bluuebunny/crossref_metadata_2025 huggingface dataset:
Estrogen receptors differentially regulate intracellular calcium handling in human nonasthmatic and asthmatic airway smooth muscle cells
Authors: Bhallamudi Sangeeta , Connell Jennifer , Pabelick Christina M , Prakash Y. S. , Sathish Venkatachalem
Published: October 2019

Asthma is defined as chronic inflammation of the airways and is characterized by airway remodeling, hyperresponsiveness, and acute bronchoconstriction of airway smooth muscle (ASM) cells. Clinical findings suggest a higher incidence and severity of asthma in adult women, indicating a concrete role of sex steroids in modulating the airway tone. Estrogen, a major female sex steroid mediates its role through estrogen receptors (ER) ERα and ERβ, which are shown to be expressed in human ASM, and their expression is upregulated in lung inflammation and asthma. Previous studies suggested rapid, nongenomic signaling of estrogen via ERs reduces intracellular calcium ([Ca2+]i), thereby promoting relaxation of ASM. However, long-term ER activation on [Ca2+]iregulation in human ASM during inflammation or in asthma is still not known. In Fura-2-loaded nonasthmatic and asthmatic human ASM cells, we found that prolonged (24 h) exposure to ERα agonist (PPT) increased [Ca2+]iresponse to histamine, whereas ERβ activation (WAY) led to decreased [Ca2+] compared with vehicle. This was further confirmed by ER overexpression and knockdown studies using various bronchoconstrictor agents. Interestingly, ERβ activation was more effective than 17β-estradiol in reducing [Ca2+]iresponses in the presence of TNF-α or IL-13, while no observable changes were noticed with PPT in the presence of either cytokine. The [Ca2+]i-reducing effects of ERβ were mediated partially via L-type calcium channel inhibition and increased Ca2+sequestration by sarcoplasmic reticulum.Overall, these data highlight the differential signaling of ERα and ERβ in ASM during inflammation. Specific ERβ activation reduces [Ca2+]iin the inflamed ASM cells and is likely to play a crucial role in regulating ASM contractility, thereby relaxing airways.
Intermittent hypoxia and hypercapnia induces inhibitor of nuclear factor-κB kinase subunit β-dependent atherosclerosis in pulmonary arteries
Authors: Imamura Toshihiro , Xue Jin , Poulsen Orit , Zhou Dan , Karin Michael , Haddad Gabriel G.
Published: October 2019

Clinical studies have shown that obstructive sleep apnea (OSA) increases atherosclerosis risk. The inflammation, especially mediated by the macrophages via nuclear factor-κB (NF-κB), has been speculated to contribute to atherogenicity in OSA patients. Inhibitor of NF-κB kinase-β (IKKβ) is an essential element of the NF-κB pathway and is linked to atherosclerosis. We previously reported that atherosclerosis was accelerated in pulmonary artery (PA) but not in aorta when low-density lipoprotein receptor knockout ( Ldlr−/−) mice were exposed to intermittent hypoxia/hypercapnia (IHH), a surrogate for recurrent upper-airway obstruction. Therefore, we hypothesized that IKKβ-dependent NF-κB activation in monocytes and macrophages plays a role in IHH-induced PA atherosclerosis. To test this hypothesis, myeloid restricted IKKβ deletion ( IkkβΔMye) or control ( IkkβF/F) mice were crossed with Ldlr−/− mice to generate double-knockout mice. Then, the mice were exposed to IHH or room air (Air) on high-fat diet for 8 or 16 wk. Lesions of PA and aorta were examined in IkkβΔMye; Ldlr−/− and IkkβF/F; Ldlr−/− male mice under IHH vs. Air. The results revealed that IKKβ deletion abolished IHH-induced PA atherosclerosis after 8-wk exposure but not after 16-wk exposure (8 wk: IkkβF/F; Ldlr−/−, IHH 13.5 ± 1.4 vs. Air 5.7 ± 0.7%, P < 0.01; IkkβΔMye; Ldlr−/−, IHH 7.4 ± 1.9% vs. Air 4.6 ± 1.3%, P = 0.24). Both IKKβ deletion and IHH had no effects on atherosclerosis in the aorta. Our findings demonstrate that IKKβ-dependent NF-κB activity in myeloid-lineage cells plays a critical role in IHH-induced PA atherosclerosis at the early stage.
Functional characterization and osmoregulatory role of the Na+-K+-2Cl−cotransporter in the gill of sea lamprey (Petromyzon marinus), a basal vertebrate
Authors: Shaughnessy Ciaran A. , McCormick Stephen D.
Published: October 2019

The present study provides molecular and functional characterization of Na+-K+-2Cl−cotransporter (NKCC1/Slc12a2) in the gills of sea lamprey ( Petromyzon marinus), the most basal extant vertebrate with an osmoregulatory strategy. We report the full-length peptide sequence for the lamprey Na-K-Cl cotransporter 1 (NKCC1), which we show groups strongly with and occupies a basal position among other vertebrate NKCC1 sequences. In postmetamorphic juvenile lamprey, nkcc1 mRNA was present in many tissues but was fivefold higher in the gill than any other examined tissue, and NKCC1 protein was only detected in the gill. Gill mRNA and protein abundances of NKCC1 and Na+-K+-ATPase (NKA/Atp1a1) were significantly upregulated (20- to 200-fold) during late metamorphosis in fresh water, coinciding with the development of salinity tolerance, and were upregulated an additional twofold after acclimation to seawater (SW). Immunohistochemistry revealed that NKCC1 in the gill is found in filamental ionocytes coexpressing NKA, which develop during metamorphosis in preparation for SW entry. Lamprey treated with bumetanide, a widely used pharmacological inhibitor of NKCC1, exhibited higher plasma Cl−and osmolality as well as reduced muscle water content after 24 h in SW; there were no effects of bumetanide in freshwater-acclimated lamprey. This work provides the first functional characterization of NKCC1 as a mechanism for branchial salt secretion in lampreys, providing evidence that this mode of Cl−secretion has been present among vertebrates for ~550 million years.
Short-term water deprivation does not increase blood pressure variability or impair neurovascular function in healthy young adults
Authors: Watso Joseph C. , Robinson Austin T. , Babcock Matthew C. , Migdal Kamila U. , Wenner Megan M. , Stocker Sean D. , Farquhar William B.
Published: October 2019

High dietary salt increases arterial blood pressure variability (BPV) in salt-resistant, normotensive rodents and is thought to result from elevated plasma [Na+] sensitizing central sympathetic networks. Our purpose was to test the hypothesis that water deprivation (WD)-induced elevations in serum [Na+] augment BPV via changes in baroreflex function and sympathetic vascular transduction in humans. In a randomized crossover fashion, 35 adults [17 female/18 male, age: 25 ± 4 yr, systolic/diastolic blood pressure (BP): 107 ± 11/60 ± 7 mmHg, body mass index: 23 ± 3 kg/m2] completed two hydration protocols: a euhydration control condition (CON) and a stepwise reduction in water intake over 3 days, concluding with 16 h of WD. We assessed blood and urine electrolyte concentrations and osmolality, resting muscle sympathetic nerve activity (MSNA; peroneal microneurography; 18 paired recordings), beat-to-beat BP (photoplethysmography), common femoral artery blood flow (Doppler ultrasound), and heart rate (single-lead ECG). A subset of participants ( n = 25) underwent ambulatory BP monitoring during day 3 of each protocol. We calculated average real variability as an index of BPV. WD increased serum [Na+] (141.0 ± 2.3 vs. 142.1 ± 1.7 mmol/L, P < 0.01) and plasma osmolality (288 ± 4 vs. 292 ± 5 mosmol/kg H2O, P < 0.01). However, WD did not increase beat-to-beat (1.9 ± 0.4 vs. 1.8 ± 0.4 mmHg, P = 0.24) or ambulatory daytime (9.6 ± 2.1 vs. 9.4 ± 3.3 mmHg, P = 0.76) systolic BPV. Additionally, sympathetic baroreflex sensitivity ( P = 0.20) and sympathetic vascular transduction were not different after WD ( P = 0.17 for peak Δmean BP following spontaneous MSNA bursts). These findings suggest that, despite modestly increasing serum [Na+], WD does not affect BPV, arterial baroreflex function, or sympathetic vascular transduction in healthy young adults.
Increased hypoxic proliferative response and gene expression in erythroid progenitor cells of Andean highlanders with chronic mountain sickness
Authors: Bermudez Daniela , Azad Priti , Figueroa-Mujíca Rómulo , Vizcardo-Galindo Gustavo , Corante Noemí , Guerra-Giraldez Cristina , Haddad Gabriel G. , Villafuerte Francisco C.
Published: October 2019

Excessive erythrocytosis (EE) is the main sign of chronic mountain sickness (CMS), a maladaptive clinical syndrome prevalent in Andean and other high-altitude populations worldwide. The pathophysiological mechanism of EE is still controversial, as physiological variability of systemic respiratory, cardiovascular, and hormonal responses to chronic hypoxemia complicates the identification of underlying causes. Induced pluripotent stem cells derived from CMS highlanders showed increased expression of genes relevant to the regulation of erythropoiesis, angiogenesis, cardiovascular, and steroid-hormone function that appear to explain the exaggerated erythropoietic response. However, the cellular response to hypoxia in native CMS cells is yet unknown. This study had three related aims: to determine the hypoxic proliferation of native erythroid progenitor burst-forming unit-erythroid (BFU-E) cells derived from CMS and non-CMS peripheral blood mononuclear cells; to examine their sentrin-specific protease 1 (SENP1), GATA-binding factor 1 (GATA1), erythropoietin (EPO), and EPO receptor (EPOR) expression; and to investigate the functional upstream role of SENP1 in native progenitor differentiation into erythroid precursors. Native CMS BFU-E colonies showed increased proliferation under hypoxic conditions compared with non-CMS cells, together with an upregulated expression of SENP1, GATA1, EPOR; and no difference in EPO expression. Knock-down of the SENP1 gene abolished the augmented proliferative response. Thus, we demonstrate that native CMS progenitor cells produce a larger proportion of erythroid precursors under hypoxia and that SENP1 is essential for proliferation. Our findings suggest a significant intrinsic component for developing EE in CMS highlanders at the cellular and gene expression level that could be further enhanced by systemic factors such as alterations in respiratory control, or differential hormonal patterns.
EEG power spectral slope differs by ADHD status and stimulant medication exposure in early childhood
Authors: Robertson Madeline M. , Furlong Sarah , Voytek Bradley , Donoghue Thomas , Boettiger Charlotte A. , Sheridan Margaret A.
Published: October 2019

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by hyperactivity/impulsivity and inattentiveness. Efforts toward the development of a biologically based diagnostic test have identified differences in the EEG power spectrum; most consistently reported is an increased ratio of theta to beta power during resting state in those with the disorder, compared with controls. Current approaches calculate theta/beta ratio using fixed frequency bands, but the observed differences may be confounded by other relevant features of the power spectrum, including shifts in peak oscillation frequency and altered slope or offset of the aperiodic 1/ f-like component of the power spectrum. In the present study, we quantify the spectral slope and offset, peak alpha frequency, and band-limited and band-ratio oscillatory power in the resting-state EEG of 3- to 7-yr-old children with and without ADHD. We found that medication-naive children with ADHD had higher alpha power, greater offsets, and steeper slopes compared with typically developing children. Children with ADHD who were treated with stimulants had comparable slopes and offsets to the typically developing group despite a 24-h medication-washout period. We further show that spectral slope correlates with traditional measures of theta/beta ratio, suggesting the utility of slope as a neural marker over and above traditional approaches. Taken with past research demonstrating that spectral slope is associated with executive functioning and excitatory/inhibitory balance, these results suggest that altered slope of the power spectrum may reflect pathology in ADHD.

NEW & NOTEWORTHY This article highlights the clinical utility of comprehensively quantifying features of the EEG power spectrum. Using this approach, we identify, for the first time, differences in the aperiodic components of the EEG power spectrum in children with attention-deficit/hyperactivity disorder (ADHD) and provide evidence that spectral slope is a robust indictor of an increase in low- relative to high-frequency power in ADHD.
Fast and specific: insights into the acquisition and generalization of motor acuity
Authors: Gonda Shahar , Shkedy Rabani Anat , Horesh Naama , Shmuelof Lior
Published: October 2019

Motor acuity is considered to be the outcome of prolonged practice and to involve morphological changes in the motor cortex. We have previously designed a curved pointing task, the arc pointing task (APT), to study motor acuity acquisition, defined as a change in the speed-accuracy tradeoff function (SAF) of the task. Here, we studied the generalization of motor acuity between hands and between tasks (drawing the arc in the opposite direction and with the untrained hand) and the effect of training duration on motor acuity. We report that training-induced motor acuity improvement did not generalize across hands and across tasks performed with the same hand, suggesting a task-specific representation of motor acuity. To our surprise, the largest gains in motor acuity, measured both by changes in SAF and by improvement in multiple kinematic variables, were seen following a short exposure to the task. Our results suggest that motor acuity training-induced improvement is task specific and that motor acuity starts to improve following a very short practice.

NEW & NOTEWORTHY We report that training induced motor acuity improvement does not generalize from one hand to another or between movements that are performed with the same effector. Furthermore, significant improvements in acuity were found following a very short exposure to the task (∼20 trials). Therefore, our results suggest that the nervous system has the capacity to rapidly improve motor acuity.
Overexpression of Mitochondrial Calcium Uniporter Causes Neuronal Death
Authors: Granatiero Veronica , Pacifici Marco , Raffaello Anna , De Stefani Diego , Rizzuto Rosario
Published: October 2019

Neurodegenerative diseases are a large and heterogeneous group of disorders characterized by selective and progressive death of specific neuronal subtypes. In most of the cases, the pathophysiology is still poorly understood, although a number of hypotheses have been proposed. Among these, dysregulation of Ca2+ homeostasis and mitochondrial dysfunction represent two broadly recognized early events associated with neurodegeneration. However, a direct link between these two hypotheses can be drawn. Mitochondria actively participate to global Ca2+ signaling, and increases of [Ca2+] inside organelle matrix are known to sustain energy production to modulate apoptosis and remodel cytosolic Ca2+ waves. Most importantly, while mitochondrial Ca2+ overload has been proposed as the no-return signal, triggering apoptotic or necrotic neuronal death, until now direct evidences supporting this hypothesis, especially in vivo, are limited. Here, we took advantage of the identification of the mitochondrial Ca2+ uniporter (MCU) and tested whether mitochondrial Ca2+ signaling controls neuronal cell fate. We overexpressed MCU both in vitro, in mouse primary cortical neurons, and in vivo, through stereotaxic injection of MCU-coding adenoviral particles in the brain cortex. We first measured mitochondrial Ca2+ uptake using quantitative genetically encoded Ca2+ probes, and we observed that the overexpression of MCU causes a dramatic increase of mitochondrial Ca2+ uptake both at resting and after membrane depolarization. MCU-mediated mitochondrial Ca2+ overload causes alteration of organelle morphology and dysregulation of global Ca2+ homeostasis. Most importantly, MCU overexpression in vivo is sufficient to trigger gliosis and neuronal loss. Overall, we demonstrated that mitochondrial Ca2+ overload is per se sufficient to cause neuronal cell death both in vitro and in vivo, thus highlighting a potential key step in neurodegeneration.
Experimental Research and Simulation on the Mechanical Performance Degradation of Corroded Stud Shear Connectors
Authors: Wang Bing , Liu Xiaoling , Du Jiantao
Published: October 2019

Electrochemical accelerated corrosion and tensile tests were conducted on six series of 30 stud specimens in this study to assess the various mechanical properties in corroded stud connectors. The results indicate that there is a gradual decline in mechanical properties (e.g., yield strength, ultimate strength, and plasticity) as stud corrosion rate increases. Degradation equations for these parameters were established via fitting analysis on the test data. A Gurson–Tvergaard–Needleman (GTN) constitutive model describing the tensile behavior of corroded studs was established based on mesodamage mechanics and finite element analysis. In the GTN model, the corrosion rate equals the original void volume fraction; the trial‐and‐error method was adopted to determine the relationship between the corrosion rate and material failure parameters. The finite element simulation results are in good agreement with the experimental results. The GTN model accurately simulates the uniaxial tensile behavior of the corroded stud.
Beneficial Effects of Qingzixiaoban Granule on Henoch–Schönlein Purpura Nephritis Mice through Inhibiting Immune Complex Deposition and Th2 Immunodeviation
Authors: Yang Hui , Guan Jing , Ma Pei , Fan Yannan , Bai Jinye , Li Shuyi , Yuan Jiqiao , Jin Yecheng , Lin Mingbao , Zhang Jianmin , Hou Qi
Published: October 2019

Background. Henoch–Schönlein purpura nephritis (HSPN) is the principal cause of morbidity and mortality in Henoch–Schönlein purpura (HSP). However, there is no absolute consensus for the best management of severe HSPN till now. Qingzixiaoban Granule (QZXB GR), a traditional Chinese medicine formula, has been applied to treat HSP in clinical in China. However, the therapeutic effects and potential mechanism of QZXB GR on HSPN is still unknown.Methods. A Gliadin plus Indian Ink-induced HSPN mice model was established. Renal histopathologic changes and the subcutaneous hemorrhage on left legs were assessed. Hematuria and proteinuria were determined using hemocytometer and bicinchoninic acid assay, respectively. The serum circular immune complex and interleukin-6 were quantified by ELISA. Using blood biochemical analyzer, the renal biochemical parameters, including serum total protein, albumin, creatinine, and blood urea nitrogen, were measured. The deposition of immune complex in renal tissues and the lymphocyte subsets in peripheral blood and spleen was investigated by immunohistochemistry and flow cytometry.Results. QZXB GR treatment significantly ameliorated renal injury in HSPN mice, by attenuating renal histopathological changes, reducing subcutaneous hemorrhage, decreasing proteinuria/hematuria, regulating renal biochemical parameters, and inhibiting the release of serum interleukin-6. Furthermore, QZXB GR treatment significantly decreased the level of serum circular immune complex, decreased immune complex IgA and IgG deposition in renal tissue, and suppressed Th2 immunodeviation.Conclusion. QZXB GR could prevent renal injury in HSPN mice, and its renoprotective mechanism might be exerted partly through suppressing immune complexes deposition and Th2 immune deviation.
Synthesis of Iron-Modified Biochar Derived from Rice Straw and Its Application to Arsenic Removal
Authors: Nguyen Thi Hanh , Pham Thi Huong , Nguyen Thi Hong Tham , Nguyen Thi Nham , Nguyen Minh-Viet , Tran Dinh Trinh , Nguyen Minh Phuong , Do Trung Quang , Phuong Thao , Hoang Thu Trang , Mai Hung Thanh Tung , Thi Viet Ha Tran
Published: October 2019

A novel iron-modified biochar (FMBC) derived from rice straw was synthesized using FeCl3 modification for efficient As(V) removal from aqueous solution. FTIR and SEM-EDX analyses were carried out to determine the mechanism involved in the removal process and also demonstrated that Fe had loaded successfully on the surface of modified biochar. The iron-modified biochar showed higher arsenic removal ability than the raw biochar. The iron-modified biochar showed a maximum adsorption with an initial solution pH of 5.0. Moreover, for the tested biochar, the As(V) removal kinetics data were well fitted by the pseudo-second-order model. Furthermore, the As(V) removal data upon being well fitted by the Langmuir model showed the maximal removal capacity of 28.49 mg/g. The simple preparation process and high adsorption performance suggest that the iron-modified biochar derived from rice straw could be served as an effective, inexpensive, and environmentally sustainable adsorbent to replace typical granular activated carbon (AC) for As(III) removal from aqueous solution.
A Review on Flavonoid Apigenin: Dietary Intake, ADME, Antimicrobial Effects, and Interactions with Human Gut Microbiota
Authors: Wang Minqian , Firrman Jenni , Liu LinShu , Yam Kit
Published: October 2019

Apigenin is a flavonoid of low toxicity and multiple beneficial bioactivities. Published reviews all focused on the findings using eukaryotic cells, animal models, or epidemiological studies covering the pharmacokinetics, cancer chemoprevention, and drug interactions of apigenin; however, no review is available on the antimicrobial effects of apigenin. Research proves that dietary apigenin passes through the upper gastrointestinal tract and reaches the colon after consumption. For that reason, it is worthwhile to study the potential interactions between apigenin and human gut microbiota. This review summarizes studies on antimicrobial effects of apigenin as well as what has been reported on apigenin and human gut microbiota. Various levels of effectiveness have been reported on apigenin’s antibacterial, antifungal, and antiparasitic capability. It has been shown that apigenin or its glycosides are degraded into smaller metabolites by certain gut bacteria which can regulate the human body after absorption. How apigenin contributes to the structural and functional changes in human gut microbiota as well as the bioactivities of apigenin bacterial metabolites are worth further investigation.
Study on the Life-Cycle Health Monitoring Technology of Water-Rich Loess Tunnel
Authors: Xue Xiaohui , Xie Yongli , Zhou Xinxing
Published: October 2019

The engineering properties of water-rich loess tunnel will decline sharply because of the existence of water, which threats the safety and stability of the tunnel seriously. In order to ensure the safety and stability of the Qiaoyuan tunnel, the life-cycle health monitoring was measured by the vibrating wire sensor and distributed optical fiber. The contact pressure, shotcrete stress, stress of steel arch rib, and strain states of the secondary liner were evaluated. The results of the life-cycle health monitoring demonstrated that the construction procedure, irrigation, and heavy rainfall significantly affected the mechanics morphology of the support structure. In particular, under the influence of irrigation, the shotcrete stress of the left shoulder had risen to 6.21 MPa from 5.30 MPa. Affordable maximum tensile stress of the right shotcrete is 2.15 MPa, which caused the cracking of primary support structure with a crack width of 3 mm to 8 mm. After irrigation and heavy rainfall, the stress of steel arch rib of the left haunch had risen to 135.7 MPa and 298.7 MPa, respectively. In addition, the strain of secondary liner rose to 1498 με from 1278 με continuously at the right sidewall on section YK9 + 685, presenting that the crack was still developing. It indicates that the vibrating wire sensor and the distributed optical fiber were successful in achieving the life-cycle health monitoring of water-rich loess tunnel. This technique has a significant impact on formulating the maintaining measures and reducing the risk of tunnel.
The Association between the Comprehensive Epstein–Barr Virus Serologic Profile and Endemic Burkitt Lymphoma
Authors: Coghill Anna E. , Proietti Carla , Liu Zhiwei , Krause Lutz , Bethony Jeff , Prokunina-Olsson Ludmila , Obajemu Adeola , Nkrumah Francis , Biggar Robert J. , Bhatia Kishor , Hildesheim Allan , Doolan Denise L. , Mbulaiteye Sam M.
Published: October 2019

Background:

The discovery of Epstein–Barr virus (EBV) in Burkitt lymphoma tumors represented the first link between a virus and cancer in humans, but the underlying role of this virus in endemic Burkitt lymphoma remains unclear. Nearly all children in Burkitt lymphoma–endemic areas are seropositive for EBV, but only a small percentage develop disease. Variation in EBV-directed immunity could be an explanatory cofactor.

Methods:

We examined serum from 150 Burkitt lymphoma cases and 150 controls using a protein microarray that measured IgG and IgA antibodies against 202 sequences across the entire EBV proteome. Variation in the EBV-directed antibody repertoire between Burkitt lymphoma cases and controls was assessed using unpaired t tests. ORs quantifying the association between anti-EBV IgG response tertiles and Burkitt lymphoma status were adjusted for age, sex, and study year.

Results:

Thirty-three anti-EBV IgG responses were elevated in Burkitt lymphoma cases compared with controls (P ≤ 0.0003). Burkitt lymphoma–associated IgG elevations were strongest for EBV proteins involved in viral replication and antiapoptotic signaling. Specifically, we observed ORs ≥4 for BMRF1 (early antigen), BBLF1 (tegument protein), BHRF1 (Bcl-2 homolog), BZLF1 (Zebra), BILF2 (glycoprotein), BLRF2 [viral capsid antigen (VCA)p23], BDLF4, and BFRF3 (VCAp18). Adjustment for malaria exposure and inheritance of the sickle cell variant did not alter associations.

Conclusions:

Our data suggest that the anti-EBV serologic profile in patients with Burkitt lymphoma is altered, with strong elevations in 33 of the measured anti-EBV IgG antibodies relative to disease-free children.

Impact:

The Burkitt lymphoma–specific signature included EBV-based markers relevant for viral replication and antiapoptotic activity, providing clues for future Burkitt lymphoma pathogenesis research.
Effects of Electronic Cigarette Constituents on the Human Lung: A Pilot Clinical Trial
Authors: Song Min-Ae , Reisinger Sarah A. , Freudenheim Jo L. , Brasky Theodore M. , Mathé Ewy A. , McElroy Joseph P. , Nickerson Quentin A. , Weng Daniel Y. , Wewers Mark D. , Shields Peter G.
Published: October 2019

Electronic cigarette (e-cig) use is continuing to increase, particularly among youth never-smokers, and is used by some smokers to quit. The acute and chronic toxicity of e-cig use is unclear generally in the context of increasing reports of inflammatory-type pneumonia in some e-cig users. To assess lung effects of e-cigs without nicotine or flavors, we conducted a pilot study with serial bronchoscopies over 4 weeks in 30 never-smokers, randomized either to a 4-week intervention with the use of e-cigs containing only 50% propylene glycol (PG) and 50% vegetable glycerine or to a no-use control group. Compliance to the e-cig intervention was assessed by participants sending daily puff counts and by urinary PG. Inflammatory cell counts and cytokines were determined in bronchoalveolar lavage (BAL) fluids. Genome-wide expression, miRNA, and mRNA were determined from bronchial epithelial cells. There were no significant differences in changes of BAL inflammatory cell counts or cytokines between baseline and follow-up, comparing the control and e-cig groups. However, in the intervention but not the control group, change in urinary PG as a marker of e-cig use and inhalation was significantly correlated with change in cell counts (cell concentrations, macrophages, and lymphocytes) and cytokines (IL8, IL13, and TNFα), although the absolute magnitude of changes was small. There were no significant changes in mRNA or miRNA gene expression. Although limited by study size and duration, this is the first experimental demonstration of an impact of e-cig use on inflammation in the human lung among never-smokers.
Hepatic Artery Embolization Induces the Local Overexpression of Transforming Growth Factor β1 in a Rat Hepatoma Model
Authors: Ueshima Eisuke , Nishiofuku Hideyuki , Takaki Haruyuki , Hirata Yutaka , Kodama Hiroshi , Tanaka Toshihiro , Kichikawa Kimihiko , Yamakado Koichiro , Okada Takuya , Sofue Keitaro , Yamaguchi Masato , Sugimoto Koji , Murakami Takamichi
Published: October 2019

Introduction: The underlying mechanism involved in the recurrence of hepatoma after hepatic arterial embolization (HAE) is not adequately examined. An immunosuppressive cytokine, transforming growth factor β1 (TGF-β1), can lead to tumor progression and is affected by hypoxia in various cancers. The study aimed to assess the effect of HAE on the expression of TGF-β1 in a rat hepatoma model. Methods: Sprague-Dawley rats bearing N1S1 hepatoma cells underwent HAE (HAE group, n = 5) or sham treatment (sham group, n = 4). The animals were euthanized at 48 h, and liver tissues were harvested. Immunohistochemistry (IHC) and quantitative polymerase chain reaction (qPCR) were performed to compare the expression of TGF-β1 and hypoxia-inducible factor 1α (HIF-1α) between the HAE and sham groups. In vitro experiments with the N1S1 cell line were also performed under normoxic (21% O2) or hypoxic (1% O2) conditions for 48 h, and the expression of TGF-β1 and HIF-1α was assessed with western blotting and enzyme-linked immunosorbent assay. Statistical data comparisons were performed by Student t test. Results: IHC showed that both the TGF-β1-positive and HIF-1α-positive tumor peripheral areas were larger in the HAE group (6.59 ± 2.49 and 10.26 ± 4.14%; p < 0.001, respectively) than in the sham group (0.34 ± 0.41 and 0.40 ± 0.84% respectively). Similarly, qPCR showed that the mRNA expression levels of TGF-β1 and HIF-1α were higher (1.95 ± 0.38-fold and 1.62 ± 0.37-fold; p < 0.001 and p = 0.002, respectively) in the HAE group than those in the sham group. TGF-β1 expression was suppressed when HIF-1α inhibitors were added (p = 0.001), and HIF-1α expression was upregulated when exogenous TGF-β1 was added (p = 0.033) in N1S1 cells. Conclusion: HAE enhanced local TGF-β1 expression in a rat hepatoma model. In vitro experiments suggest that HAE-induced hypoxic stress may trigger the interdependent expression of TGF-β1 and HIF-1α.
Pancreas- and Pylorus-Preserving Duodenectomy for Advanced Familial Duodenal Polyposis
Authors: Leite Júlio S. , Tralhão José Guilherme , Manso António , Fernandes Miguel , Cunha Inês , Amaro Pedro
Published: October 2019

Most patients with familial adenomatous polyposis (FAP) will develop duodenal polyps and 5% progress to cancer. Those with Spigelman stage IV have a 36% risk of cancer at 10 years. Endoscopic surveillance is necessary with local ablation for early disease. Unresectable duodenal disease and severe dysplasia are an indication for prophylactic radical surgery by pancreaticoduodenectomy or pancreas-sparing duodenectomy. Some preliminary results have shown better outcomes with duodenectomy. A 45-year-old female with FAP had restorative proctocolectomy at 24 years, desmoid of the mesentery with regression after sulindac, two pregnancies, and at the age of 37 years had duodenal polyposis stage III carpeting the periampullary region. Endoscopic papillectomy and extensive piecemeal mucosectomy was performed but was unsuccessful due to recurrence. After 7 years of regular endoscopic surveillance, focal high-grade dysplasia was diagnosed at the last evaluation. Some diminutive polyps were seen in the small-bowel capsule endoscopy. MRCP showed a normal biliary and pancreatic duct without visualization of the Santorini duct. A pancreas and pylorus-preserving duodenectomy was performed with 3 main steps: (1) duodenectomy with preservation of the pancreas and the pylorus; (2) reconstruction with an advanced jejunal limb and duodenojejunostomy; (3) reimplantation of the biliary and pancreatic duct in the jejunal loop. The patient was discharged on the 11th postoperative day without complications. In conclusion, pancreas- and pylorus-preserving duodenectomy is a promising alternative to pancreaticoduodenectomy for advanced duodenal polyposis that allows complete endoscopic surveillance.
Integration of Bronchoscopic Transesophageal Ultrasound Examination of the Left Adrenal Gland into Routine Lung Cancer Staging Workup: A Prospective Trial
Authors: Darwiche Kaid , Becker Jonathan , Winantea Jane , Karpf-Wissel Ruediger , Funke Faustina , Stenzel Elena , Hautzel Hubertus , Hager Thomas , Eisenmann Stephan
Published: October 2019

Background: Endobronchial ultrasound (EBUS) with transbronchial needle aspiration increases the diagnostic yield of lung cancer staging. The left adrenal gland (LAG) is a common site for lung cancer metastasis. The modality of transesophageal examination with an EBUS bronchoscope (EUS-B) routinely for LAG has not been assessed. Objective: The aim of this study was to prospectively assess if evaluation and tissue sampling of the LAG could routinely be implemented in an EBUS procedure. Methods: Patients referred for EBUS between March and August 2017 had assessment of the LAG via EUS-B. Fine-needle aspiration (FNA) was performed in cases with a suspicious LAG. The detection rate, procedure time, and learning curve of four experienced EBUS-bronchoscopists was assessed, plus the diagnostic accuracy and complication rate of FNA. Results: In total, 313 consecutive patients were included. The overall LAG detection rate was 87.5%. After the initial learning curve, the detection rate for all four bronchoscopists was >93%. The detection rate did not correlate with any patient characteristics. EUS-B-FNA revealed nine LAG metastases, with a sensitivity, specificity, and accuracy of 75%, 100%, and 99%, respectively. The mean EUS-B operation time was 194.4 s, with 594.8 s for FNA. There were no FNA-associated complications. Conclusions: Evaluation of the LAG with EUS-B could routinely be included in an EBUS procedure if necessary. A high detection rate can be achieved after an initial learning period. FNA of the LAG was feasible and safe. EUS-B of the LAG could be integrated into the usual EBUS/EUS-B procedure in lung cancer staging workup.
Metabolic Disorders in Patients with Central Nervous System Infections: Associations with Neurosyphilis
Authors: Xiao Yao , Chen Mei-Jun , Shen Xu , Lin Li-Rong , Liu Li-Li , Yang Tian-Ci , Niu Jian-Jun
Published: October 2019

Introduction: Recently, neurosyphilis was found to be associated with diabetes mellitus (DM). Whether the association was specific to neurosyphilis among central nervous system (CNS) infections, and whether neurosyphilis is associated with other prevalent metabolic disorders deserves further study. Methods: An in-depth cross-sectional study was conducted with 74 neurosyphilis patients and 74 sex- and age-matched patients with other CNS infections. DM-, hypertension-, and dyslipidemia-related factors were compared between patients with neurosyphilis and those with other CNS infections. Results: The prevalence rates of hypertension and hyperlipidemia in neurosyphilis patients were 45.9 and 21.4%, respectively, which were higher than those in patients with other CNS infections (45.9 vs. 28.4%, p = 0.027; 21.4 vs. 8.3%, p = 0.028). In addition, neurosyphilis patients had significantly higher systolic blood pressure (BP; median 139 mm Hg; interquartile range [IQR] 121–151 mm Hg), ­diastolic BP (median 83 mm Hg; IQR 76–89 mm Hg), total cholesterol (median 4.86 mmol/L; IQR 3.80–5.51 mmol/L), low-density lipoprotein (median 3.39 mmol/L; IQR 2.52–3.95 mmol/L), and apolipoprotein A1 (apoA1; median 1.31 g/L; IQR 1.06–1.52 g/L) levels and lower apoB/A1 ratios (median 0.67; IQR 0.49–0.99) than patients with other CNS infections (p< 0.05). There were no differences in the DM-related factors between patients with neurosyphilis and those with other CNS infections (p> 0.05). Conclusion: Potential association between neurosyphilis and metabolic disorders was found among CNS infections. The results could have important implications for clinical practice, alerting more clinicians to this issue.
CD73 Promotes Age-Dependent Accretion of Atherosclerosis
Authors: Sutton Nadia R. , Bouïs Diane , Mann Kris M. , Rashid Imran M. , McCubbrey Alexandra L. , Hyman Matt C. , Goldstein Daniel R. , Mei Annie , Pinsky David J.
Published: October 2019

Objective:

CD73 is an ectonucleotidase which catalyzes the conversion of AMP (adenosine monophosphate) to adenosine. Adenosine has been shown to be anti-inflammatory and vasorelaxant. The impact of ectonucleotidases on age-dependent atherosclerosis remains unclear. Our aim was to investigate the role of CD73 in age-dependent accumulation of atherosclerosis.

Approach and results:

Mice doubly deficient in CD73 and ApoE (apolipoprotein E; (

cd73
−
/−
/apoE
−/−

) were generated, and the extent of aortic atherosclerotic plaque was compared with

apoE
−/−

controls at 12, 20, 32, and 52 weeks. By 12 weeks of age,

cd73
−/−
/apoE
−/−

mice exhibited a significant increase in plaque (1.4±0.5% of the total vessel surface versus 0.4±0.1% in

apoE
−/−

controls,
P
<0.005). By 20 weeks of age, this difference disappeared (2.9±0.4% versus 3.3±0.7%). A significant reversal in phenotype emerged at 32 weeks (9.8±1.2% versus 18.3±1.4%;
P
<0.0001) and persisted at the 52 week timepoint (22.4±2.1% versus 37.0±2.1%;
P
<0.0001). The inflammatory response to aging was found to be comparable between

cd73
−/−
/apoE
−/−

mice and

apoE
−/−

controls. A reduction in lipolysis in CD73 competent mice was observed, even with similar plasma lipid levels (

cd73
−/−
/apoE
−/−

versus

apoE
−/−

at 12 weeks [16.2±0.7 versus 9.5±1.4 nmol glycerol/well], 32 weeks [24.1±1.5 versus 7.4±0.4 nmol/well], and 52 weeks [13.8±0.62 versus 12.7±2.0 nmol/well],
P
<0.001).

Conclusions:

At early time points, CD73 exerts a subtle antiatherosclerotic influence, but with age, the pattern reverses, and the presence of CD73 promoted suppression of lipid catabolism.
Spectrum of Mutations and Long-Term Clinical Outcomes in Genetic Chylomicronemia Syndromes
Authors: D’Erasmo Laura , Di Costanzo Alessia , Cassandra Francesca , Minicocci Ilenia , Polito Luca , Montali Anna , Ceci Fabrizio , Arca Marcello
Published: October 2019

Objective:

Familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia syndrome (MCS) are the prototypes of monogenic and polygenic conditions underlying genetically based severe hypertriglyceridemia. These conditions have been only partially investigated so that a systematic comparison of their characteristics remains incomplete. We aim to compare genetic profiles and clinical outcomes in FCS and MCS.

Approach and Results:

Thirty-two patients with severe hypertriglyceridemia (triglyceride >1000 mg/dL despite lipid-lowering treatments with or without history of acute pancreatitis) were enrolled. Rare and common variants were screened using a panel of 18 triglyceride-raising genes, including the canonical
LPL
,
APOC2
,
APOA5
,
GP1HBP1
, and
LMF1
. Clinical information was collected retrospectively for a median period of 44 months. Across the study population, 37.5% were classified as FCS due to the presence of biallelic, rare mutations and 59.4% as MCS due to homozygosity for nonpathogenic or heterozygosity for pathogenic variants in canonical genes, as well as for rare and low frequency variants in noncanonical genes. As compared with MCS, FCS patients showed a lower age of hypertriglyceridemia onset, higher levels of on-treatment triglycerides, and 3-fold higher incidence rate of acute pancreatitis.

Conclusions:

Our data indicate that the genetic architecture and natural history of FCS and MCS are different. FCS expressed the most severe clinical phenotype as determined by resistance to triglyceride-lowering medications and higher incidence of acute pancreatitis episodes. The most common genetic abnormality underlying FCS was represented by biallelic mutations in
LPL
while
APOA5
variants, in combination with high rare polygenic burden, were the most frequent genotype of MCS.
Association Between High Perceived Stress Over Time and Incident Hypertension in Black Adults: Findings From the Jackson Heart Study
Authors: Spruill Tanya M. , Butler Mark J. , Thomas S. Justin , Tajeu Gabriel S. , Kalinowski Jolaade , Castañeda Sheila F. , Langford Aisha T. , Abdalla Marwah , Blackshear Chad , Allison Matthew , Ogedegbe Gbenga , Sims Mario , Shimbo Daichi
Published: October 2019

Background

Chronic psychological stress has been associated with hypertension, but few studies have examined this relationship in blacks. We examined the association between perceived stress levels assessed annually for up to 13 years and incident hypertension in the Jackson Heart Study, a community‐based cohort of blacks.

Methods and Results

Analyses included 1829 participants without hypertension at baseline (Exam 1, 2000–2004). Incident hypertension was defined as blood pressure≥140/90 mm Hg or antihypertensive medication use at Exam 2 (2005–2008) or Exam 3 (2009–2012). Each follow‐up interval at risk of hypertension was categorized as low, moderate, or high perceived stress based on the number of annual assessments between exams in which participants reported “a lot” or “extreme” stress over the previous year (low, 0 high stress ratings; moderate, 1 high stress rating; high, ≥2 high stress ratings). During follow‐up (median, 7.0 years), hypertension incidence was 48.5%. Hypertension developed in 30.6% of intervals with low perceived stress, 34.6% of intervals with moderate perceived stress, and 38.2% of intervals with high perceived stress. Age‐, sex‐, and time‐adjusted risk ratios (95% CI) associated with moderate and high perceived stress versus low perceived stress were 1.19 (1.04–1.37) and 1.37 (1.20–1.57), respectively (
P
trend<0.001). The association was present after adjustment for demographic, clinical, and behavioral factors and baseline stress (
P
trend=0.001).

Conclusions

In a community‐based cohort of blacks, higher perceived stress over time was associated with an increased risk of developing hypertension. Evaluating stress levels over time and intervening when high perceived stress is persistent may reduce hypertension risk.
Abstract 100: Dual Activation of PKA and PKG by PDE1 Inhibition Facilitates Proteasomal Degradation of Misfolded Proteins and Protects Against Proteinopathy-Based HFpEF
Authors: Zhang Hanming , Pan Bo , Wu Penglong , Rekhter Mark D , Goldberg Alfred L , Wang Xuejun
Published: October 2019

No current treatment is intended to target cardiac proteotoxicity or can reduce mortality of heart failure with preserved ejection fraction (HFpEF), a prevalent form of heart failure (HF). Selective degradation of misfolded proteins by the ubiquitin-proteasome system (UPS) is vital to the cell. Proteasome impairment is recently implicated in HF genesis. Activation of the cGMP-protein kinase G (PKG) or the cAMP-protein kinase A (PKA) pathways facilitates proteasome functioning. Phosphodiesterase 1 (PDE1) hydrolyzes both cyclic nucleotides and accounts for the majority of PDE activities in human myocardium. Here we report the preclinical therapeutic efficacy and a new mechanism of action of PDE1 inhibition (IC86430) for cardiac proteinopathy caused by Arg120Gly missense mutant αB-crystallin (CryAB
R120G
). In mice expressing GFPdgn, an inverse reporter of UPS proteolytic activity, IC86430 treatment increased myocardial 26S proteasome activities and substantially decreased GFPdgn protein levels. Myocardial PDE1A expression was highly upregulated in CryAB
R120G
mice. HFpEF was detected in CryAB
R120G
mice at 4 months; IC86430 treatment initiated at this stage markedly attenuated HFpEF, substantially delayed mouse premature death, increased myocardial levels of Ser14-phosphorylated Rpn6 (the primary proteasome target of PKA), and reduced the steady state level of the misfolded CryAB species in these mice. In cultured cardiomyocytes, IC86430 treatment increased proteasome activities and accelerated proteasomal degradation of GFPu and CryAB
R120G
in a PKA- and PKG- dependent manner. We conclude that PDE1 inhibition induces PKA- and PKG-mediated promotion of proteasomal degradation of misfolded proteins in cardiomyocytes and effectively treats HFpEF caused by CryAB
R120G
; hence, PDE1 inhibition represents a potentially new therapeutic strategy for HFpEF and heart disease with increased proteotoxic stress.
Abstract 102: Molecular, Cellular and Systemic Mechanism of Nonlinear Dynamic Patterns of Ventricular Repolarization and Spontaneous Arrhythmic Sudden Death in Non-ischemic Heart Failure
Authors: Vieira Daiana C , Crocker Jeffrey S , Desai Krina , Sanagala Neha Reddy , Wendelken Daniel R , Parks Kenneth G , Liu Ting , O'Rourke Brian , Dey Swati , DeMazumder Deeptankar
Published: October 2019

Introduction:
Sudden cardiac death (SCD) is the leading cause of death in USA. Heart failure (HF) confers high SCD risk, but most SCD victims do not have HF or well-defined genetic abnormalities. The underlying mechanisms are poorly understood, precluding the design of more effective strategies for risk stratification and therapy. We previously showed that distinct non-linear patterns of cardiac repolarization strongly and independently predict SCD in HF patients [PMID: 27044982]. We also showed in a unique guinea pig HF model that increased levels of mitochondrial reactive oxygen species (mROS) drive spontaneous SCD, even before HF onset [PMID: 29898892]. Herein, we further dissect the underlying mechanisms.

Hypothesis:
Increased mROS levels in pressure overloaded hearts reduce K+ currents, destabilize the resting membrane potential, increase repolarization lability and cause SCD.

Methods:
Guinea pigs were randomized to Sham, aortic banding (AC), or AC with daily brief low-dose β-adrenergic stress (ACi) with and without
in vivo
mROS scavenger MitoTEMPO (ACi+MT). We performed time series analyses on recordings of: (1) 24-hour ECG QT interval in freely ambulating animals before sacrifice at 4 weeks; (2) pressure-volume and electrophysiology (EP) in excised perfused hearts; and (3) duration of action potential (APd), calcium transient (CaTd) and sarcomere shortening (SSd) in isolated LV myocytes.

Results:
About 50% of ACi animals had SCD by 4 weeks. Increased QT entropy in ACi (at 1 week) predicted SCD over followup, similar to HF patients. Compared to Sham and ACi+MT, LV myocytes isolated from AC and ACi had reduced inward (IK1) and delayed slow (IKs) and rapid (IKr) rectifier currents; and increased beat-to-beat lability in APd, CaTd and SSd. The late Na and L-type Ca currents were similar between models. Acute exposure to isoproterenol (Iso) and carbachol (CCh) increased lability in LV myocytes compared to Iso or CCh alone.

Conclusions:
High mROS levels reduce repolarization reserve in LV myocytes and contribute, at least in part, to the non-linear dynamics of ventricular repolarization (reflected by high QT entropy), leading to spontaneous arrhythmic SCD. These findings provide important new mechanistic insight with direct clinical implications.