bluuebunny/crossref_metadata_2025 huggingface dataset:
Error Self-Calibration Algorithm for Acoustic Vector Sensor Array
Authors: Wang Peng , Kong Yujun , Zhang Mingxing
Published: September 2019

In this paper, the errors of acoustic vector sensor array are classified, the impact factor of each error for the array signal model is derived, and the influence of each type of error on the direction-of-arrival (DOA) estimation performance of the array is compared by Monte Carlo experiments. Converting the directional error and location error to amplitude and phase errors, the optimization model and error self-calibration algorithm for acoustic vector sensor array are proposed. The simulation experiments and field experiment data processing of MEMS vector sensor array show that the proposed self-calibration algorithm has good parameter estimation performance and certain engineering practicability.
PD-1 and LAG-3 Dominate Checkpoint Receptor–Mediated T-cell Inhibition in Renal Cell Carcinoma
Authors: Zelba Henning , Bedke Jens , Hennenlotter Jörg , Mostböck Sven , Zettl Markus , Zichner Thomas , Chandran Anoop , Stenzl Arnulf , Rammensee Hans-Georg , Gouttefangeas Cécile
Published: September 2019

Drugs targeting the programmed cell death protein 1 (PD-1) pathway are approved as therapies for an increasing number of cancer entities, including renal cell carcinoma. Despite a significant increase in overall survival, most treated patients do not show durable clinical responses. A combination of checkpoint inhibitors could provide a promising improvement. The aim of the study was to determine the most promising checkpoint blockade combination for renal cell carcinoma patients. Tumor-infiltrating lymphocytes (TIL) and autologous peripheral blood mononuclear cells (PBMC) were isolated from patients undergoing surgery for primary tumors. Cells were stained for multicolor flow cytometry to determine the (co)expression of five inhibitory receptors (iR), PD-1, LAG-3, Tim-3, BTLA, and CTLA-4, on T-cell populations. The function of these TILs was assessed by intracellular cytokine staining after in vitro stimulation in the presence or absence of PD-1 ± LAG-3 or Tim-3–specific antibodies. Although the percentage of iR+ T cells was low in PBMCs, both CD4+ and CD8+ T cells showed increased frequencies of PD-1+, LAG-3+, and Tim-3+ cells on TILs. The most frequent iR combination was PD-1 and LAG-3 on both CD4+ and CD8+ TILs. Blockade of PD-1 resulted in significant LAG-3, but not Tim-3, upregulation. The dual blockade of PD-1 and LAG-3, but not PD-1 and Tim-3, led to increased IFNγ release upon in vitro stimulation. Together, these data suggest that dual blockade of PD-1 and LAG-3 is a promising checkpoint blockade combination for renal cell carcinoma.
Single-Cell Transcriptome Analysis Reveals Gene Signatures Associated with T-cell Persistence Following Adoptive Cell Therapy
Authors: Lu Yong-Chen , Jia Li , Zheng Zhili , Tran Eric , Robbins Paul F. , Rosenberg Steven A.
Published: September 2019

Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) can mediate responses in some patients with metastatic epithelial cancer. Identifying gene signatures associated with successful ACT might enable the development of improved therapeutic approaches. The persistence of transferred T cells in the peripheral blood is one indication of clinical effectiveness, but many T-cell and host factors may influence T-cell persistence. To limit these variables, we previously studied a patient with metastatic colorectal cancer treated with polyclonal TILs targeting the KRAS(G12D) hotspot mutation, who experienced a partial response for 9 months. Three dominant clonotypes specifically recognizing KRAS(G12D) epitopes were identified, but we found that only two clonotypes persisted 40 days after ACT. Because of these findings, in this study, we performed the single-cell transcriptome analysis of the infused TILs. The analysis revealed a total of 472 genes that were differentially expressed between clonotypes 9.1-NP and 9.2-P single cells, and 528 genes between 9.1-NP and 10-P. Following these clonotypes in the peripheral blood after ACT, the gene expression patterns changed, but IL7R, ITGB1, KLF2, and ZNF683 remained expressed in the persistent 9.2-P and 10-P cells, compared with the nonpersistent 9.1-NP cells. In addition, four autologous TILs, which were used for treatment but persisted poorly 1 month after ACT, did not express the gene profiles associated with persistence. These results suggest that certain TIL populations possess a unique gene expression profile that can lead to the persistence of T cells. Thus, this single-patient study provides insight into how to improve ACT for solid cancer.
Ungual Tuberculosis: A Unique Clinical Case
Authors: da Silva Sousa Ana Cristina , Sousa Manuel , Tente David , Menezes Nuno , Baptista Armando , Guedes Rita
Published: September 2019

Cutaneous manifestations of tuberculosis (TB) are rare, particularly from an exogenous source. Involvement of the nail apparatus is extremely rare and has only previously been reported as a secondary involvement. We report the case of a 76-year-old female patient referred to our department with onychodystrophy with purulent drainage of the first left finger, which had developed during the preceding year. She had no previous traumatic history and had received treatment with multiple cycles of oral antibiotics and antimycotics, with no clinical improvement. Physical examination showed paronychia and onychodystrophy of the entire nail plate. Biopsy evaluation revealed epithelioid granulomas with central foci of necrosis, and laboratory cultures were positive for Mycobacterium tuberculosiscomplex. Chest computed tomography excluded primary pulmonary TB. X-ray of the left hand revealed the presence of dactylitis on the distal phalanx. Based on these findings, the patient was treated with rifampicin, isoniazid, pyrazinamide, and ethambutol for 2 months and with rifampicin and isoniazid for 7 months, resulting in complete resolution of the lesions. Cutaneous TB is a diagnostic challenge, particularly in rare cases such as involvement of the nail apparatus. It should be considered as a diagnostic hypothesis in cases of painless paronychia with refractory purulent drainage and associated onychodystrophy.
Management of a Portal Hypertensive Polyp: Case Report of a Rare Entity
Authors: Seleem Waseem M. , Hanafy Amr Shaaban
Published: September 2019

Portal hypertensive polyposis is a rare finding represented in about 2.5% of all patients with portal hypertension. The diagnostic criteria are not yet clearly defined. It has been mentioned in a few case reports; its distribution was mainly duodenal and less frequently gastric. Here, a patient with type 2 diabetes and liver cirrhosis was hospitalized for vomiting, abdominal pain, and melena. The patient was admitted to the intensive care unit for stabilization and urgent esophagogastroduodenoscopy (EGD). EGD revealed a single antral polyp occluding the pyloric ring which was the cause of gastric outlet obstruction. Complete debulking by argon plasma was done which improved gastric outlet obstruction and melena. We conclude that argon plasma coagulation is a safe, rapid, and effective method for treating portal hypertensive polyposis.
Diffuses Irismelanom: Augenerhaltende Therapie durch Protonenbestrahlung
Authors: Seibel Ira , Bertelmann Eckart
Published: September 2019

Objectives: Iris melanomas represent 2-3% of uveal melanomas; the diffuse variant accounts for approximately 10% of all iris melanomas. Different treatment modalities for diffuse iris melanomas (DIM) have been proposed depending on the local status as well as the age and general condition of the patient. Methods: This study is a single-centre retrospective case series describing the diagnosis, treatments and outcomes of DIM. Treatment consisted of enucleation or proton beam therapy (PT) of the whole anterior segment. Patients who were treated with PT benefitted from limbal stem cell preservation before irradiation. Results: Between 1996 and 2016, a total of 14 patients with DIM presented to our institution and were included in the database. The global survival was 86%. The median follow-up was 4.6 years (range 4 months to 15 years). Only 1 patient (7%) developed metastatic disease of the DIM (gastric location). No patient developed liver metastasis. Seven patients were treated by enucleation and 7 by PT after limbal stem cell preservation. After a conservative attempt, local tumour recurrence occurred in 2 patients at 2 years, requiring enucleation. The cornea was clear after irradiation in all patients. Cataract (n = 6) and glaucoma (n = 4) were the main complications after irradiation. Conclusions: DIM is a very rare tumour. The global survival is excellent. Conservative treatment with PT is an efficient alternative to enucleation and allows good local tumour control. Cataract and glaucoma are the main radiation-related complications, but the corneal status was excellent due to the stem cell harvest prior to radiotherapy.
Langzeitoutcome von Patienten mit Pars-plana-Vitrektromie nach rhegmatogener Netzhautablösung
Authors: Treder Maximilian
Published: September 2019

Purpose: To determine the long-term outcome of patients operated with pars plana vitrectomy (PPV) for primary rhegmatogenous retinal detachment (RRD) and to identify potential predictors for poor visual outcome. Methods: Prospective, observational 30-month study of patients operated for primary RRD with PPV. Examinations were performed preoperatively and after months 2, 6, and 30. Results: Eighty-four patients (84 eyes) were included and 73 (86.9%) participated at month 30. The macula was attached in 30 (35.7%) patients at primary operation. The majority of patients (n = 59, 80.8%) achieved a good final best corrected visual acuity (BCVA ≤0.3 logMAR, ≥0.5 Snellen) with a better outcome in patients with the macula attached than detached (0.02 vs. 0.17 logMAR, p = 0.007). Variables associated with poor visual outcome were baseline BCVA >0.3 logMAR (p = 0.03), female gender (p = 0.02), silicone oil (p = 0.03), and larger areas of retinal detachment (p = 0.01). In multivariable regression analysis, female gender (OR = 8.5 [95% CI 1.8-39.8]) was the strongest risk factor for poor visual outcome. Conclusion: The majority of patients operated for primary RRD achieved a reasonable long-term visual outcome. Notably, female gender was associated with poor visual outcome, indicating a need for closer follow-up.
Lückenlos: Ein aktueller Blick in die Stellungnahme zur Therapie venöser retinaler Gefäßverschlüsse
Authors: Hattenbach Lars-Olof
Published: September 2019

Die vorliegende Stellungnahme zum retinalen Venenverschluss (RVV) beschränkt sich explizit auf die Indikationsstellung und Behandlung der Visusverschlechterung infolge eines Makulaödems mit intravitrealen Medikamenten oder Laser. Die adäquate Betreuung von RVV-Patienten ist aufgrund der Datenfülle komplexer geworden. Deshalb hat die Makulakommission beschlossen, die Empfehlungen zur Behandlung des Makulaödems mittels Stellungnahmen zu aktualisieren und die umfassenderen Betreuungsempfehlungen bei RVV-Patienten in eine danach zu erstellenden AWMF-Leitlinie zu dokumentieren. Überschneidungen (z.B. Empfehlungen zu Kontrollintervallen) können dabei nicht gänzlich vermieden werden. Als Grundlage der Bewertung dient die Tabelle 1, auf die im Text verwiesen wird. Die dort aufgezählten Studien wurden nach einer systematischen Suche in Medline, sowie der Cochrane-Bibliothek ermittelt. Auswahlkriterien waren ein prospektives Design, eine Nachbeobachtungszeit von mindestens 6 Monaten, eine Gruppengröße von mindestens 10 Probanden und eine Aufzählung der meisten, in Tabelle 1 erfassten Parameter. Nicht berücksichtigt wurden chirurgische Studien, Behandlungsversuche mittels intravenöser Fibrinolyse, Studien zur isovolämischen Hämodilution und die gleichzeitige Gabe unterschiedlicher IVOM-Substanzen. Diese Behandlungskonzepte werden in der Leitlinie diskutiert werden. Im Langtext sollen die Kernaussagen erläutert und ergänzt werden. Dazu werden folgende Fragen zum Makulaödem bei RVV bearbeitet: 1. Kann man aus den Daten eine Behandlungsempfehlung für die Bevorzugung einer Substanzgruppe ableiten? 2. Kann man aus den Daten eine Behandlungsempfehlung für die Bevorzugung eines intravitrealen Medikamentes ableiten? 3. Gibt es eine Empfehlung für die Bevorzugung einer Behandlungsstrategie? 4. Gibt es Daten zur Umsetzung und Ergebnisse aus dem klinischen Alltag (Real-Life)? 5. Gibt es eine Behandlungsempfehlung für die Anwendung einer Lasertherapie? 6. Welche Konsequenzen ergeben sich daraus für zukünftige RVV-Studien?
Cartografia da Lusofonia de Língua Portuguesa no Mundo e em Timor-Leste
Authors: Paulino Vicente
Published: September 2019

Timor-Leste, jovem país do sudeste asiático que viu reconhecida a sua independência no início do séc. XXI, após 400 anos de colonialismo português e 24 anos de invasão indonésia, é um verdadeiro mosaico linguístico. Aí encontramos um “multilinguíssimo endógeno” (CAVALLI et al., 2009), fruto da deambulação e de miscigenações naquele espaço e um “multilinguíssimo exógeno” (Idem, 2009), resultado da abertura da sociedade à diversidade, mas também de interesses económicos vários e na sequência e como consequência de processos histórico-políticos. Atualmente, o português é uma das línguas cooficiais deste jovem país, depois de ter estado proibido durante o período da ocupação indonésia. Neste artigo abordamos as relações entre o português e as restantes línguas que circulam naquele território, quer do ponto de vista da política linguística, quer numa perspetiva mais pessoal, no âmbito das representações dos sujeitos. Para tal, recorreremos, em parte, ao estudo de Soares (2014), realizado a partir de dados recolhidos no terreno, em 2010, e a fontes escritas oficiais e não oficiais sobre as línguas em presença.
Expert Consensus Recommendations for the Suspicion and Diagnosis of Transthyretin Cardiac Amyloidosis
Authors: Maurer Mathew S. , Bokhari Sabahat , Damy Thibaud , Dorbala Sharmila , Drachman Brian M. , Fontana Marianna , Grogan Martha , Kristen Arnt V. , Lousada Isabelle , Nativi-Nicolau Jose , Cristina Quarta Candida , Rapezzi Claudio , Ruberg Frederick L. , Witteles Ronald , Merlini Giampaolo
Published: September 2019

Cardiomyopathy is a manifestation of transthyretin amyloidosis (ATTR), which is an underrecognized systemic disease whereby the transthyretin protein misfolds to form fibrils that deposit in various tissues and organs. ATTR amyloidosis is debilitating and associated with poor life expectancy, especially in those with cardiac dysfunction, but a variety of treatment options have recently become available. Considered a rare disease, ATTR amyloidosis may be more prevalent than thought, particularly in older persons. Diagnosis is often delayed because of a lack of disease awareness and the heterogeneity of symptoms at presentation. Given the recent availability of effective treatments, early recognition and diagnosis are especially critical because treatment is likely more effective earlier in the disease course. The Amyloidosis Research Consortium recently convened a group of experts in ATTR amyloidosis who, through an iterative process, agreed on best practices for suspicion, diagnosis, and characterization of disease. This review describes these consensus recommendations for ATTR associated with cardiomyopathy as a resource to aid cardiologists and others in the recognition and diagnosis of ATTR associated with cardiomyopathy. Included in this review is an overview of red flag signs and symptoms and a recommended diagnostic approach, including testing for monoclonal protein, scintigraphy, or biopsy and, if ATTR associated with cardiomyopathy is identified, TTR genotyping.
Abstract 001: Hypertension Control to Systolic Blood Pressure <140 and <130. Implications for Hypertension Guidelines and Performance Metrics Based on Sprint Pop Data
Authors: Egan Brent M , Sutherland Susan E
Published: September 2019

Background:
Value-based healthcare rewards quality, e.g. 90
th
percentile performance, which requires more than 77% of eligible adults 18 - 85 years with hypertension have BP below 140/90 on the last visit of 2019. Systolic (S)BP (mmHg) below140 on most visits leads to fewer cardiovascular events (CVE) than less consistent control. Goal SBP was lowered to below 130 in the 2017 ACC / AHA Hypertension Guideline as treated patient groups with mean SBP 120-124 had fewer CVE than groups with higher mean SBP. Stricter treatment targets and incentives for excellent performance may lead to group mean SBP less than 120, i.e., below the evidence.

Methods:
SPRINT POP Year 2 data were analyzed given more treatment adjustments in Year 01 and fewer patients active in Year 3 and later. The % of patients controlled on various % of visits and mean SBP on the last visit for each group are provided (Table). SEM for SBP less than 0.5 mmHg.

Results:
Standard and intensive therapy, respectively, consistently controlled (more than 75% visits) SBP to less than 140 in 29.9% and 78.0% (mean 128.4, 117.6) and SBP to less than 130 in 5.1% and 53.8% (mean 118.5, 114.8) of SPRINT participants.

Discussion:
Group mean SBP falls as the (% visits and patients at goal rise. Consistent control to SBP less than 140 likely requires group mean SBP 118-128 on the last yearly visit. Consistent control to SBP less than 130 likely requires group mean SBP 115-119, which is below the evidence of 120-124. BP variability, the impact of single point assessment, and incentives for excellent control are items to consider in hypertension guideline and performance metrics as mean SBP below the evidence may be attained.
Abstract 004: Antihypertensive Treatment Stops Cognition Decline in Elderly Chinese With Hypertension
Authors: Rui Shumin , Li Chihua , Lumey L H
Published: September 2019

Background:
Hypertension and cognition decline are common problems among mid-aged and elderly populations. We examined the impact of hypertension and its treatment on cognitive function between 2011 and 2015 using the China Health and Retirement Longitudinal Study (CHARLS).

Methods:
A national sample of 10958 mid-aged and elderly Chinese was followed for four years. Hypertension was defined by a mean systolic blood pressure of ≥ 140 mmHg or a mean diastolic blood pressure of ≥ 90 mmHg or by antihypertensive treatment. Cognition was estimated by a composite score of the Telephone Interview of Cognition Status (TICS) (score range: 0-11) and the immediate and delayed recall of 10 simple nouns (score range: 0-10). In linear regression models, the relation between hypertension status, treatment, and cognitive decline over time was examined in different age groups adjusting for baseline cognition score. We further examined the role of selected covariates related to hypertension and cognition, including gender, education level, and residency (rural vs urban).

Results:
Overall cognition scores declined significantly from 11.01(SD: 3.96) in 2011 to 10.24 (SD: 4.29) in 2015 (p < 0.01). For participants aged 55 years and over (n = 6971), the cognition of hypertensive patients who were not aware of their condition (n = 1377) showed a 0.57 point larger decline (p < 0.01) compared to participants without hypertension (n = 4128); patients on antihypertensive treatment (n = 1466) showed a 0.56 point smaller cognition decline (p < 0.01) compared to patients who were not aware of their condition. The cognition decline of patients on antihypertensive treatment was comparable to the decline among non-hypertensive participants, (difference: -0.01 p = 0.96). Results were similar after adjusting for education, gender, and residency. For participants aged 45 to 54 years, there were no differences in cognition decline comparing any of these groups.

Conclusions:
Hypertension may accelerate cognitive decline over a four-year observational period in elderly Chinese but this decline is counteracted by antihypertensive treatment. Efforts to expand medical insurance for hypertension and treatment for the elderly in China may therefore also delay cognition decline in this population.
Abstract 005: Intensity of Hypertensive Exposure in Young Adulthood and Subclinical Atherosclerosis in Middle Age
Authors: Xiong Zhenyu , Li Jiaying , Zhuang Xiaodong , Liao Xinxue
Published: September 2019

Background and aims:
To measure the association between intensity of hypertensive exposure and coronary artery calcification (CAC) during a 25-year period in young adulthood.

Methods:
The Coronary Artery Risk Development in Young Adults (CARDIA) Study enrolled 5,115 healthy black and white American aged 18-30 years at baseline (March 1985-June 1986 to June 2010-May 2011). Durations of hypertension was estimated based on their identification at examinations 7, 10, 15, 20, and 25 years later, and cumulative BP exposure (millimeters of mercury х year) were used to represent long-term exposure to BP levels. CAC was identified by computed tomography (CT) at years 15, 20, and 25.

Results:
Among 2057 participants at year 0, 30.8% (634 of 2057) developed stage 1 hypertension and 13.8% (284 of 2057) developed stage 2 hypertension. After adjustment, the hazard ratio for the presence CAC was 1.07 (95% CI 0.99, 1.17) and 1.14 (95% CI 1.02, 1.29) times higher for each follow-up years longer duration of stage 1 and stage 2 hypertension respectively. For cumulative BP exposure at year 25, the odds ratio (ORs) for CAC were 1.58 (95% CI 1.39, 1.80) in cumulative SBP, 1.45 (95% CI 1.28, 1.64) in cumulative DBP, 1.26 (95% CI 1.13, 1.41) in cumulative PP, and 1.55 (95% CI 1.36, 1.76) in cumulative MAP for each SD increment.

Conclusions:
In early adulthood, more severe intensity of hypertensive exposure, durations of hypertension or exposure to BP, is associated with subclinical atherosclerosis in middle age.

Key Words:
coronary artery calcification, hypertension, young adult
Abstract 010: Neutrophil Gelatinase Associated Lipocalin From Immune Cells is Involved in Renal Damages Induced by Mineralocorticoid Excess
Authors: Bonnard Benjamin , MartÍnez-MartÍnez Ernesto , Buonafine Mathieu , Ibarrola Jaime , Fernández-Celis Amaya , López-Andrés Natalia , Jaisser Frederic
Published: September 2019

Introduction:
Neutrophil Gelatinase-Associated Lipocalin (NGAL) (or lipocalin 2) is a novel mineralocorticoid biotarget in the cardiovascular system. NGAL is also described as an acute renal lesion biomarker and NGAL serum concentration is associated with the severity of renal damages patients with a chronic kidney disease (CKD).
Lipocalin2
(Lcn2) gene invalidation in a CKD mouse model protects from proteinuria and renal lesions.

Objective:
Since the immune system is involved in renal inflammation and fibrosis process, we hypothesized that the production of NGAL/Lcn2 by immune cells plays an important role in the deleterious mineralocorticoid effects in the kidney.

Methods:
The role of Lcn2 produced by immune cells was analyzed using full Lcn2 knock out mice (Full KO) and mice depleted for Lcn2 in their immune cells by bone marrow transplantation (BMT lcn2 KO). These mice were challenged with uni-Nephrectomy, Aldosterone 200μg/kg/day, Salt 1% (NAS model) during 6 weeks.

Results:
NAS induced a significant increase in the expression (relative values, mean±SEM, compared to 1 in the control samples, p<0.05, n=6-9) of proinflammatory proteins such as MCP-1 (5.00±0.26), TNF-α (8.58±0.31), OPN (1.60±0.07), RANTES (3.98±0.20) and extracellular matrix proteins such as collagen IV (1.94±0.10), α-SMA (2.04±0.13) and fibronectin (3.38±0.20) in the kidney of WT mice. This effect was blunted in both KO mouse models (Full KO and BMT KO). Kidney fibrosis was induced by NAS (relative values, mean±SEM, compared to 1 in the control samples, p<0.05, n= 6-9) (5.98±0.19). this increase was fully prevented in Full KO NAS mice and partly corrected in BMT KO NAS mice. Macrophages isolated from Full Lcn2 KO or WT mice were co-treated with aldosterone (10
-8
M) and NaCl (40mM). In WT macrophages, mRNA expression (relative values, mean±SEM, compared to 1 in the control samples, p<0.05, n=6) of Lcn2 (22.06±1.36) as well as a the RANTES/CCl5 chemokine (10.88±0.88) is increased. The increase of RANTES/CCl5 was fully blunted in Lcn2 KO macrophages.

Conclusion:
NGAL produced by immune cells plays a critical role in renal interstitial fibrosis and inflammation induced by mineralocorticoid excess. The role of RANTES/CCl5 in the renal NGAL-mineralocorticoid pathways is currently analyzed.
Abstract 011: TRPM7 is Cardiovascular Protective in Aldosterone-Induced Hypertension
Authors: Rios Francisco J , Zou ZhiGuo , Hood Katie Y , Harvey Adam P , Neves Karla B , Nichol Sarah E , Camargo Livia L , Montezano Augusto C , Touyz Rhian M
Published: September 2019

TRPM7 is a chanzyme that influences cellular Mg
2+
homeostasis and vascular signaling. We demonstrated that aldosterone mediates cellular effects through TRPM7-dependent signaling pathways. Since hyperaldosteronism causes hypertension and Mg
2+
wasting, we questioned whether TRPM7 plays a role in aldosterone-induced hypertension. Wild-type (WT) and TRPM7-deficient (M7+/Δ) mice were treated with aldosterone (600μg/Kg/day) and/or 1% NaCl (drinking water) (aldo, salt or aldo/salt) for 4 weeks. Blood pressure (BP) was evaluated by tail-cuff. Vessel function was investigated in mesenteric arteries by wire and pressure myography. Protein expression was assessed by western-blot and histology. Cardiac fibroblasts (CF) were isolated from WT and M7+/Δ. M7+/Δ exhibited increased BP by aldo (140mmHg), salt (135mmHg) and aldo/salt (137mmHg) vs M7+/Δ-veh (117mmHg) (p<0.05), whereas in WT, BP was increased only by aldo/salt (134mmHg). All treatments induced endothelial dysfunction in M7+/Δ as observed in acetylcholine-relaxation curves [Emax % M7+/Δ: aldo (81±4), salt (69±4) and aldo/salt (75±3.0), p<0.05], whereas in WT, Emax % was reduced after aldo (68±4) and aldo/salt (80±3). Phenylephrine-contraction and SNP-relaxation curves were similar among groups. Pressure myography showed that in WT, aldo/salt increased wall/lumen ratio (83%) inducing eutrophic inward remodeling, whereas M7+/Δ-veh presented 62% reduction in cross-sectional area vs WT, which was increased by salt and aldo/salt, resulting in hypertrophic outward remodeling. Collagen was increased in aortas from M7+/Δ by aldo (31%) and aldo/salt (45%) and no changes in WT. Aldo/salt induced higher collagen deposition in hearts (68%) and kidneys (126%) from M7+/Δ vs WT. Hearts and kidneys from M7+/Δ veh exhibited increased α-SMA (2-fold) and p-Stat1 (1.5-fold), whereas tissues from WT exhibited 3-fold increase only after treatments. CF from M7+/Δ stimulated with aldosterone (100nM) showed increased activation of Stat1 (177%), Smad3 (300%) and reduced pStat3 (70%) vs WT, p<0.05. We define a novel protective role of TRPM7 in the cardiovascular system, which when downregulated, promotes increased blood pressure, vascular remodeling and cardiac fibrosis mediated by aldosterone and salt.
Abstract 012: Regulation of Cardiomyocyte Fibrosis by a Negative Feedback Loop Between Aldosterone-Induced Osteopontin Up-Regulation and beta
2
-Adrenergic Receptor Signaling
Authors: Pollard Celina M , Desimine Victoria L , Wertz Shelby L , Perez Arianna , Parker Barbara M , Maning Jennifer , McCrink Katie A , Shehadeh Lina A , Lymperopoulos Anastasios
Published: September 2019

Cardiac β
2
-adrenergic receptors (ARs) are known to inhibit collagen production and fibrosis in cardiac fibroblasts and myocytes. β
2
AR is a Gs protein-coupled receptor (GPCR) and, upon its activation, stimulates generation of cyclic 3`, 5`-adenosine monophosphate (cAMP). cAMP has two effectors: protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac). Epac1 has been shown to inhibit cardiac fibroblast activation and fibrosis. Osteopontin (OPN) is a ubiquitous pro-inflammatory and pro-fibrotic cytokine, including in the heart. We report here that the cardiotoxic hormone aldosterone upregulates OPN via the mineralocorticoid receptor (MR) in H9c2 cardiomyoblasts. This is prevented by β
2
AR-activated GPCR-kinase (GRK)-5. GRK5 directly phosphorylates and inhibits the MR in cardiomyocytes. Additionally, CRISPR-mediated OPN deletion enhances β
2
AR-dependent cAMP generation in H9c2 cardiomyocytes and upregulates Epac1. OPN deletion also enables the β
2
AR to completely abrogate transforming growth factor (TGF)-β-dependent fibrosis in H9c2 cardiomyocytes. Mechanistically, OPN interacts with G
α
s subunits in H9c2 cardiomyocytes to facilitate recruitment of GRK2, the major GRK phosphorylating and desensitizing the cardiac β
2
AR. This, in turn, augments the GRK2-dependent functional desensitization of the β
2
AR, thereby opposing this receptor`s anti-fibrotic cAMP/Epac1 signaling. In conclusion, we have uncovered a direct inhibitory effect of OPN in cardiac β
2
AR`s anti-fibrotic signaling via facilitation of GRK2-mediated receptor desensitization. Thus, OPN blockade could be of value in the treatment and/or prevention of cardiac fibrosis.
Abstract 017: Cytolytic Natural Killer Cells Play a Direct Role in Causing Hypertension and Intrauterine Growth Restriction in Pregnant Rats
Authors: Travis Olivia K , Baik Cedar H , Jackson Carmilya , Giachelli Chelsea , Williams Jan M , Cornelius Denise C
Published: September 2019

The
R
educed
U
terine
P
erfusion
P
ressure (RUPP) rat model of placental ischemia mirrors many of the hallmark features of preeclampsia (PE) such as hypertension, intrauterine growth restriction (IUGR), and immune activation, which includes increased cytolytic natural killer cells (cNKs). We have previously demonstrated that depletion of NK cells in RUPP rats improves PE pathophysiology. In this study we tested the hypothesis that RUPP-stimulated NKs have increased cytotoxicity and play a direct role in inflammation, oxidative stress, hypertension, and intrauterine growth restriction in pregnant rats. NK cells were isolated from the placentas of normal pregnant (NP) and RUPP rats on gestation day (GD) 19 and assessed for cytotoxic activity. RUPP NK cells demonstrated a 5-fold increase in cytotoxic activity vs NP NK cells. On GD 12, 5x10
6
NK cells from RUPP rats were infused into a subset of NP rats. On GD 19, circulating and placental total NK cells and cNKs were quantified via flow cytometry in NP, RUPP, and NP+RUPP NK rats. MAP, fetal and placental weights, placental reactive oxygen species (ROS), and placental cytokines were also measured. Placental cNK cells (%gated) were significantly increased in RUPP (18.5±3.6%) and NP+RUPP NK (16.1±3.6%) compared to NP (4.1±0.8%) controls. Circulating cNKs followed a similar trend. MAP increased from 100 mmHg in NP to 126 mmHg in RUPP, and 119 mmHg in NP+RUPP NK (p<0.05 vs NP). Fetal weight decreased from 2.4±0.03 g in NP to 2.0±0.04 g in RUPP and to 2.1±0.02 g in NP+RUPP NK (p<0.05 vs NP). Placental weights followed a similar trend. Placental cNK cytokines were significantly increased in RUPP and in NP recipients of RUPP NK cells: TNF-α: NP- 23±3.1, RUPP- 62.3±7.8 pg/mg, NP+RUPP NK-43.9±5.7 pg/mg (p<0.05 vs NP); IFNγ: NP- 3.3±0.7, RUPP- 7.6±1.2 pg/mg, NP+RUPP NK-6.6±1.9 pg/mg (p<0.05 vs NP). Placental VEGF decreased from 6.5±1.3 pg/mg in NP to 2±0.8pg/mg in RUPP and 2.9±0.6 pg/mg in NP+RUPP NK. Circulating levels followed a similar trend. Placental ROS significantly increased from 27.3±4.6 RLUs/min/mg in NP to 63.1±5.7 RLUs/min/mg in RUPP and 84±17.6 RLUs/min/mg in NP+RUPP NK. These data demonstrate a direct role for cNKs in causing PE pathophysiology and identifies cNKs as a novel therapeutic target for treatment of PE.
Abstract 026: Attended Versus Unattended Blood Pressure Measurement in Patients With Cardiovascular Disease: Does It Matter?
Authors: Villanueva Matthew , Chen Yiqing E , Smith Steven M , Gong Yan , Handberg Eileen M , Pepine Carl J , Keeley Ellen C , Cooper-Dehoff Rhonda M
Published: September 2019

Introduction:
Nearly one half of the subjects in SPRINT had their blood pressure (BP) measured absent an observer (unattended), whereas most prior trials have used attended measurement. This has created controversy in interpreting the relationship between achieved systolic BP (SBP) and outcomes in SPRINT. Accordingly, we prospectively examined the difference between attended and unattended office SBP measured using the same automated device used in SPRINT among patients with documented CV disease.

Methods:
We randomized patients attending a routinely scheduled cardiology clinic visit to have their BP measured using an attended, followed by an unattended method, or vice versa, after a controlled rest period. All study BP measurements were obtained in triplicate using the automated Omron HEM-907XL BP monitor, and averaged. The outcome of interest was the difference in SBP between the two measurement techniques. At the same visit, we obtained a routinely measured office BP from the medical record, and compared with attended and unattended measurements.

Results:
A total of 102 patients were enrolled, mean age was 63 years, 48% (49 of 102) men and 75% (76 of 102) were Caucasian. The mean attended and unattended SBP was 125.4 ± 20.4 and 122.6 ± 21.0 mm Hg, respectively. The mean SBP recorded by the clinic nursing staff was 130.6 ± 23.6 mm Hg. On average, the attended SBP was 2.7 mmHg higher than the unattended measurement (P=0.0002, 95% CI 1.3 to 4.1). The clinic staff SBP measurement was 5.2 mmHg higher than the attended SBP (P=0.0003, 95% CI 2.4 to 8.0) and 8.0 mmHg higher than the unattended SBP (P<0.0001, 95% CI 5.4 to 10.5).

Conclusion:
Among CVD patients being evaluated in a cardiology clinic, there is only a small (~3 mmHg) but statistically significant difference between attended and unattended automated SBP. More importantly, the routine office measured SBP was significantly higher than either the attended or unattended SBP. Our findings suggest that observing the BP measurement in patients with established CVD affects the BP, but much less than previously suggested. Factors such as measurement timing and non-standardized measurement technique are likely to have a larger impact on BP measurement than observer attendance.
Abstract 027: Changes in Renin Angiotensin System Monitored Across Time Following Bariatric Surgery
Authors: Oliveras Anna , Benito David , Ho Wong Tai M , Álvarez Sara , Outon Sara , Goday Albert , Vázquez Susana , Faura Anna , Pascual Julio , Riera Marta
Published: September 2019

There is scarce information regarding the complete renin-angiotensin-aldosterone system (RAAS) and its changes after bariatric surgery (BS) in patients with morbid obesity (MO).

Objective:
to analyze changes (Δ) in RAAS components in MO after BS at several follow-up time points.

Methods:
Fifty-five MO patients (78% women, 40% hypertensives, age 43.4±8.9yr, BMI 42.4±5.3Kg/m
2
) were evaluated prospectively before and 1,3,6 and 12 months(m) after BS, with assessment of anthropometrics, RAAS components and 24h-systolic BP (SBP).

Results:
at 12m body weight (-35.1±9.7 Kg) and waist circumference (-27±9.2 cm) decreased (p<0.001). At 1,3 and 6m, there was a reduction in angiotensin-converting enzyme (ACE) and ACE-2 activity, as well as a decrease in plasma renin activity (PRA) and aldosterone from 3m on (Table). The decrease in 24h-SBP at 1m was 6.2 mmHg (3.6 to 8.8), p<0.001.

There were correlations (p<0.05) between ΔPRA/Δ24h-SBP at 1m (r=-0.332), 3m (r=-0.330) and 12m (r=-0.322). ΔPRA and Δbody weight correlated only at 1m (r=-0.427). Δaldosterone and Δwaist circumference correlated at 12m (r=-0.372). ΔACE and Δ24h-SBP correlated at 6 and 12m (r=0.451 and r=0.635, respectively). Correlations between Δ24h-SBP and Δbody weight were statistically significant only at 6m (r=0,366; p=0,016).

Conclusions:
there are sequential changes in several components of the RASS after BS, with an increase in ACE and ACE2 activity as early as 1m after BS that lasts until 6m, and a decrease in PRA and plasma Aldosterone that initiates at 3m and remains 12m after BS. These changes correlate with the decrease of 24h-SBP. RAAS components, but not body weight, appear to correlate with changes in BP after BS.
Abstract 031: Association Between Non-Oral Hormonal Contraceptives and Blood Pressure: A Systematic Review
Authors: Kalenga Cindy Z , Metcalfe Amy , Ahmed Sofia B , Sharanya Ramesh , MacRae Jennifer M , Nerenberg Kara , Sola Darlene Y , Dumanski Sandi
Published: September 2019

Background:
Combined oral contraceptives (COCs) are associated with increased blood pressure (BP) and hypertension. Whether non-oral forms of hormonal contraceptive (NOHC) have similar associations is unknown.

Methods:
We conducted a systematic review investigating the association between NOHC use and blood pressure compared to women using COC and non-hormonal contraception (NHC). Three databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials) were searched for articles published from database inception through October 2018. Primary studies examining women using NOHC [transdermal, hormonal intrauterine device (IUD), implant, vaginal ring or injectables] compared with women using COC or NHC were included. Two independent investigators screened identified abstracts. Data on study population, hormonal exposure, outcomes, study quality and risk of bias were independently extracted from each eligible study. Primary outcomes were change in BP or prevalence of hypertension. Quality of case control and cohort studies was assessed using the Newcastle-Ottawa scale. Quality of randomized control trials was assessed using the Cochrane risk of bias tool.

Results:
Of 3981 studies reviewed, 22 met inclusion criteria (12 studies on injectables, 6 on implants, 4 on hormonal IUDs, 3 on the vaginal ring). Some studies examining the effect of IUD use showed a significantly lower BP compared to COC use, and no difference compared to NHC users. No differences in BP were reported with vaginal ring use compared to COC or NHC use. Conflicting results were presented with implant use compared to NHC use, but no change in BP compared to COC. Five studies reported increased BP with injectable use compared to COC and NHC, while seven studies showed no change in BP. All women remained in the normotensive range in all included studies.

Conclusion:
Non-oral hormonal contraceptive use is associated with increases in blood pressure, though the effects differ by route of administration. These results may inform contraceptive choices in women with or at risk of hypertension.
Abstract 032: A Pilot Study of Antihypertensive Medication Adherence Trends by Sex and Drug Class
Authors: Cooper-Dehoff Rhonda M , Holmes Henry R , Li Qian , Xu Ke , Kim Seungbum , Richards Elain M , Keeley Ellen C , Handberg Eileen M , Smith Steven M , Raizada Mohan K , Pepine Carl J
Published: September 2019

Background:
Antihypertensive medication nonadherence is believed to be a prevalent issue but is very difficult to accurately assess. As a result, using a variety methods, nonadherence rates ranging from 3-86% have been suggested. To clarify this problem among hypertensive patients attending a CVD outpatient clinic, we utilized high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS) to assess antihypertensive medication adherence and identify trends by sex and drug class

Methods:
Plasma was obtained from patients with either drug-controlled or drug resistant hypertension (RHTN) and analyzed via HPLC-MS for antihypertensive drugs which were categorized by drug class as: beta blockers, aldosterone antagonists, thiazide diuretics, ACE inhibitor/ARBs, or calcium antagonists. Clinic blood pressure (BP) measurements, sex, and prescription regimens were extracted from patient medical records at or near the time of plasma collection. “Adherence” or “nonadherence” was determined by comparison of the patient’s prescribed drug regimen and the presence/absence of prescribed drug(s) in their plasma.

Results:
Among 76 patients (47 women, mean age 63 ± SD 10), and 53% (43 of 76) white. Overall, nonadherence was confirmed in 29% (22 of 76). RHTN was more frequently identified in women than men (55%, 26 of 47 vs 38% 11 of 29) and nonadherence was higher in women than men (34%, 16 of 47 vs 21%, 6 of 29). As expected, BP in those who were fully adherent to prescribed antihypertensive drugs was significantly lower than in those who were nonadherent with one or more medications (129/75 vs 145/83 mm Hg, p=0.0015). Overall, ACE inhibitors or ARBs were associated with the least nonadherence. Among women, nonadherence was highest for aldosterone antagonists, whereas among men, nonadherence was highest for thiazide diuretics. Nonadherence appeared among those with RHTN (38%, 14 of 37) and those with controlled HTN (21%, 8 of 39).

Conclusion:
We observed nonadherence was more frequent among older women in a cohort of HTN and RHTN patients based on HPLC-MS confirmed drug levels. Nonadherence was variable based on drug class but lowest with angiotensin II active agents, which, if validated, should be considered when optimizing antihypertensive prescribing.
Abstract 034: Differential Regulation of Renal Injury in
Npr1
Gene-Targeted Male and Female Mice: Role of Class I-Specific HDAC Inhibitor
Authors: Kumar Prerna , Pandey Kailash N
Published: September 2019

The objective of the present study was to gain insight into the effect of class I-specific histone deacetylase (HDAC) inhibitor, mocetinostat (MGCD0103; MGCD) on
Npr1
(coding for natriuretic peptide receptor-A; NPRA) gene expression and regulation of renal pathology. Adult male and female
Npr1
haplotype (1-copy;
Npr1
+/-
), wild-type (2-copy;
Npr1
+/+
), and gene-duplicated (3-copy;
Npr1
++/+
) mice were injected intraperitoneally with MGCD (2 mg/kg) at alternate days for 2-weeks. The renal NPRA protein levels were significantly increased in the treated male (1-copy, 2.1-fold; 2-copy, 2.3-fold; and 3-copy, 1.5-fold; p < 0.05) and female mice (1-copy, 3.6-fold; 2-copy, 2.1-fold; and 3-copy, 1.7-fold; p < 0.05) compared with untreated animals. After MGCD treatment, the renal guanylyl cyclase-A (GC-A) activity significantly increased in male mice (1-copy, 77.4 ± 0.5 vs. control 30.7 ± 0.5; 2-copy 126.1 ± 5.0 vs. control 76.3 ± 6.3; and 3-copy, 182.7 ± 2.8 vs. control 141.2 ± 6.4; p < 0.05; cGMP/mg protein/ 30 min) and female mice (1-copy, 108.2 ± 6.8 vs. control 51.9 ± 3.0; p < 0.05). Male mice exhibited significantly higher systolic blood pressure (SBP) than females and treatment with MGCD decreased SBP in both 1-copy male (106 ± 0.6 vs. control, 129 ± 1.9; mmHg) and female mice (97 ± 2.2 vs. control, 110 ± 2.1, p < 0.001). Higher urinary albumin to creatinine ratio was detected in male mice compared with female mice, which was attenuated by MGCD treatment in male mice (1-copy, 0.39 ± 0.04 vs. untreated 0.71 ± 0.05; 2-copy 0.31 ± 0.01 vs. untreated 0.46 ± 0.05; and 3-copy, 0.2 ± 0.02 vs. untreated 0.21 ± 0.02; p < 0.05). HDAC activity was significantly higher in male mice (1-copy, 24.4 ± 2.8; 2-copy, 15.9 ± 1.2; and 3-copy, 6.4 ± 0.7; ng/min/mg protein) than female mice (1-copy, 13.7 ± 1.4; 2-copy, 8.5 ± 0.9; and 3-copy, 4.7 ± 0.9, p < 0.05); however, MGCD treatment significantly attenuated HDAC activity in both male and female animals (p < 0.05). The present results indicate MGCD upregulates
Npr1
expression in 1-copy haplotype mice via inhibition of HDAC activity, lowers SBP and repairs renal injury differentially in male vs. female mice. These findings will have important implications for treatment of hypertension and renal injury in humans in a sex-related manner.
Abstract 036: Genetics and Epigenetics on Circadian Blood Pressure and Variability in Rats Compared With Ambulatory Blood Pressure Variability in Human
Authors: Lee Mary S , Lee John S , Lee Jong Y , Azar Silvia H , Halberg Franz
Published: September 2019

Hypertension is associated with high morbidity and mortality. Blood pressure (BP) levels vary widely due to predictable biological rhythms and unpredictable environmental factors. Daily (circadian) rhythm characteristics are considered essential parameters for recognizing and treating increased risks in BP. Franz Halberg spent most of his academic career in cardiovascular research, focused on ambulatory monitoring and developing chronobiological methods for clinical application. To compare BP Variability (BPV), automatically monitored ambulatory BP around the clock at 30-60 min intervals in 20 human subjects was compared with telemetered circadian BP in rats after one-cell homozygous embryo-transfer into spontaneously hypertensive (SHR, pup:shr) or normotensive (WKY, pup:wky) rats' oviducts (embryos: s,w; oviduct-uterus: S,W) and cross-suckled at birth (nurses S,W). The circadian response peaked in the late afternoon hours in most human subjects and early morning hours in rats. Human circadian double amplitudes (2A) varied from 8 to 26 mm Hg with higher 2A in elder adults, and 3-8 mm Hg in rats with significantly higher fluctuations in SHR groups (7.5±0.7 for sSS, 8.3±0.6 for sSW vs. 4.7±0.3 mm Hg for wWW). The circaseptan 2A in the adolescents were 10±1 for SBP and 12±3 mm Hg for DBP, and sharp increased winter 2A (SBP 54; HR 48, both P<0.0001) were observed. In rats, mostly clustered peaks around the light-on hours, while sWS and wSS groups showed peak-hour variations (19:18 to 08:06 and 02:58 to 09:10 hrs, respectively). The peak-hour in shr strains was shifted to earlier or delayed in the WKY uterus (sWW and sWS groups) with large deviations as compared to the wWW group. Hypertensive-prone shr strains showed significantly lowered BPs in WKY uterine and/or WKY nursing environments indicating that environment can strongly modify genetic influence, yet the lowered shr MESORs by the WKY environments remained above the MESORs encountered in wky donors. Thus, the maternal environment may be a major factor that affects the offspring’s BP and BPV later in life. Chronomes broader than circadian BPs are considered as a gauge of vascular disease status. Abnormal BP/BPV modifications may lead to novel implications in preventive and therapeutic strategies in CVD.
Abstract 037: Monogenic Hypertension Associated With a Pathogenic STX16 Mutation
Authors: Wan Elizabeth , Sofat Reecha , Cross Jennifer , Walsh Stephen B
Published: September 2019

Hypertension is the most important modifiable risk factor for death worldwide. Finding novel model mechanisms for blood-pressure (BP) regulation is an important goal and Mendelian syndromes have been very helpful in that regard.

Pseudohypoparathyroidism type 1B (PHP1B) is an example in which affected individuals are invariably hypertensive for unknown reasons.

We encountered a 48 year-old woman with severe, five-drug-resistant, hypertension. Her father and two aunts were also severely hypertensive. Her two young sons have developed drug-dependent hypertension before age 20 years. We measured 24-h ambulatory blood pressure and excluded all known secondary causes. However, the proband’s sons and their grandfather have the PHP1B phenotype, while our index patient and her two hypertensive aunts do not. The blood pressure phenotype in this pedigree suggested autosomal dominant inheritance. The Syntaxin 16 (STX16) gene encodes a snare protein and mutations cause PHP1B. Mutated STX16 causes methylation defects of Guanine Nucleotide Binding Protein, Alpha Stimulating (GNAS), a G protein regulator. Since GNAS is an imprinted gene, only inheritance from the mother causes the PHP1B phenotype. Subsequently, we sequenced
STX16
in our kindred. We found a heterozygous deletion involving exons 5 and 6. We were also able to show complete loss of methylation in
GNAS
exon 1A. All hypertensive persons in our kindred have the
STX16
mutation and are hypertensive. However, only those with maternal inheritance show the PHP1B phenotype. The methylation target region influenced by
STX16
encompasses 7 genes. Our candidate is endothelin-3 encoded by
EDN3
. Our data separate the hypertension-PHP1B phenotypes. We imply separate mechanisms are involved. We suggest new targets of blood pressure-raising relevance.