazard ratio [HR], 1.45; 95% confidence interval [CI], 1.24–1.70;
P
<0.001), with weaker associations found for partially calcified (HR, 1.37; 95% CI, 1.18–1.60;
P
<0.001) and calcified plaques (HR, 1.23; 95% CI, 1.16–1.30;
P
<0.001). All HRP features were strongly associated with MACE, including napkin-ring sign (HR, 5.06; 95% CI, 3.23–7.94;
P
<0.001), low-attenuation plaque (HR, 2.95; 95% CI, 2.03–4.29;
P
<0.001), positive remodeling (HR, 2.58; 95% CI, 1.84–3.61;
P
<0.001), and spotty calcification (HR, 2.25; 95% CI, 1.26–4.04;
P
=0.006). The presence of ≥2 HRP features had highest risk of MACE (HR, 9.17; 95% CI, 4.10–20.50;
P
<0.001).

Conclusions—

These data demonstrate that HRP is most likely an independent predictor of MACE, which supports the inclusion of HRP reporting in clinical practice. However, at this point, it remains unclear whether HRP reporting has clinical implications.
Dimensions and Slope in the Nineteenth and Twentieth Dynasty Royal Tombs
Authors: Rossi Corinna
Published: January 2018

After the work carried out by the Theban Mapping Project in the Valley of the Kings, it is finally possible to compare the ancient texts and drawings that refer to the quarrying of the Theban royal tombs with accurate and reliable surveys of these monuments. Two issues in particular are discussed here: the degree of correspondence between written records and actual tombs, and the way in which the slope of the descending corridors was established and measured. The available evidence suggests that the dimensions of the initial plan may have been significantly modified during the work, and that the ancient architects might have measured the length of the sloping passages in a way that does not correspond to our modern graphic conventions.
Panakhtemipet Et Ses Complices (à Propos Du Papyrus Bm Ea 10054, R° 2, 1–5)
Authors: Gasse Annie
Published: January 2018

P. BM 10054 preserves the testimony of a number of tomb robbers. For col. 2 of the recto, some fragments unknown to Peet and hitherto unedited confirm that the passage records the deposition of the fisherman Panakhtemipet. His participation in two separate episodes of robbery, which are not likely to have been far apart in time, argues in favour of a revision of the chronology of the end of the New Kingdom and especially of the period of wḥm mswt.
Molten salt oxidation of organic hazardous waste with high salt content
Authors: Lin Chengqian , Chi Yong , Jin Yuqi , Jiang Xuguang , Buekens Alfons , Zhang Qi , Chen Jian
Published: January 2018

Organic hazardous waste often contains some salt, owing to the widespread use of alkali salts during industrial manufacturing processes. These salts cause complications during the treatment of this type of waste. Molten salt oxidation is a flameless, robust thermal process, with inherent capability of destroying the organic constituents of wastes, while retaining the inorganic ingredients in the molten salt. In the present study, molten salt oxidation is employed for treating a typical organic hazardous waste with a high content of alkali salts. The hazardous waste derives from the production of thiotriazinone. Molten salt oxidation experiments have been conducted using a lab-scale molten salt oxidation reactor, and the emissions of CO, NO, SO2, HCl and dioxins are studied. Impacts are investigated from the composition of the molten salts, the types of feeding tube, the temperature of molten carbonates and the air factor. Results show that the waste can be oxidised effectively in a molten salt bath. Temperature of molten carbonates plays the most important role. With the temperature rising from 600 °C to 750 °C, the oxidation efficiency increases from 91.1% to 98.3%. Compared with the temperature, air factor has but a minor effect, as well as the composition of the molten salts and the type of feeding tube. The molten carbonates retain chlorine with an efficiency higher than 99.9% and the emissions of dioxins are below 8 pg TEQ g-1 sample. The present study shows that molten salt oxidation is a promising alternative for the disposal of organic hazardous wastes containing a high salt content.
Backlash in gender equality? Fathers’ parental leave during a time of economic crisis
Authors: Sigurdardottir Heida Maria , Garðarsdóttir Ólöf
Published: January 2018

In Europe, there has been an increasing emphasis on the equal rights of men and women to parental leave. Nordic countries such as Iceland are often seen as forerunners in the implementation of laws that promote gender equality by giving each parent non-transferable rights to parental leave. In October 2008, the Icelandic banking system collapsed and a severe economic recession followed. This can be seen as a natural experimental intervention and provides a unique opportunity to study potential changes in fathers’ use of parental leave in response to drastic economic changes and resulting policy changes. Our data show that during the years 2003–2007, a time of economic prosperity, Icelandic fathers on average used 3 full months of parental leave. After this event, fathers’ use of parental leave declined, while the reverse could be seen for mothers who progressively took a longer leave with partial pay. Our analysis suggests that a decline in fathers’ use of parental leave can be traced back to the dramatic collapse of the economic system and the subsequent substantial lowering of the maximum payment during parental leave. The most dramatic changes were seen for fathers in high-income groups whose payments during parental leave were most severely cut. The data suggest that after the economic collapse and resulting policy changes, women have become increasingly responsible and men decreasingly responsible for childcare duties – an alarming trend from the standpoint of gender equality. Possible remedies and courses of action are discussed.