bluuebunny/crossref_metadata_2025 huggingface dataset:
Life-Threatening Rupture of an Idiopathic Left Hepatic Artery Pseudoaneurysm Successfully Treated with Endovascular Coil Embolization
Authors: Sandelis-Pérez Jorge E. , Córdova-Toro Andrés , García-Santiago Steven , Otero-Cárdenas Erica G. , de Rubio-Cruz Pedro Gil , Márquez-Márquez Suheiry , Rodríguez-Malavé Mary J. , Febles-Negrón Arelis , Colon-Márquez José A. , Hidalgo-Ríos Alejandro
Published: September 2020

Hepatic artery pseudoaneurysm is a rare condition; they are multifactorial, most of them locating in the extrahepatic vasculature and the mortality associated to its rupture may reach up to 70%. We report a 77 years old female who was admitted due to headache and uncontrolled hypertension and that on her second hospital day developed sudden hemodynamic instability, abdominal pain, fatigue, skin-mucosa pallor, and anemia. Abdominal CT scan with contrast showed a left hepatic artery pseudoaneurysm associated with extensive hemoperitoneum. Patient required emergent hemodynamic stabilization and finally was treated successfully with a superselective endovascular coil embolization. Our patient represents an atypical case of a spontaneous rupture of an idiopathic hepatic artery pseudoaneurysm. Hence, the importance of having a high index of clinical suspicion. Endovascular coil embolization has become the first-line treatment.
Analysis of Dynamic Damage-Induced Porosity Changes of Granites in Leaching Mining Technique Based on SHPB Test
Authors: Miao Yichen , Liu Changwu , He Zhiliang , Ma Yuanjun , Wu Haikuan , Wang Ding
Published: September 2020

In situ leaching was a very important technical approach in ion-adsorption rare earth mining, because it can effectively avoid the geological hazards, protect the environment, and reduce the mining costs. The critical issue of this mining technique was to increase the permeability of ion-adsorption rare earth deposits. Due to the close relationship between the permeability and the porosity, in this paper, several experiments were conducted to find the dynamic characteristics of the granite deposit and the relationship between the dynamic characteristics and the porosity. Moreover, the SHPB test system was equipped to conduct the dynamic test, and the ultrasonic wave detector with high precision was employed to obtain the damage factor of granites. The test results showed that the failure mode under dynamic load and static load was close, and they both had splitting failure. Besides, when cyclic dynamic loading velocity was between 5.8 m/s and 8.4 m/s, the specimen was not a failure, but it caused the damage and changed the porosity. And the dynamic thresholds of failure stress and damage stress were found. Finally, a linear relationship between the porosity and the damage factor was found, which would help to analyze and predict the change of porosity under different dynamic loading velocities.
Improvising in Endoscopy: Endoscopic Removal of Sharp Foreign Bodies in the Upper GI Tract, Using a Handmade Protective Device
Authors: Miltiadou Konstantinos , Solomos Zisimangelos , Lygkos Dimitrios , Chatzidakis Alexandros , Rizos Evripidis , Papanikolaou Ioannis S. , Triantafyllou Konstantinos
Published: September 2020

Introduction. Foreign body ingestion is a common problem in large-volume endoscopic departments. Several techniques and devices have been described for the safe endoscopic removal of these objects. However, these devices may not be suitable in every clinical setting or—as in our case—they may not even be available. Case Presentation. We report the case of a 34-year-old patient, presenting with sharp foreign body ingestion. The foreign bodies were safely removed using a handmade protective hood due to lack of a commercial device. In our case, improvisation proved to be of great benefit for the patient as well as for the endoscopist. Discussion. Improvised interventions can be of special interest in the setting of insufficiently funded or equipped endoscopic departments.
Leptin Promoted IL-17 Production from ILC2s in Allergic Rhinitis
Authors: Wen Yanhui , Zeng Qingxiang , Luo Xi , Ma Renqiang , Tang Yiquan , Liu Wenlong
Published: September 2020

Background. Interleukin-17 plays important roles in allergic diseases. Several studies proved that leptin promoted Th17 immune responses by inducing RORγt transcription. ILC2 is an important member of the early stage of immune response. Therefore, we aimed to explore the effect of leptin on the IL-17 production by ILC2 in AR in this study.Methods. Fifteen AR patients and fifteen healthy controls were enrolled. Serum leptin levels were measured, and their correlation with the frequency of IL-17+ ILC2 cells was analyzed using enzyme-linked immunosorbent assay (ELISA) and flow cytometry. ILC2 was stimulated by leptin, and the expression of IL-17, IL-5, and IL-13 was detected by ELISA. The correlated pathways were confirmed by real-time PCR.Results. We found that serum leptin and the frequency of IL-17-producing ILC2s in AR were significantly higher compared with those in controls. After being incubated with leptin, the frequency of IL-17+ ILC2 cells and IL-17 production from ILC2 was upregulated compared with that in controls. We also found that leptin induced RORγt and Ahr expression by ILC2. Moreover, leptin-induced IL-17-producing ILC2 concomitantly expressed IL-5 and IL-13.Conclusions. Our data provide preliminary evidence that leptin-induced IL-17 production from ILC2 cells is dependent on RORγt and Ahr expression and the blockade of leptin may be a promising target for the treatment of AR.
Routing Optimization for Shared Electric Vehicles with Ride-Sharing
Authors: Ren Chuanxiang , Wang Jinbo , You Yongquan , Zhang Yu
Published: September 2020

Shared electric vehicles (SEVs) are becoming a new way for urban residents to travel because of their environmental protection, energy saving, and sustainable development. However, at present, the operation mode of shared electric vehicles has the problem that the vehicle cannot be utilized efficiently. For this reason, this paper studied the mode of SEVs with ride-sharing (MSEVRS) and SEVs routing optimization under this mode. Firstly, the operation principle of MSEVRS is presented, which includes the collection of user demand information and SEVs information and the routing optimization of SEVs, both of which are completed by the user and SEVs management center. Secondly, the routing optimization model of SEVs with ride-sharing is proposed, in which the SEVs operation cost, user time cost, user rental cost, and user ride-sharing bonus are taken into account. And the genetic algorithm is designed to solve the model. Finally, a case study is carried out to illustrate the effectiveness of the proposed model. The results show that the proposed routing optimization model achieves the optimal SEVs route, realizes the MSEVRS, and improves the utilization rate of SEVs. Compared with the current SEVs mode (CSEVM), the MSEVRS reduces the number of vehicles, user rental cost, the total cost of users, and the total cost of user and company of SEVs. And the total distance is reduced, which means saving energy. Moreover, it shows that MSEVRS obtains a better cost performance and service for users and has a better application prospect.
Modeling Resistance and Recurrence Patterns of Combined Targeted–Chemoradiotherapy Predicts Benefit of Shorter Induction Period
Authors: McClatchy David M. , Willers Henning , Hata Aaron N. , Piotrowska Zofia , Sequist Lecia V. , Paganetti Harald , Grassberger Clemens
Published: September 2020

Optimal integration of molecularly targeted therapies, such as tyrosine kinase inhibitors (TKI), with concurrent chemotherapy and radiation (CRT) to improve outcomes in genotype-defined cancers remains a current challenge in clinical settings. Important questions regarding optimal scheduling and length of induction period for neoadjuvant use of targeted agents remain unsolved and vary among clinical trial protocols. Here, we develop and validate a biomathematical framework encompassing drug resistance and radiobiology to simulate patterns of local versus distant recurrences in a non–small cell lung cancer (NSCLC) population with mutated EGFR receiving TKIs and CRT. Our model predicted that targeted induction before CRT, an approach currently being tested in clinical trials, may render adjuvant targeted therapy less effective due to proliferation of drug-resistant cancer cells when using very long induction periods. Furthermore, simulations not only demonstrated the competing effects of drug-resistant cell expansion versus overall tumor regression as a function of induction length, but also directly estimated the probability of observing an improvement in progression-free survival at a given cohort size. We thus demonstrate that such stochastic biological simulations have the potential to quantitatively inform the design of multimodality clinical trials in genotype-defined cancers.

Significance:

A biomathematical framework based on fundamental principles of evolution and radiobiology for in silico clinical trial design allows clinicians to optimize administration of TKIs before chemoradiotherapy in oncogene-driven NSCLC.
A Comparative Analysis of Allergen Proteins between Plants and Animals Using Several Computational Tools and Chou’s PseAAC Concept
Authors: Behbahani Mandana , Rabiei Parisa , Mohabatkar Hassan
Published: September 2020

Background: A large number of allergens are derived from plant and animal proteins. A major challenge for researchers is to study the possible allergenic properties of proteins. The aim of this study was in silico analysis and comparison of several physiochemical and structural features of plant- and animal-derived allergen proteins, as well as classifying these proteins based on Chou’s pseudo-amino acid composition (PseAAC) concept combined with bioinformatics algorithms. Methods: The physiochemical properties and secondary structure of plant and animal allergens were studied. The classification of the sequences was done using the PseAAC concept incorporated with the deep learning algorithm. Conserved motifs of plant and animal proteins were discovered using the MEME tool. B-cell and T-cell epitopes of the proteins were predicted in conserved motifs. Allergenicity and amino acid composition of epitopes were also analyzed via bioinformatics servers. Results: In comparison of physiochemical features of animal and plant allergens, extinction coefficient was different significantly. Secondary structure prediction showed more random coiled structure in plant allergen proteins compared with animal proteins. Classification of proteins based on PseAAC achieved 88.24% accuracy. The amino acid composition study of predicted B- and T-cell epitopes revealed more aliphatic index in plant-derived epitopes. Conclusions: The results indicated that bioinformatics-based studies could be useful in comparing plant and animal allergens.
Frequency and Timing of Endovascular Therapy in Acute Stroke Patients: A Population-Based Analysis Using the Bremen Stroke Register
Authors: Kastrup Andreas , Brunner Freimuth , Roth Christian , Papanagiotou Panagiotis
Published: September 2020

Background and Purpose: In patients with large vessel occlusions (LVOs), endovascular treatment (ET) has become the standard of care, so that the potential number of these patients needs to be considered for the effective implementation of comprehensive stroke services. However, population-based data on the incidence of ET are scarce. Methods: Using our prospective stroke register, in which all endovascular procedures on the 557,464 inhabitants of the city of Bremen are included, we performed a population-based analysis on the frequency and timing of ET in acute stroke patients with LVOs in the year 2017. Results: Out of a total of 1,448 acute ischemic stroke patients, 173 patients (12%) had received ET (161 patients in the anterior circulation and 12 patients in the posterior circulation). Among these, 95 patients were inhabitants of Bremen. The population-based incidence thus was 17 (95% confidence interval [CI]: 14–21) ET cases per 100,000 person-years. The number of stroke procedures per month varied from 9 to 19 (median: 14.5; interquartile range [IQR]: 12–17). The number of stroke procedures per month and 100,000 inhabitants varied from 0.7 to 2.1 (median: 1.4; IQR: 0.9–1.7). Many procedures (53%) were performed during nonwork hours (between 17:00 h and 06:59 h or weekends). Conclusions: Approximately 12% of all ischemic stroke patients received ET, and the incidence of ET was 17 (95% CI: 14–21) cases per 100,000 person-years. However, despite being a high-volume center, the absolute number of stroke procedures per month was low, and many patients were treated during nonwork hours.
Molecular Etiology of Isolated Congenital Cataract Using Next-Generation Sequencing: Single Center Exome Sequencing Data from Turkey
Authors: Taylan Sekeroglu Hande , Karaosmanoglu Beren , Taskiran Ekim Z. , Simsek Kiper Pelin O. , Alikasifoglu Mehmet , Boduroglu Koray , Coskun Turgay , Utine Gulen Eda
Published: September 2020

Congenital cataract, which refers to lenticular opacity diagnosed at birth or more commonly during the first year of life, is one of the leading causes of childhood blindness. Molecular understanding of the disease pathogenesis has evolved thanks to many studies based on modern technologies. In this study, we aimed to identify and discuss the molecular etiology of nonsyndromic or nonmetabolic bilateral congenital cataract by whole-exome sequencing (WES). Patients with bilateral congenital cataract presumed to be isolated after metabolic and genetic evaluation were enrolled in the study. All patients underwent detailed ophthalmological examination and bilateral cataract surgery. DNA samples of the probands, parents, and available affected family members were analyzed by WES. Variants were validated and confirmed by Sanger sequencing in all probands and in available affected family members. A total of 4 patients (3 girls and 1 boy) were recruited. Two patients had nuclear, 1 patient had total, and 1 patient had combined lamellar and sutural cataract. One family had consanguinity. A heterozygous c.215+1G>A mutation in CRYBA1, heterozygous c.432C>G (p.Tyr144Ter) mutation in CRYGC, heterozygous c.70A>C (p.Pro24Thr) mutation in CRYGD, and a heterozygous c.466G>A (p.Gly156Arg) mutation in CRYBB3 were detected. All these mutations were confirmed by Sanger sequencing in selected affected individuals. The current study identified all causative mutations of congenital cataract in the crystalline genes. The results confirmed that WES is a very useful tool in the investigation of the diseases with heterogeneous genetic background.
Effectiveness of iStent Trabecular Microbypass System Combined with Phacoemulsification versus Phacoemulsification Alone in Patients with Glaucoma and Cataract Depending on the Initial Intraocular Pressure
Authors: Kozera Milena , Konopińska Joanna , Mariak Zofia , Rękas Marek
Published: September 2020

Introduction: To assess the effect of iStent trabecular microbypass implantation combined with phacoemulsification on intraocular pressure (IOP) and glaucoma medications and to compare this to outcomes of phacoemulsification alone in patients with mild to moderate primary open-angle glaucoma (POAG) depending on initial IOP. Materials and Methods: Eighty subjects with cataract and POAG were randomized 1:1 into either iStent implantation and cataract surgery (iStent group) (n = 44) or cataract surgery alone (control group) (n = 36). Groups were divided according to initial IOP (after washout period) into IOP <26 mm Hg and IOP ≥26 mm Hg. Patients were assessed preoperatively and at postoperative day 1, week 1, and months 1, 3, 6, 12, and 24. Outcome measures included best-corrected visual acuity, IOP, and glaucoma medications. Results: Postoperatively at 24 months, mean IOP decreased from 20.93 ± 1.28 to 17.79 ± 2.50 mm Hg in the IOP subgroup <26 mm Hg and from 26.00 ± 0.00 to 19.86 ± 2.19 in the subgroup ≥26 mm Hg in the control group. In the iStent group <26 mm Hg, IOP decreased from 22.04 ± 1.64 to 15.57 ± 2.13 mm Hg and from 26.6 ± 1.09 to 17.06 ± 2.43 mm Hg in the iStent group ≥26 mm Hg. Conclusion: In patients with open-angle glaucoma and cataract, iStent implantation combined with cataract surgery reduced IOP significantly through 2 years, with greater reductions achieved versus phacoemulsification alone. In patients with baseline IOP <26 mm Hg, surgery reduced IOP and medication use significantly declined through 2 years, with greater reductions achieved versus patients with baseline IOP ≥26 mm Hg. The study was registered at ClinicalTrials.gov under the number NCT03807869.
Abstract 10: Mouse Recombinant Soluble PRR-induced Increase Of Blood Pressure Is Sex-dependant In High Fat-fed Mice
Authors: Poupeau Audrey A , Gatineau Eva , Arthur Gertrude , Su Wen , Gong Ming C , Yiannikouris Frederique B
Published: September 2020

Obesity is a major risk factor for hypertension. Although the renin-angiotensin system (RAS) contributes to the sex difference of blood pressure (BP) control, whether the prorenin receptor (PRR) and its soluble form (sPRR) play a role in the sexual dimorphism of BP is not clear. We previously demonstrated that, in high fat (HF)-fed male C57BL/6 mice, the infusion of mouse recombinant sPRR increased systolic blood pressure (SBP) by the sympatho-excitatory effects of leptin on BP. Therefore, in the present study, we aim to address whether mouse recombinant sPRR influences the BP in HF-fed female mice. To test this hypothesis, C57BL/6 female mice were fed a HF diet for 32 weeks and were implanted with radiotelemetry transmitter. After 24 weeks of high fat feeding, female mice (5-6/group) were implanted with osmotic pumps and infused with either saline (veh) or sPRR for 3 to 4 weeks. In contrast to male mice, the infusion of sPRR (30 μg/kg/day) did not change significantly the SBP (24hSBP; veh: 135 ± 7; sPRR: 134 ± 4 mmHg; P>0.05) and the baroreflex sensitivity. The decrease in BP mediated by chlorisondamine treatment was not significantly different between female mice infused with vehicle or sPRR (ΔSBP; veh: -11 ± 9; sPRR: -16 ± 7 mmHg; P>0.05). In addition, sPRR infusion did not affect the bradycardic or tachycardic responses after propranolol or atropine treatment respectively. Moreover, the decrease of SBP induced by losartan was similar in mice infused with vehicle or sPRR (ΔSBP; veh: -9 ± 4; sPRR: -10 ± 3 mmHg; P>0.05). Similar results were obtained using higher dose of sPRR (60 μg/kg/day). In female mice, sPRR infusion did not increase significantly the body weight (veh: 32.7 ± 2.5 g; sPRR: 35.8 ± 4.2 g; P>0.05), the white adipose tissue weight (WAT; veh: 3.0 ± 0.7g; sPRR: 3.7 ± 1.6 g; P>0.05) or circulating leptin levels (veh: 12.0 ± 7.6 ng/ml; sPRR: 15.5 ± 9.5 ng/ml; P>0.05). In conclusion, in contrast to male, female mice are protected from sPRR-induced increase in BP. sPRR did not increase circulating leptin suggesting that sPRR-induced leptin increase is regulated in a sex-dependent manner. Other pathways could participate to the protection against sPRR-induced increase in BP in female mice such as the vasodilator arm of the RAS and/or the hormonal status of the female mice.
Abstract 7: Activation Of Neuronal At
1
R Exacerbates Hypertension-induced Reduction In Neuronal Function.
Authors: Xu Jiaxi , Lazartigues Eric D
Published: September 2020

Hypertension has now been considered as one of the risk factors of Alzheimer's disease (AD), due to its contribution to the dysfunction of cerebrovascular system. To investigate its neuronal contribution, hypertension was induced in C57BL/6j male mice by either systemic infusion of Ang-II (600 ng/kg/min, s.c., 14 days) or DOCA-salt treatment (1 mg/g, s.c., 21 days), then markers for neuronal function were measured via qRT-PCR. In the hippocampus, Ang-II treatment significantly down-regulated the mRNA levels of BDNF (brain-derived neurotrophic factor) and DLG4 (discs large homolog 4, encoding PSD95), while DOCA-salt treatment only down-regulated BDNF expression (P<0.05 vs. sham, n=6). Notably, the expression of PI4KIIIβ, a key kinase for phosphatidylinositol-4,5-isphosphate (PIP
2
) re-synthesis, was found to be markedly down-regulated in the hippocampus of both hypertension models (P<0.05 vs. sham, n=6). PI4K activity has been closely associated with the progression of neurodegenerative disorders, especially AD, therefore suggesting that reduction of neuronal function could be a part of the etiology of hypertension-related cognitive decline. We have demonstrated that neuronal AT
1
R plays pivotal role in the maintenance of neurogenic hypertension, and here we hypothesized that activation of AT
1
R could also exacerbate hypertension-induced reduction in neuronal function. In mice with DOCA-salt hypertension, the function of cortical neurons was shown to be improved by selective deletion of neuronal AT
1a
R, as evidenced by significantly higher mRNA levels of BDNF and PI4KIIIβ, compared to the controls (P<0.05 vs. sham, n=6). To further study the possible involvement of neuronal AT
1
R in AD, 5хFAD mice were bred with mice with neuronal AT
1
R deletion (AT1NKO). AD-associated reduction of ACE2 protein, mainly in neurons, was found to be slightly ameliorated in the prefrontal cortex of 5хFAD-AT1NKO, compared to the age/sex-matched 5хFAD, showing by immunocytochemistry (24610 ±4182 vs. 13420 ±3720 AFU, n=6 slices). Although the detailed mechanism is still unknown, our data suggest that, neuron-expressing AT
1
R could participate in the development of hypertension-associated cognitive impairment and AD, independently of vascular AT
1
R.
Abstract 9: Histone Deacetylases 1 And 2 Regulate Six2 Function To Maintain Nephron Progenitor Cells During Nephrogenesis
Authors: Liu Hongbing , Koduri Mahitha M , Dragon Andrea , Chen Chao Hui , El-Dahr Samir S
Published: September 2020

Low nephron endowment is strongly associated with cardiovascular disease, especially hypertension. Sine oculis homeobox 2 (Six2) is the master transcriptional regulator in balancing self-renewal and differentiation of nephron progenitor cells (NPCs) for appropriate nephron endowment. Loss of
Six2
in mice causes early-onset loss of self-renewal and premature differentiation of NPCs. However, it is unclear how Six2 is functionally regulated during nephrogenesis.
In vivo
interaction of histone deacetylase1 and 2 (Hdac1/2) to Six2 was detected in developing kidney by co-immunoprecipitation and proximity ligation assay. Chromatin immunoprecipitation and DNA sequencing experiments in isolated E16.5 NPCs revealed 1,180 (84.58%) of the Six2 peaks overlapped with Hdac2 peaks, implying the involvement of Hdac1/2 in Six2 DNA binding and its function in NPCs. To test whether Hdac1/2 are required for Six2 function to regulate nephron formation, we employed Six2
GC
mouse line, in which the eGFP and Cre fusion gene (GC) replaces and fully recapitulates the endogenous Six2 gene expression pattern. Analysis of kidneys at embryonic day (E) 19.5 and newborn (P0) showed that Six2 heterozygous (Six2
GC
) together with three alleles knockout of
Hdac1/2
resulted in severely hypoplastic kidneys, while three alleles knockout of
Hdac1/2
by transgenic Six2-Cre only led to very subtle phenotypes. Immunostaining at E 19.5 and P0 revealed about 50% reduction of Six2 level in the kidney of Six2
GC
only and Six2
GC
together with three alleles knockout of
Hdac1/2
mice. In the kidneys of Six2 heterozygous mice, no change was observed for most of the NPC identity makers for self-renewal, including the three Six2 targets, Pax2, Sall1 and WT1. However, sequential removal of three alleles of
Hdac1/2
of Six2
GC
mice did not change Six2 protein level but significantly decreased the expression of Pax2, Sall1 and WT1, suggesting the requirement of Hdac1/2 for Six2’s function to transcriptionally activate the expression of its target genes. We also observed the premature differentiation and decreased nephron formation in mutant kidneys. Therefore, we conclude that Hdac1/2 are required for Six2’s function to promote NPC self-renewal and repress premature differentiation during nephrogenesis.
Abstract MP01: Vasopressin Contributes To Differences In The Physiology Of Hypertension Between Non-Hispanic Blacks And Whites
Authors: Lobo Ronstan , Schwartz Gary L , Donato Leslie J , Hickson LaTonya J , Lieske John C , Hodge David O , Chapman Arlene , Turner Stephen T , Jaffe Allan S
Published: September 2020

Objective:
Vasopressin increases water permeability and activity of the epithelial sodium channel ENaC in the distal nephron of the kidney, favoring increased water and sodium retention. We hypothesized that genetically mediated differences in circulating vasopressin concentrations could contribute to features of hypertension that vary between non-Hispanic blacks and whites. To test this hypothesis we measured copeptin, a fragment of pre-pro arginine vasopressin with a prolonged half-life that is more easily quantified.

Methods:
The Genetic Epidemiology of Responses to Antihypertensives (GERA) I study was designed to identify predictors of response to diuretic therapy in non-Hispanic black and non-Hispanic white adults with essential hypertension. Blood samples were obtained after a 4 week washout of anti-hypertensive medication while on a sodium intake of 2 mmol/kg. Copeptin was measured from thawed EDTA plasma samples using the copeptin proAVP homogeneous automated immunofluorescent assay on the BRAHMS Kryptor Compact PLUS (Thermo Fisher).

Results:
Copeptin was significantly higher in blacks (median: 7.4 pmol/L, IQR: 4.4-10.2 pmol/L) than in whites (median: 5.4 pmol/L, IQR: 3.6-8.0 pmol/L) (p <0.001), while renin was lower (Table 1). Racial differences remained significant (p = 0.001) in multivariate models that included 24 hour urine sodium excretion and calculated plasma osmolality.

Conclusions:
Higher copeptin (vasopressin) concentrations in non-Hispanic blacks compared to whites may contribute to the distinct differences in the hypertensive phenotypes between these racial groups. The underlying mechanism(s) require further study.
Abstract MP16: Metabolic Predictors Of Target Organ Damage In Adolescents: The SHIP AHOY Study
Authors: Price Joshua J , Urbina Elaine M , Carlin Kristen , Ferguson Michael A , Lande Marc B , Meyers Kevin , Rosner Bernard , Samuels Joshua A , Flynn Joseph T
Published: September 2020

The development of cardiovascular disease in adults has been directly linked to a metabolic phenotype that includes hypertension, obesity and dyslipidemia. While there is evidence that the development of these risk factors in childhood is linked with persistence into adulthood and eventual development of cardiovascular disease, less is known about whether these risk factors contribute to target organ damage during childhood. We collected data from 379 otherwise healthy adolescents (mean age 15.5 +/- 1.8, 60% male, 37% Non-White) across the blood pressure spectrum to determine if there is a metabolic phenotype that predicts target organ damage in adolescents. A cardiovascular risk score was calculated (1 point each for: LDL >155 or HDL <40 or TG >150; BMI
>
95%; fasting glucose >100; HOMA-IR > 2.5). Generalized linear models were constructed to determine if the cardiovascular risk score was independently associated with measures of target organ damage. Cardiovascular risk score was significantly associated increased left ventricular mass index (β = 1.64, R
2
0.19) , increased pulse wave velocity (β = 0.05, R
2
0.21) and several echocardiographic parameters of diastolic dysfunction (e’/a’: β = -0.07 R
2
0.27; E/A: β = -0.04, R
2
0.11; E/e’: β =0.03, R
2
0.13) after correction for age, sex, race, HR, creatinine, uric acid and log CRP (all models P<0.0009). We found no association with peak longitudinal strain or microalbuminuria. Our study suggests that presence of cardiovascular risk factors in adolescence predicts target organ damage at a young age and could potentially be modified to prevent progression of disease.
Abstract MP22: GRP78 Protects Against Angiotensin II-induced Protein Aggregation, Profibrotic VSMC Phenotype, And Vascular Remodeling
Authors: Cicalese Stephanie , Okuno Keisuke , Preston Kyle , Eguchi Satoru
Published: September 2020

Arterial stiffening is a critical risk factor contributing to the development of cardiovascular disease and end organ damage. Vascular smooth muscle cell (VSMC) hypercontractility, vessel fibrosis, and proinflammatory responses are involved. The renin angiotensin system plays critical roles in the development of VSMC stiffness phenotype, as well as CVD pathophysiology. Angiotensin II (Ang II) stimulation induces these stiffness-promoting mechanisms, however, the involvement of dysfunctional proteostasis governing Ang II contribution to vascular stiffness remains underdefined. While endoplasmic reticulum (ER) stress has been implicated in the development of arterial stiffness and hypertension, it is unknown whether the protein aggregation potentially due to maladapted unfolded protein response (UPR) in VSMCs is involved. We hypothesize AngII induced ER stress initiates protein misfolding and effects VSMC stiffness phenotype. We identify a significant increase in protein aggregate size (P<0.001: from 1,000 to 4,500 pixel/aggregate) and number per cell (P<0.01: from 20 to 100 aggregate #/cell) in rat VSMCs stimulated with AngII, which is attenuated with adenoviral overexpression of resident ER chaperone, GRP78 (P<0.01: 2000 pixels/aggregate and P<0.05: 25 aggregate #/cell). Furthermore, UPRosome associated IRE1α phosphorylation induced at 3 and 6 h following AngII stimulation is reduced in GRP78 overexpressing VSMCs (P<0.05), which may contribute to reduced monocyte adhesion (P<0.001), assessed utilizing THP-1 cells. In mice, pharmacological chaperone 3-HNA reduced AngII induced vascular hypertrophy (P=0.056), cardiac perivascular fibrosis (P=0.065), and pulse propagation velocity from 0.35 m/s to 0.23 m/s (P<0.05). A trend in pre-amyloid oligomer accumulation was seen in the medial layer of thoracic aortas following 2 weeks of AngII infusion, which was reduced with 3-HNA treatment. Similar findings were investigated in a SM22α cre-GRP78 mouse model, where a trend in reduction of these parameters are also seen. Overall, GRP78 regulation over VSMC proteostasis influences vascular stiffness phenotype and therefore, these findings may elude new pharmacological intervention for arterial stiffness and aging associated CVD.
Abstract MP24: Correlation Between Blood Pressure And Inflammation In The Thoracic Aorta Of HIV Patients With And Without Cocaine Use As Assessed By FDG-PET/CT
Authors: Bhattaru Abhijit , Rojulpote Chaitanya , Ghorpade Rina , Bravo Paco E , Patil Shivaraj , Gonuguntla Karthik , Karambelkar Pranav , Vuthaluru Kiranmayi , Zhang Vincent , Werner Thomas , Alavi Abass
Published: September 2020

Objectives:
Cocaine exerts various adverse effects on the cardiovascular system, something that can be further exasperated in HIV positive individuals. In this study, we aimed to assess the atherosclerotic activity in the thoracic aorta of HIV patients with and without cocaine use, hypothesizing that there is a stronger association between blood pressure and inflammation in individuals with cocaine use as quantified by FDG-PET/CT.

Methods:
Patients with HIV on antiretroviral therapy (viral load <200 copy/ml) were enrolled with written consent by the University of Pennsylvania. Patients were injected with 15 mCi of 18F-FDG and full-body PET scans were acquired 120 minutes post-injection; low dose CT was used for anatomical localization of PET images. Artifact in either PET or CT images led to exclusion from analysis. OsirixMD (v9.0.02) was used to place regions of interest on axial slices surrounding ascending aorta, aortic arch, and descending aorta. Total average standard uptake mean (aSUVmean) was calculated for the aorta of each patient. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded pre-imaging; mean arterial pressure (MAP) was calculated. Linear regressions were employed for statistical analysis.

Results:
There was a positive correlation between SBP, DBP, and MAP and uptake in HIV patients with cocaine use (N=11; SBP: r=0.66, p=0.0270; DBP: r=0.65, p=0.0299; MAP: r=0.68, p=0.0207). No correlations were seen in HIV patients without cocaine use (N=18; SBP: r=0.33, p=0.1850; DBP: r=0.19, p=0.4593; MAP: r=0.29, p=0.2502).

Conclusions:
In our study, blood pressure correlated positively with increased FDG uptake in patients with cocaine use. This highlights the added effect of cocaine use on aortic inflammation in HIV individuals.
Abstract MP26: Endothelial-derived Microvesicles From Andean Highlanders With Excessive Erythrocytosis Induce A Deleterious Cardiomyocyte Phenotype
Authors: Brewster L. Madden , Fandl Hannah , Bain Anthony , Garcia Vinicius P , Stone Rachel , Greiner Jared , DeSouza Noah M , Tymko Michael M , Villafuerte Francisco C , Ainslie Philip N , Desouza Christopher
Published: September 2020

Background:
Excessive erythrocytosis (EE), defined as Hb ≥21 g/dL in men and ≥19 g/dL in women, is a pathologic consequence of residing at high altitude (>2500 m) and is common in Andean highlanders. EE is associated with increased cardiovascular risk and cardiac dysfunction. Specifically, EE has been linked to congestive heart failure as well as right ventricular hypertrophy in high altitude dwellers. The mechanisms responsible for diminished cardiac function in adults with EE remain unclear. Endothelial microvesicles (EMVs) play an important role in mediating interaction between the vascular endothelium and cardiac function. The experimental aim of this study was to determine the effects of EMVs isolated from adults with EE on markers of cardiomyocyte fibrosis, hypertrophy and autophagy as well as endothelial nitric oxide synthase (eNOS).

Methods:
Twenty-four male residents of Cerro de Pasco, Peru (4,340 m) were studied: 12 highlanders without EE (Healthy; age: 40±4 yr; BMI: 26.4±1.7; Hb: 17.4±0.5 g/dL) and 12 highlanders with EE (EE: 45±5 yr; 26.7±1.0; 24.4±0.4 g/dL). All subjects were non-obese, normotensive, normolipidemic and non-diabetic. EMVs (CD31+/CD42b-) were identified, enumerated, and isolated from plasma by flow cytometry. Human induced pluripotent stem cell cardiomyocytes were cultured and treated with EMVs from either healthy or EE men.

Results:
EMVs from EE men induced significantly greater expression of specific markers of fibrosis: TGF-β (91.1±4.0 vs 52.7±3.8 AU) and alpha-1 type I collagen (85.6±5.6 vs 59.7±4.8 AU) and hypertrophy: troponin T (41.4±2.0 vs 16.9±1.4 AU) and α-actinin (95.3±6.7 vs 62.4±5.0 AU) than EMVs from healthy men. Cell autophagy was not significantly affected by EE EMVs. Intercellular expression of phosphorylated eNOS at the primary activation site, Ser1177 (13.3±1.1 vs 18.9±1.2 AU), and inhibitory site, Thr495 (56.7±3.4 vs 40.8±2.7 AU), were ~35% lower and ~30% higher (both P<0.05), respectively, in cells treated with EMVs from EE compared with healthy men.

Conclusions:
These data indicate that EMVs from Andean highlanders with EE negatively affect cardiomyocyte function and, therefore, may contribute to the increased risk of heart failure and cardiac dysfunction associated with EE.
Abstract MP27: Human Hypertension And Endothelial Cell Activation Promote The Formation And Activation Of Axl
+
Siglec-6
+
Dendritic Cells Via Endothelial Release Of Growth Arrest Specific 6
Authors: Van Beusecum Justin P , Barbaro Natalia R , Smart Charles D , Patrick David M , Shibao Cyndya A , Harrison David G
Published: September 2020

We have shown that dendritic cells (DCs) from hypertensive mice convey hypertension when adoptively transferred to recipients. Recently a novel subset of DCs in humans that express Axl and Sigelc-6
+
(AS DCs) have been identified which drive T cell proliferation and produce IL-1β, IL-6 and IL-23, consistent with DCs we have observed in hypertension. We hypothesized that AS cells are increased in hypertension and contribute to immune activation in this disease. We quantified circulating AS DCs by flow cytometry in normotensive (n=23) and hypertensive (n=11) subjects and found a more than 2-fold increase in circulating AS DCs in hypertensive compared to normotensive subjects (297 ± 73 vs. 108 ± 26/ml;
p
=0.0304). To investigate the mechanism by which AS DCs are formed in hypertension, we co-cultured human aortic endothelial cells (HAECs) undergoing either normotensive (5%) or hypertensive (10%) cyclical stretch for 48 hours with CD14
+
monocytes from normotensive donors. Co-culture of monocytes with HAECs exposed to 10% stretch significantly increased AS DCs and AS DC IL-1β production when compared to 5% stretch alone as assessed by flow cytometry (21 ± 5 vs. 131 ± 32 IL-1β
+
AS DCs). Moreover, inhibition of Axl signaling with R248, completely abolished the production of IL-1β in AS DCs (34 ± 8 IL-1β
+
AS DCs). In additional experiments we found that 10% stretch caused a 50% increase in release of growth arrest 6 (GAS6), the ligand for Axl, from HAECs compared to 5% stretch. Treatment of human monocytes with GAS6 mimicked the effect of 10% stretch in promoting AS cell formation and IL-1β production. Based on the increased secretion of GAS6 from HAECs, we used a J-wire to harvest human endothelial cells from 23 additional volunteers to assess endothelial cell activation and GAS6 secretion in vivo. We found a positive association between pulse pressure and plasma GAS6 (R
2
=0.25,
p
=0.0079) and a striking positive association between GAS6 and ICAM-1 (R
2
=0.39,
p
=0.0012). These data show that secretion of GAS6 by an activated endothelial seems to promote the formation and activation of AS DCs. Thus, the interplay between endothelial-derived GAS6 and AS DCs seem to be an important mechanism in human hypertension and might be a novel therapeutic target for this disease.
Abstract MP28: A New Gut Microbial Metabolite Derived From Low Fibre Intake
Authors: Xu Chudan , Nakai Michael , Muralitharan Rikeish , Dinakis Evany , Jama Hamdi , Tsyganov Kirill , Gabriela Khoury , Carrington Melinda , Yiallourou Stephanie , Head Geoffrey , Creek Darren , Barlow Christopher , Kaye David M , Marques Francine Z
Published: September 2020

Low fermentable fibre intake has emerged as an important risk factor for hypertension through changes in the gut microbiota, but the biological pathways and specific metabolites involved are unknown. We performed untargeted liquid-chromatography mass spectrometry metabolomic profiling on plasma samples from 16 mice fed low or high fibre diets and 70 participants with ambulatory blood pressure recordings. Mouse gut microbiome was analysed using 16S rRNA gene sequencing
. In vitro
experiments were performed in human peripheral blood mononuclear cells (PBMCs) to assess the role of a new metabolite in inflammatory responses. The phenylalanine, tyrosine and tryptophan biosynthesis pathway was upregulated in hypertensive compared to normotensive participants, as well as in low compared to high fibre fed mice (both
q
<0.05, pathway impact factor=1.0). In particular, p-cresol glucuronide (pCG), an end-product of tyrosine metabolism, was higher in mice fed with low compared to high fibre in both angiotensin II-treated (
q
=4.83 x10
-4
, fold change= 88) and sham groups (
q
=1.56 x10
-4
, fold change= 297). pCG is derived from p-Cresol, which is produced by the gut microbiota. β-diversity analyses showed that distinct gut microbiome compositions were associated with levels of pCG in plasma (q<0.05). While diet had a major effect on the gut microbiome (~30%), we found that pCG levels were associated with 5.7-6.3% of the total gut microbiome variation. This is relevant as pCG’s precursor, p-cresol, may inhibit the growth of certain types of bacteria. To understand the possible role of pCG in hypertension, human PBMCs obtained commercially were treated with physiological levels of pCG for 24 hours. This resulted in an increase in proinflammatory
IL-17A
mRNA (
P
=0.01, fold change= 1.79) and a decrease in anti-inflammatory
IL-10
mRNA (
P
=0.014, fold change= -2.32) when compared to untreated and mock-treated cells. In conclusion, tyrosine biotransformation was associated with both human hypertension and low fibre intake. pCG, a key microbial metabolite derived from the metabolism of tyrosine, was associated with distinct gut microbiome compositions and modulated inflammatory response, suggesting it may be involved in the genesis of hypertension.
Abstract MP32: Effectiveness Of Investigational RNAi Therapeutics Targeting Liver Angiotensinogen In Experimental Chronic Kidney Disease
Authors: Bovee Dominique M , Ren Liwei , Foster Don , Danser A.H. J
Published: September 2020

Background:
RNAi therapeutics targeting angiotensinogen (AGT) lower blood pressure in animal models of essential hypertension, but whether this treatment is beneficial in hypertensive chronic kidney disease (CKD) is yet unknown. Our aim was to assess the effectiveness of a small interfering RNA (siRNA) targeting hepatic AGT in a rat model of hypertensive CKD.

Methods:
Sprague Dawley rats (n=7-12 per group) were subjected to 5/6th nephrectomy, allowed to recover for four weeks, and subsequently subjected to one of five treatments: (1) vehicle, (2) AGT siRNA (10-30 mg/kg, s.c. every 2 weeks), (3) AGT siRNA + losartan (30 mg/kg/d), (4) losartan (30 mg/kg/d), or (5) losartan + captopril (30 and 6 mg/kg/d). Mean arterial pressure (MAP) was measured by radiotelemetry for 4 weeks, glomerular filtration rate (GFR) was measured by transcutaneous FITC-sinistrin clearance.

Results:
AGT siRNA and AGT siRNA + losartan reduced plasma AGT by 96.5 ± 1.4% and 97.0 ± 2.3%, respectively. Over the course of 4 weeks, proteinuria increased with vehicle and this increase was abrogated by all treatments (Δ proteinuria at 4 weeks versus baseline: +0.17 [0.12, 0.23], +0.02 [-0.04, 0.05], -0.01 [-0.07, 0.06], -0.05 [-0.12, 0.00], -0.01 [-0.06, 0.11] for vehicle, AGT siRNA, AGT siRNA + losartan, losartan, losartan + captopril, P < 0.05 for all groups compared with vehicle). Similarly, heart weight was equally reduced by all treatments except vehicle. No intervention affected GFR. Over the course of 4 weeks, MAP increased (from a baseline of 154 ± 18 mmHg) during vehicle treatment and this rise was prevented by AGT siRNA (+13 ± 15 mmHg vs. -2 ± 14 mmHg, P > 0.05 for difference between groups). Combination treatment with AGT siRNA + losartan, losartan + captopril, and losartan alone caused a similar and marked reduction in MAP (-17 ± 14 mmHg, -21 ± 17 mmHg, and -33 ± 20 mmHg, P < 0.05 versus vehicle for all; differences between groups not significant).

Conclusion:
In experimental CKD, AGT siRNA monotherapy appears to reduce proteinuria and heart weight in a blood pressure-independent fashion, to a similar degree as losartan or combination treatment. Thus, an siRNA targeting hepatic AGT may be a potential therapeutic approach for providing renal and cardioprotection in CKD.
Abstract MP33: Hypertension Control In The U.s. 2009 To 2018: Rapidly Reversing Years Of Progress.
Authors: Egan Brent M , Li Jiexiang , Sutherland Susan E , Rakotz Michael , Wozniak Gregory
Published: September 2020

Background:
Prior reports show that blood pressure (BP, mmHg) control to <140/<90 in the U.S. rose from 32.2% in 1999-2000 to 54.5% in 2013-14, then fell to 48.0% in 2015-16. In 2014, the BP goal was raised to <150/<90 in adults ≥60 years without diabetes, then lowered to <130/<80 for all adults in 2017. We assessed if the fall in BP control to <140/<90 continued in 2017-2018 and if any decline was limited to adults ≥60 years.

Methods:
BP control was assessed in adults ≥18 years in NHANES 2009-2018 (age-adjusted to 2010). BP control and its determinants were assessed by age group 18-39, 40-59, and ≥60 years in NHANES 2009-2012 and 2015-2018 (before/after 2014). Terms: Hypertension, BP ≥140 &/or ≥90 or self-reported current BP medication use (Treated); Aware, ‘Yes” to, “Have you been told you have hypertension?”; Treatment efficiency, proportion of treated adults controlled ([Cont]rolled/Treated); BP control, <140/<90.

Results:
For all adults, BP control peaked in 2013-2014 at 54.5%, declining to 48.0% in 2015-2016 and 43.4% in 2017-2018 (11.1% fall, p<0.001). Comparing 2015-2018 to 2009-2012, BP control, awareness and treatment fell [Table]) in adults 40-59; BP control and treatment efficiency fell in adults ≥60 years (Table); SBP rose 3-4 mm Hg (p≤0.01) in all age groups.

Conclusion:
Despite the 2017 BP goal <130/<80 in all adults, control to <140/<90 continued to fall in 2017-2018. The fall in BP control impacted adults both ≥60 years, reflecting lower treatment efficiency, and 40-59 years, reflecting less awareness and treatment. Adverse changes in BP and control could increase cardiovascular events and merit prompt attention to drivers of poor control.
Abstract MP41: A Role Of Isolevuglandins In Systemic Lupus Erythematosus Associated Autoimmunity And Hypertension
Authors: Patrick David M , de la Visitacion Nestor , Ormseth Michelle J , Stein Charles , Davies Sean S , Yermalitsky Valery N , Crofford Leslie J , Williams Jonathan M , Dikalov Sergey I , Xiao Liang , Van Beusecum Justin P , Fogo Agnes , Kirabo Annet , Harrison David G
Published: September 2020

Essential hypertension and systemic lupus erythematosus (SLE) are devastating conditions that disproportionately affect women. SLE has heterogeneous manifestations and treatment is limited to the use of non-specific global immunosuppression. Importantly, there is an increased prevalence of hypertension in women with SLE compared to healthy controls. Isolevuglandins (IsoLGs) are oxidation products of fatty acids that form as a result of reactive oxygen species. These molecules adduct covalently to lysine residues of proteins. Adducted proteins are then presented as autoantigens to T-cells resulting in immune cell activation. Previous studies have shown an essential role of IsoLGs in immune cell activation and the development of hypertension in animal models. We hypothesize that isoLGs are important for the development of hypertension and systemic immune activation in SLE. We first examined isoLG adduct accumulation within monocytes of human subjects with SLE compared to healthy controls. By flow cytometry, we found marked accumulation of isoLG adducts within CD14
+
monocytes (34.2% ± 12.4% vs 3.81% ± 2.1% of CD14
+
, N = 10-11, P <0.05). We confirmed this increase in isoLG adducts by mass spectrometry. To determine a causative role of isoLG adducts in immune activation and hypertension in SLE, we employed the
B6.SLE123
and
NZBWF1
mouse models of SLE. Animals were treated with the isoLG scavenger 2-hydroxybenzylamine (2-HOBA) or vehicle beginning at 7 weeks and were sacrificed at 32 weeks of age.
C57BL/6
and
NZW
were used as controls. Importantly, treatment with 2-HOBA attenuated blood pressure in both mouse models (systolic BP 136.2 ± 5.6 mmHg for
B6.SLE123
vs 120.9 ± 4.46 mmHg for
B6.SLE123
+2HOBA; 164.7 ± 24.4 mmHg for
NZBWF1
vs 136.9 ± 14.9 mmHg for
NZBWF1
+2HOBA, N = 6-8, P < 0.05). Moreover, treatment with 2-HOBA reduced albuminuria and renal injury in the
B6.SLE123
model (albumin/creatinine ratio 33.8 ± 2.0 x 10
-2
μg/mg for
B6.SLE123
vs 5.5 ± 0.9 x 10
-2
μg/mg for
B6.SLE123
+2HOBA, N = 7-9, P < 0.05). Finally, immune cell accumulation in primary and secondary lymphoid organs is significantly attenuated by 2-HOBA. These studies suggest a critical role of isoLG adduct accumulation in both systemic immune activation and hypertension in SLE.