bluuebunny/crossref_metadata_2025 huggingface dataset:
Blind Channel and Data Estimation Using Fuzzy Logic-Empowered Opposite Learning-Based Mutant Particle Swarm Optimization
Authors: AsadUllah Muhammad , Khan Muhammad Adnan , Abbas Sagheer , Athar Atifa , Raza Syed Saqib , Ahmad Gulzar
Published: December 2018

Multiple-input and multiple-output (MIMO) technology is one of the latest technologies to enhance the capacity of the channel as well as the service quality of the communication system. By using the MIMO technology at the physical layer, the estimation of the data and the channel is performed based on the principle of maximum likelihood. For this purpose, the continuous and discrete fuzzy logic-empowered opposite learning-based mutant particle swarm optimization (FL-OLMPSO) algorithm is used over the Rayleigh fading channel in three levels. The data and the channel populations are prepared during the first level of the algorithm, while the channel parameters are estimated in the second level of the algorithm by using the continuous FL-OLMPSO. After determining the channel parameters, the transmitted symbols are evaluated in the 3rd level of the algorithm by using the channel parameters along with the discrete FL-OLMPSO. To enhance the convergence rate of the FL-OLMPSO algorithm, the velocity factor is updated using fuzzy logic. In this article, two variants, FL-total OLMPSO (FL-TOLMPSO) and FL-partial OLMPSO (FL-POLMPSO) of FL-OLMPSO, are proposed. The simulation results of proposed techniques show desirable results regarding MMCE, MMSE, and BER as compared to conventional opposite learning mutant PSO (TOLMPSO and POLMPSO) techniques.
Risk Analysis for Invasive Fungal Infection after Living Donor Liver Transplantation: Which Patient Needs Potent Prophylaxis?
Authors: Utsumi Masashi , Umeda Yuzo , Yagi Takahito , Nagasaka Takeshi , Shinoura Susumu , Yoshida Ryuich , Nobuoka Daisuke , Kuise Takashi , Fuji Tomokazu , Takagi Kosei , Takaki Akinobu , Fujiwara Toshiyoshi
Published: December 2018

Background: Invasive fungal infection (IFI) is associated with high mortality after living donor liver transplant (LDLT). The aim of this study was to identify the risk factors for post-LDLT IFI for early diagnosis and improvement of antifungal treatment outcome. Methods: Risk analysis data were available for all 153 patients who underwent LDLT between January 2005 and April 2012. Results: During the follow-up period (1,553 ± 73 days, range 20–2,946 days), 15 patients (9.8%) developed IFI classified as “proven” (n = 8) and “probable” (n = 7) with fungal pathogens including Candida spp. (n = 10), Aspergillus spp. (n = 4), and Trichosporon (n = 2). Of these patients, 7 patients with IFI died despite treatment. The 1-, 3-, and 5-year survival rates were lower in patients with IFI than those without IFI (66.7/59.3/44.4 vs. 90.4/85.7/81.8%, respectively; p = 0.0026). Multivariate analysis identified model for end-stage liver disease score of ≥26 (OR 16.0, p = 0.0012) and post-transplant acute kidney injury (RIFLE criteria I- or F-class; OR 4.87, p = 0.047) as independent risk factors for IFI. Conclusion: Preoperative recipients’ status and postoperative kidney dysfunction can affect an occurrence of post-transplant IFI. These risk factors would be taken into consideration for designation of proper antifungal therapy.
The 12-Word Philadelphia Verbal Learning Test Performances in Older Adults: Brain MRI and Cerebrospinal Fluid Correlates and Regression-Based Normative Data
Authors: Gifford Katherine A. , Liu Dandan , Neal Jacquelyn E. , Babicz Michelle A. , Thompson Jennifer L. , Walljasper Lily E. , Wiggins Margaret E. , Turchan Maxim , Pechman Kimberly R. , Osborn Katie E. , Acosta Lealani Mae Y. , Bell Susan P. , Hohman Timothy J. , Libon David J. , Blennow Kaj , Zetterberg Henrik , Jefferson Angela L.
Published: December 2018

Background/Aims: This study evaluated neuroimaging and biological correlates, psychometric properties, and regression-based normative data of the 12-word Philadelphia Verbal Learning Test (PVLT), a list-learning test. Methods: Vanderbilt Memory and Aging Project participants free of clinical dementia and stroke (n = 230, aged 73 ± 7 years) completed a neuropsychological protocol and brain MRI. A subset (n = 111) underwent lumbar puncture for analysis of Alzheimer’s disease (AD) and axonal integrity cerebrospinal fluid (CSF) biomarkers. Regression models related PVLT indices to MRI and CSF biomarkers adjusting for age, sex, race/ethnicity, education, APOE-ε4 carrier status, cognitive status, and intracranial volume (MRI models). Secondary analyses were restricted to participants with normal cognition (NC; n = 127), from which regression-based normative data were generated. Results: Lower PVLT performances were associated with smaller medial temporal lobe volumes (p < 0.05) and higher CSF tau concentrations (p < 0.04). Among NC, PVLT indices were associated with white matter hyperintensities on MRI and an axonal injury biomarker (CSF neurofilament light; p < 0.03). Conclusion: The PVLT appears sensitive to markers of neurodegeneration, including temporal regions affected by AD. Conversely, in cognitively normal older adults, PVLT performance seems to relate to white matter disease and axonal injury, perhaps reflecting non-AD pathways to cognitive change. Enhanced normative data enrich the clinical utility of this tool.
Virtual Reality Simulation in Peritoneal Dialysis Training: The Beginning of a New Era
Authors: Zgoura Panagiota , Hettich Daniel , Natzel Jonathan , Özcan Fedai , Kantzow Boris
Published: December 2018

Background/Aim: Peritonitis rates in peritoneal dialysis (PD) vary considerably not only across countries but also between centers in the same country. Patient education has been shown to significantly reduce infection rates but up till now training lacks standardization with patients being trained using different methods and media (e.g., illustrations, videos). As a result, patients may be insufficiently experienced in performing PD, which might be one of the causes for high peritonitis rates. To address these issues, we developed a PD training program based on virtual reality (VR). Methods: To become acquainted with the PD procedure, patients are equipped with a VR headset and controllers. They are presented with a virtual PD set, which simulates the feeling of sitting in front of a real PD set. The patient is enabled to run through the program as often as necessary to become familiarized with the whole PD procedure. The aim is to standardize, facilitate, and accelerate the individual learning process. To compare the effect of the applied training method to traditional training, a randomized controlled trial is underway. Conclusion: Previous studies on the effectiveness of learning showed that VR training applications are superior to traditional methods, such as text- or video-based training. However, no study has been undertaken in the context of dialysis. We believe that the implementation of VR training programs in clinical practice will be beneficial in improving the patient’s proficiency, and thereby the quality and safety of PD.
Getting “Stuck” in the Future or the Past: Relationships between Dimensions of Time Perspective, Executive Functions, and Repetitive Negative Thinking in Anxiety
Authors: Åström Elisabeth , Seif Ali , Wiberg Britt , Carelli Maria Grazia
Published: December 2018

Background/Aim: Anxiety disorders are associated with impairments in several aspects of cognitive processing. In this study we investigated three such aspects, i.e., time perspective, repetitive negative thinking (worry and rumination), and executive functioning, in persons with anxiety disorders compared to healthy controls and examined the influence of negative past and negative future time perspective and executive functioning on worry and rumination. Method: Thirty-six psychiatric outpatients with anxiety disorders (mean age = 30.83, SD = 11.74; 30 females and 6 males) and 44 healthy controls (mean age = 28.89, SD = 9.54; 24 females and 20 males) completed inventories of time perspective and repetitive negative thinking, and tasks measuring executive functioning (shifting and inhibition). Results: The groups (patient vs. control) differed significantly on all time perspective dimensions (past, present, and future), with largest effect sizes observed for negative past and negative future. Regression analyses with executive functioning, negative past, and negative future time perspectives as predictors, and worry and rumination as outcomes, showed that negative past time perspective was the best predictor for rumination, whereas negative future time perspective more strongly predicted worry. Executive functioning was not a significant predictor of either worry or rumination. Conclusions: Individuals with anxiety disorders demonstrated systematic biases in all time perspective dimensions, particularly negative past and negative future time perspective, which was further related to worry and rumination. Thus, interventions targeting temporal focus may be one way of reducing repetitive negative thinking. A major limitation of this study was the use of a cross-section design.
Incidentally Detected Amyloid Light-Chain Amyloidosis Caused by Monoclonal Gammopathy of Undetermined Significance: Possible Time-Dependent Change in Colonic Findings
Authors: Fukui Toshiro , Tanimura Yuji , Matsumoto Yasushi , Horitani Shunsuke , Tomiyama Takashi , Okazaki Kazuichi
Published: December 2018

Amyloid light-chain (AL) amyloidosis is associated with plasma cell disorder and monoclonal light chains. This type of amyloidosis is the prominent type involving the gastrointestinal tract. Monoclonal gammopathy of undetermined significance (MGUS) is the most common plasma cell disorder and a known precursor of more serious diseases. A 72-year-old male was treated for high blood pressure, diabetes, and gout at the clinic of a private physician. Due to a positive fecal occult blood test discovered during colon cancer screening, he underwent colonoscopy and was diagnosed with adenomatous polyps by biopsies. Two months later, he was referred to our hospital for endoscopic resection of the polyps. Although the polyps were successfully removed, a colonoscopy revealed two types of ulcerative lesions. Immunohistopathological evaluations obtained from these lesions and polyps confirmed amyloid deposition. Although esophagogastroduodenoscopy results were normal, a biopsy specimen from the patient’s stomach showed the same type of amyloid deposition. Immunoelectrophoresis showed M-proteins for anti-IgG-λ in the serum and λ type Bence-Jones protein in the urine. His blood, bone marrow, and urine test results led to a diagnosis of MGUS. A coronary angiography revealed multivessel stenosis, and the patient’s cardiac function improved after coronary artery stenting. Hereafter, a combination therapy with bortezomib, lenalidomide, and dexamethasone is planned. This is a case report of systemic AL amyloidosis caused by MGUS, which was incidentally detected by colonoscopy.
Impact of Hybrid Therapy Comprising Peritoneal Dialysis and Hemodialysis on Acute Cardiovascular Events
Authors: Banshodani Masataka , Kawanishi Hideki , Moriishi Misaki , Shintaku Sadanori , Tsuchiya Shinichiro
Published: December 2018

Background: The impact of hybrid therapy comprising peritoneal dialysis (PD) and hemodialysis on cardiovascular events in PD patients remains unclear. Objective: We aimed to evaluate the effect of hybrid therapy on cardiovascular events. Methods: A total of 93 PD patients undergoing hybrid therapy for ≥3 years were divided into 2 groups according to left ventricular ejection fraction (LVEF): lower ejection fraction (LEF [n = 29], LVEF < 60%) and normal ejection fraction (NEF [n = 64], LVEF ≥60%). Hospitalization rates and echocardiographic parameters were evaluated. Results: The 1-year hospitalization rate for acute cardiovascular events decreased after the therapy initiation in both groups (LEF: 0.36–0.11, p = 0.02 and NEF: 0.43–0.06, p < 0.001). In generalized linear mixed models, LVEF (44 ± 15%) improved at 1, 2, and 3 years after initiation (53 ± 18, 55 ± 17, and 58 ± 7%; p < 0.05) in the LEF group, whereas, in the NEF group, LVEF (68 ± 5%) was maintained at 1, 2, and 3 years after initiation (67 ± 8, 67 ± 9, and 68 ± 9%; p > 0.05). Mitral inflow E velocity to tissue Doppler e′ ratio was maintained at the same level at 1–3 years after initiation in both groups. Left ventricular mass index (LVMI; 189 ± 41 g/m2) was decreased at 1 (178 ± 35 g/m2; p = 0.8), 2 (160 ± 45 g/m2; p = 0.008), and 3 (166 ± 47 g/m2; p = 0.05) years after initiation in the LEF group, whereas in the NEF group, LVMI (157 ± 45 g/m2) was maintained at 1, 2, and 3 years after initiation (153 ± 40, 155 ± 54, and 158 ± 52 g/m2; p > 0.05). Conclusion: Hybrid therapy decreased acute cardiovascular events and improved systolic cardiac function in PD patients in the LEF group.
Downregulation of microRNA-376a in Gastric Cancer and Association with Poor Prognosis
Authors: Zhang Cheng , Liang Yu , Ma Ming-Hui , Wu Kun-Zhe , Zhang Chun-Dong , Dai Dong-Qiu
Published: December 2018

Background/Aims: MicroRNAs have a significant role in the tumorigenesis and progression of cancers, including gastric cancer (GC). Our study aimed to identify a novel biomarker to predict the prognosis of patients with GC. Methods: The GC microarray dataset, GSE28700, was downloaded from the Gene Expression Omnibus (GEO) database and screened for differentially expressed miRNAs (DEMs). The downregulation of miR-376a expression was verified in GC cell lines and 82 paired GC tissues by performing RT-qPCR and the correlation between its expression and clinicopathological characteristics was also explored. The target genes of miR-376a were predicted using TargetScan7.1, miRDB, and DIANA website tools. A functional enrichment analysis was performed to explore the biological role of the common target genes. Results: Bioinformatics analysis found that miR-376a was downregulated in GC tissues. Compared with the control group, RT-qPCR results showed that the expression of miR-376a in GC cell lines and tissues were also significantly decreased. The expression of miR-376a was statistically associated with T and N stage. Survival analysis with Kaplan–Meier showed that GC patients in the low expression group had a poorer prognosis than those in the high expression group (median survival of 26.4 and 46.9 months, respectively). Univariate and multivariate analysis demonstrated that low miR-376a expression was an independent prognostic marker for poor survival. Functional enrichment analysis indicated that the common targets genes were involved in cell–cell communication, VEGF and mTOR1-mediated signaling, and epithelial-to-mesenchymal transition (EMT). Conclusion: The results suggest that miR-376a could play an important role in the tumorigenesis and progression of GC and act as a novel therapeutic target and prognostic indicator in patients with GC.
Clinical Drug Response Prediction by Using a Lq Penalized Network-Constrained Logistic Regression Method
Authors: Huang Hai-Hui , Dai Jing-Guo , Liang Yong
Published: December 2018

Background/Aims: One of the most important impacts of personalized medicine is the connection between patients’ genotypes and their drug responses. Despite a series of studies exploring this relationship, the predictive ability of such analyses still needs to be strengthened. Methods: Here we present the Lq penalized network-constrained logistic regression (Lq-NLR) method to meet this need, in which the predictors are integrated into the gene expression data and biological network knowledge and are combined with a more aggressive penalty function. Response prediction models for two cancer targeting drugs (erlotinib and sorafenib) were developed from gene expression data and IC50 values from a large panel of cancer cell lines by utilizing the proposed approach. Then the drug responders were tested with the baseline tumor gene expression data, yielding an in vivo drug sensitivity prediction. Results: These results demonstrated the high effectiveness of this approach. One of the best results achieved by our method was a correlation of 0.841 between the cell line in vitro drug response and patient’s in vivo drug response. We then applied these two drug prediction models to develop a personalized medicine approach in which the subsequent treatment depends on each patient’s gene-expression profile. Conclusion: The proposed method is much better than the existing approach and can capture a more accurate reflection of the relationship between genotypes and phenotypes.
A Novel Angiotensin II–Induced Long Noncoding RNA
Giver
Regulates Oxidative Stress, Inflammation, and Proliferation in Vascular Smooth Muscle Cells
Authors: Das Sadhan , Zhang Erli , Senapati Parijat , Amaram Vishnu , Reddy Marpadga A. , Stapleton Kenneth , Leung Amy , Lanting Linda , Wang Mei , Chen Zhuo , Kato Mitsuo , Oh Hyung Jung , Guo Qianyun , Zhang Xinyue , Zhang Bin , Zhang Haitong , Zhao Qinghao , Wang Wei , Wu Yongjian , Natarajan Rama
Published: December 2018

Rationale:

AngII (angiotensin II)-mediated vascular smooth muscle cell (VSMC) dysfunction plays a major role in hypertension. Long noncoding RNAs have elicited much interest, but their molecular roles in AngII actions and hypertension are unclear.

Objective:

To investigate the regulation and functions of a novel long noncoding RNA growth factor– and proinflammatory cytokine–induced vascular cell-expressed RNA (
Giver
), in AngII-mediated VSMC dysfunction.

Methods and Results:

RNA-sequencing and real-time quantitative polymerase chain reactions revealed that treatment of rat VSMC with AngII increased the expression of
Giver
and
Nr4a3
, an adjacent gene encoding a nuclear receptor. Similar changes were observed in rat and mouse aortas treated ex vivo with AngII. RNA-FISH (fluorescence in situ hybridization) and subcellular fractionation showed predominantly nuclear localization of
Giver
. AngII increased
Giver
expression via recruitment of Nr4a3 to
Giver
promoter. Microarray profiling and real-time quantitative polymerase chain reaction validation in VSMC showed that
Giver
knockdown attenuated the expression of genes involved in oxidative stress (
Nox1
) and inflammation (
Il6
,
Ccl2
,
Tnf
) but increased
Nr4a3
. Conversely, endogenous
Giver
overexpression showed opposite effects supporting its role in oxidative stress and inflammation. Chromatin immunoprecipitation assays showed
Giver
overexpression also increased Pol II (RNA polymerase II) enrichment and decreased repressive histone modification histone H3 trimethylation on lysine 27 at
Nox1
and inflammatory gene promoters. Accordingly,
Giver
knockdown inhibited AngII-induced oxidative stress and proliferation in rat VSMC. RNA-pulldown combined with mass spectrometry showed
Giver
interacts with nuclear and chromatin remodeling proteins and corepressors, including NONO (non-pou domain-containing octamer-binding protein). Moreover, NONO knockdown elicited similar effects as
Giver
knockdown on the expression of key
Giver
-regulated genes. Notably,
GIVER
and
NR4A3
were increased in AngII-treated human VSMC and in arteries from hypertensive patients but attenuated in hypertensive patients treated with ACE (angiotensin-converting enzyme) inhibitors or angiotensin receptor blockers. Furthermore, human
GIVER
also exhibits partial functional conservation with rat
Giver
.

Conclusions:

Giver
and its regulator
Nr4a3
are important players in AngII-mediated VSMC dysfunction and could be novel targets for antihypertensive therapy.
Abstract 001: Loss of ET
B
Receptor Function Activates Inflammasome Signaling Pathways and Dendritic Cells in the Renal Outer Medulla During Type 1 Diabetes
Authors: De Miguel Carmen , Pollock David M , Pollock Jennifer S
Published: December 2018

Renal inflammation is a hallmark of diabetic kidney disease. Endothelin-1 (ET-1), a potent vasoactive peptide that acts through two receptors (ET
A
and ET
B
), has been implicated in diabetes and is upregulated in patients with diabetic nephropathy (DN) and in animal models of diabetic kidney injury. ET
B
receptors are highly expressed in renal outer medulla (OM). ET-1 exerts pro-inflammatory actions in the kidney; however, the mechanisms by which ET-1 mediate these effects are unclear. The present studies were designed to determine the role of the ET
B
receptor in priming inflammasome signaling pathways, as well as its role in the activation of dendritic cells (DCs), in the renal OM during type 1 diabetes. Diabetes was induced in ET
B
deficient (ET
B
def) and transgenic (TG) control rats by i.v. injection of streptozotocin (STZ). 10 wk later, 24-h urine and kidneys were collected for analysis of kidney damage. Diabetic ET
B
def rats presented exaggerated kidney damage compared to diabetic TG controls, with greater excretion of protein, albumin and ET-1, cortical expression of KIM-1 (respectively: 90±12 vs. 45±6 mg/day, 41±8 vs. 12±4 mg/day, 18±1 vs. 15±1 pg/day, 12±1 vs. 7±1 pg/mg prot; n=4- 6/group, p<0.05), and excessive kidney fibrosis, tubular dilation and cell death. Immunohistochemistry for the DC activation marker CD83 also demonstrated exaggerated activation of DCs in renal OM of diabetic ET
B
def rats. Expression of inflammasome genes in renal OM was assessed by RT-PCR array. Diabetes led to upregulation of NLRP5 (4-fold increase vs. TG controls; n=3/group; p<0.05) and IL-1β (~3-fold increase vs. TG controls; n=3/group; p<0.05) in OM of ET
B
def rats. In addition, PSTPIP1, a negative regulator of the inflammasome, was decreased in OM of diabetic ET
B
def rats vs. TG controls. Together, these results demonstrate that dysfunction of the ET
B
receptor leads to worsening of diabetic kidney injury and overactivation of the inflammasome and DCs specifically in the renal OM. These results highlight the protective role of ET
B
receptors against the development of diabetes- induced kidney inflammation and damage. Funded by NIH T32 DK007545 to CDM and P01 HL69999, P01HL136267, AHA SFRN 24450002 and U01HL117684 to DMP and JSP.
Abstract 003: Mrap2 Dissociate Mc4r-Mediated Sympathetic Control of Metabolism and Blood Pressure
Authors: Guo Deng-Fu , Bell Balyssa , Morgan Donald A , Cui Huxing , Sebag Julien A , Rahmouni Kamal
Published: December 2018

The brain melanocortin-4 receptor (MC4R) plays an important in the control of food intake and energy expenditure by increasing thermogenic sympathetic nerve activity (SNA). In addition, brain MC4R-mediated activation of SNA subserving cardiovascular organs such as the kidneys increase blood pressure. The melanocortin receptor accessory protein 2 (MRAP2) regulates the activity of the MC4R and other G-protein coupled receptors, but its specific role in MC4R-containing neurons is not clear

. We hypothesized that MRAP2 in MC4R neurons is essential for the regulation of SNA, energy homeostasis and blood pressure.

We generated mice (MRAP2
MC4R
) that lack MRAP2 in MC4R neurons by crossing MRAP2
fl/fl
mice with MC4R
Cre
mice and confirmed Cre recombinase activity in MC4R neurons using td-Tomato reporter mice. Interestingly, the MRAP2
MC4R
mice displayed obesity as indicated by the increased (p<0.05) body weight (males: 40.1±2.2 vs 32.9±0.9g in littermate controls, females: 28.6±2.8 vs 24.2±1.3g in controls at 16 weeks of age) and fat mass, but not lean mass. Weights of fat pads and liver were also significantly elevated in the MRAP2
MC4R
relative to littermate controls. Food intake was increased in the MRAP2
MC4R
mice relative to littermate controls (males: 4.7±0.3 vs 3.9±0.3g and females: 3.5±0.2 vs 2.8±0.2g). Glucose and insulin tolerance tests revealed impaired glucose tolerance and insulin-induced glucose clearance in MRAP2
MC4R
mice compared to littermate controls. Baseline brown adipose tissue (BAT) SNA tended to be lower in MRAP2
MC4R
mice relative to controls. Moreover, intracerebroventricular (icv) injection of MTII (MC4R agonist, 1 μg) increased BAT SNA in control mice (107±31%) but not in MRAP2
MC4R
mice (18±24%, p=0.02). On the other hand, icv the MTII (1 and 2 μg)-induced increase in renal SNA (p=0.2) and blood pressure (p=0.4) was not different in MRAP2
MC4R
(100±32% and 15±8mmHg, respectively) relative to controls (74±24% and 12±6mmHg). These findings support a critical role for MRAP2 in uncoupling neuronal MC4R-mediated control of regional sympathetic traffic impacting energy metabolism versus blood pressure.
Abstract 031: Thresholds for Defining Home Blood Pressure Elevation Among US adults
Authors: Lodhi Hamza , Ayers Colby , Das Sandeep , Berry Jarett , Khera Amit , Victor Ronald , Li Feng-Chang , Viera Anthony , Yano Yuichiro , de Lemos James , Vongpatanasin Wanpen
Published: December 2018

Background:
Most hypertension guidelines have recommended lower home than clinic BP thresholds based on epidemiological studies conducted in non-US populations. However, diagnostic thresholds to define home BP elevation have never been determined in the general population in the United States.

Methods:
We analyzed data from 2 US cohorts with home and clinic BP data in the same participants, the Dallas Heart Study (DHS, n=5,768) and the North Carolina Masked Hypertension study (NCMH, n = 420). Home BP thresholds for stage 1 (BP ≥ 130/80 mmHg) and stage 2 hypertension (BP ≥ 140/90 mmHg) were identified using a regression-based approach in both cohorts and an outcome-derived approach in the DHS cohort. The composite of all-cause mortality or a cardiovascular disease (CVD) event was used in the outcome-derived approach. For this approach, BP thresholds were identified only for systolic BP (SBP) as clinic diastolic BP (DBP) was not associated with the outcome.

Results:
Among untreated participants in DHS, the regression-derived thresholds for home BP corresponding to clinic BP for stage 1 and stage 2 hypertension were 130/81 and 137/88 mmHg in blacks and 127/79 and 135/86 mmHg in nonblacks, respectively. The results are virtually identical in the NCMH cohort. The 11-year composite CVD and mortality events corresponding to stage 1 (clinic SBP ≥ 130) and stage 2 (clinic SBP ≥ 140 mmHg) were higher in untreated blacks than untreated non-blacks [13.3 (11.06-15.54) and 17.59 (14.8-20.37)% vs. 6.78 (5.17-8.39) and 9.86 (6.94-12.77)%, respectively]. Using a race/ethnicity-specific composite outcome, the outcome-derived thresholds from the DHS for home SBP corresponding to stage 1 and stage 2

hypertension were 131 and 140 mmHg in untreated blacks and 130 and 139 mmHg in untreated nonblacks, respectively.

Conclusions:
Based on the regression-derived approach, we found home BP thresholds for stage 1 and 2 hypertension from both cohorts to be similar to the current ACC/AHA guidelines. The outcome-derived approach also identified similar home SBP thresholds for stage 1 hypertension but slightly higher home SBP thresholds for stage 2 hypertension than recommended guidelines.
Abstract 033: Identification of s Primary Renal AT
2
Receptor Defect in Spontaneously Hypertensive Rats (SHR)
Authors: Howell Nancy L , Kemp Brandon A , Keller Susanna R , Gildea John J , Shao Weijian , Navar L. G , Carey Robert M
Published: December 2018

Angiotensin III (Ang III) [des-aspartyl
1
-Ang II] is the predominant endogenous agonist for angiotensin type-2 receptor (AT
2
R)-induced natriuresis in rats. Hypertensive 12 wk-old SHR lack natriuretic responses to Ang III, and renal interstitial (RI) Ang III administration induces natriuresis in 4 wk-old Wistar-Kyoto rats (WKY), but not in 4 wk-old pre-hypertensive SHR. The defect in natriuresis could be explained by the concurrent observation that in WKY, but not SHR, Ang III induced AT
2
R translocation to renal proximal tubule apical plasma membranes and internalization/inactivation of Na
+
-transporters Na
+
- H
+
exchanger-3 (NHE-3) and Na
+
/K
+
ATPase (NKA). These findings suggest an Ang III/AT
2
R signaling defect in pre-hypertensive SHR. The present study sought to determine the cause of the defect: (1) accelerated intrarenal Ang III metabolism or (2) a primary AT
2
R (or post-receptor) signaling defect. Selective AT
2
R agonist Compound-21 (C-21) was infused interstitially [20, 40 and 60 ng/kg/min, each dose for 30 min] into experimental (left) kidneys of 4 wk-old WKY and SHR (N=7) pretreated for 24h with systemic infusion of Ang type-1 receptor (AT
1
R) antagonist candesartan (0.01 mg/kg/min by osmotic minipump); vehicle was infused into control (right) kidneys. Pre-infusion urinary Na
+
excretion (U
Na
V) was 0.022 ± 0.004 μmol/min in WKY and 0.024 ± 0.005 μmol/min in SHR (P=NS). In WKY, C-21 dose-dependently increased U
Na
V from 0.022 ± 0.004 to 0.058 ± 0.017, 0.078 ± 0.014 and 0.079 ± 0.079 μmol/min (P=0.01 from pre-infusion and time control kidneys). In contrast, SHR did not increase U
Na
V in response to C-21 [highest U
Na
V 0.033 ± 0.007 μmol/min (P=NS from pre-infusion and time control kidneys)]. Mean arterial pressure (MAP) was 64.6 ± 1.80 mmHg in WKY and 76.4 ± 2.2 mmHg (P<0.01) in SHR and did not change with C-21 or vehicle in WKY and SHR. In a separate set of 4 wk-old WKY and SHR (N=8), RI Ang II and III concentrations were measured by HPLC and ELISA assay. RI Ang II and Ang III levels, respectively, in WKY were 55 ± 20 and 59 ± 17 pg/ml (P=NS) and in SHR were 37 ± 7 and 181± 44 pg/ml (P=0.01 vs SHR Ang II; P<0.025 vs WKY Ang III). These findings exclude accelerated Ang III metabolism as a cause and identify a primary renal AT
2
R defect as responsible for increased Na
+
reabsorption in SHR.
Abstract 040: Vascular Dysfunction and Androgen Deficiency - Insights From Children With Hypospadias
Authors: Lucas-Herald Angela K , Alves-Lopes Rheure , Haddow Laura , O'Toole Stuart , Amjad Syed Basith , Flett Martyn , Steven Mairi , Lee Boma , Montezano Augusto C , Ahmed Syed Faisal , Touyz Rhian M
Published: December 2018

Background:
Hypospadias in boys may be associated with a lack of androgen exposure during the masculinisation programming window. As testosterone has effects on the vasculature, we assessed whether boys with hypospadias show any evidence of vascular dysfunction.

Methods:
Excess foreskin tissue was obtained from boys undergoing hypospadias repair (cases) or circumcision (controls) and small arteries dissected from this tissue. Vascular contractility was assessed by wire myography in response to U46619 (thromboxane A2 analogue). Vascular smooth muscle cells (VSMCs) were cultured and generation of reactive oxygen species (ROS) was measured by amplex red and chemiluminescence. NADPH oxidase (Nox) mRNA expression was measured by qPCR.

Results:
19 cases and 22 age-matched controls were enrolled in this study (median age 1.9 (range 1.3,12.2) years). There were no differences in clinical cardiometabolic or biochemical parameters between the cases and controls. Arteries from cases demonstrated increased constriction to U46619 compared to controls (Emax 175.6 vs 66.3 p<0.001), an effect inhibited by the ROS scavenger N-acetylcysteine (NAC). VSMC superoxide anion (5.3 fold) production and H
2
0
2
(3.3 fold) levels were increased in cases compared to controls (p<0.05). Expression of Nox5, a major ROS-generating oxidase in vascular cells, was increased in cases (2.6 fold,p<0.05). Exposure of vessels to testosterone increased vasoconstriction to U46619 (Emax 66.3 to 124.6 p<0.001) in controls, but not in cases. Incubation with NAC abolished the testosterone-induced vascular effects. Vascular hypercontractility in boys with hypospadias was associated with reduced endothelium-dependent and -independent vasorelaxation, compared with controls.

Conclusions:
These novel data, from a unique cohort of patients, demonstrate that small arteries from boys with hypospadias exhibit increased vascular contractility and decreased vasorelaxation with associated increased Nox-derived ROS generation. The functional significance of vascular dysfunction in these boys is unclear but may play a role in immediate surgical outcome as well as altered long-term cardiovascular risk.
Abstract 043: Targeting the Angiotensin Type 2 Receptor With Relaxin Confers Protection Against Renal Fibrosis and Vascular Dysfunction in Female Stroke Prone-Spontaneously Hypertensive Rats
Authors: Barsha Giannie , Kwok Edmund , Mirabito Colafella Katrina M , Hilliard Lucinda M , Gaspari Tracey , Widdop Robert E , Samuel Chrishan S , Denton Katherine M
Published: December 2018

The angiotensin type 2 receptor (AT
2
R) mediates cardiovascular and renal protection in females of reproductive age, a mechanism that is lost with advancing age. Recently, we demonstrated that the nitric oxide-promoting and transforming growth factor-β1 inhibitory actions of relaxin (RLX) involve an interaction between the relaxin-insulin like family peptide receptor 1 (RXFP1) and the AT
2
R. In the present study, we aimed to determine whether RLX induces cardio-renal protection and slows the progression of end-organ damage, via an AT
2
R-dependent mechanism. In female stroke prone-spontaneously hypertensive rats (SP-SHR) at 6 (young) and 14-15 (aged reproductively senescent) months of age arterial pressure, cardiac function, glomerular filtration rate (GFR) and proteinuria were measured before and after 4 weeks of treatment with vehicle (sodium acetate s.c.), RLX (serelaxin; 0.5mg/kg/day s.c.) or RLX+PD123319 (AT
2
R antagonist; 3mg/kg/day s.c). In addition, aortic endothelium-dependent relaxation in response to acetylcholine was assessed and cardiac and renal tissues were histologically analyzed for fibrosis. An age-related decline in GFR and increases in arterial pressure, proteinuria and cardiac and renal fibrosis were observed (all P<0.05; n=4-8). RLX treatment had no significant effect on these variables in the aged group. However, in aged animals, RLX markedly improved endothelial function (~30% increase in maximal vasodilation as compared to vehicle counterparts, P=0.0002; n=4-6). This effect was partially reversed by co-infusion with PD123319, relative to RLX alone (~14% reduced maximal vasodilation, P=0.03; n=6). In young females, RLX+PD123319 as compared to RLX treatment alone, exacerbated glomerular (11.6±1.2% vs 8.5±0.7%, respectively, P=0.04) and tubulointerstitial (3.3±0.2% vs 1.6±0.2%, respectively, P=0.0002) fibrosis. In conclusion, the cardio-renal protective actions of relaxin are dependent in part, upon an interaction with the AT
2
R. Thus, targeting the RXFP1-AT
2
R axis may be a therapeutic option for the treatment of cardiovascular disease and associated end-organ damage in hypertensive women.
Abstract 052: Role of Dopamine D2 Receptors in The Regulation of Cell Proliferation in Renal Injury
Authors: Kumar Megha , Asico Laureano , Konkalmatt Prasad , Freyberg Zach , Jose Pedro A , Armando Ines
Published: December 2018

The dopamine D2 receptor (D2R) in the kidney has a direct and significant role in blood pressure (BP) control and in negatively regulating the mechanisms involved in the development of inflammation and injury. Impaired D2R function results in renal inflammation and end organ damage. Injury to the kidney triggers a cell proliferation response that can be adaptive, leading to repair of the tubular epithelium, or maladaptive, leading to fibrosis and chronic kidney disease. We investigated the role of renal D2Rs in the cell proliferation response in models of renal injury in mice and human renal proximal tubule cells (hRPTCs). Renal selective silencing of the D2R in mice resulted in an increase in the mRNA expression of the proliferation marker Ki-67 (2.8±0.8 vs 1.0±0.1 fold; qRT-PCR; P<0.05; n=4-5) along with an increase in the number of proliferating cells in renal cortical slices determined by nuclear Ki-67 staining (36±3 vs 6±1; positive cells/ field; P<0.05) in comparison with mice with no silencing. Rescue of D2R function in these mice by the ureteral infusion of AAV carrying a D2R vector reduced the expression of cortical Ki-67 mRNA (42±3 vs 100±5 %; P<0.05; n=4) and the number of positive cells/field (16±2 vs 32±5; P<0.05) in comparison with mice treated with a control AAV. In mice subjected to renal ischemia reperfusion KI-67 mRNA expression was higher (1.5±0.03 vs 1.0±0.05 fold; P<0.05; n=3-4) than in mice with sham operation. Treatment with AAV carrying D2R after ischemic injury reduced Ki-67 expression (0.65±0.05 vs 1±0.1; P<0.05) and the number of Ki-67 positive cells in kidney sections. Rescue of function or D2R overexpression reduced tissue damage, fibrosis and the increase in BP in these models. Treatment of hRPTCs with the nephrotoxic, aristolochic acid (5 μg/ml, 24h), increased mRNA Ki-67 expression (2.8±0.2 fold; P<0.05) in comparison with cells treated with vehicle while the presence in the medium of a D2R agonist, quinpirole (1μM, 24h), reduced the increase by 42%. The D2R agonist also reduced the increase in fibronectin 1 and collagen 1a1 elicited by aristolochic acid. Our data suggest that regulation of cell proliferation is one of the mechanisms involved in the protective effect of D2R function on renal inflammation and injury.
Abstract 053: Dietary Sodium Restriction versus Diuretics for Salt-Sensitive Hypertension in Chronic Kidney Disease
Authors: Bovée Dominique M , Danser Alexander H , Zietse Robert , Hoorn Ewout J
Published: December 2018

Fluid overload and salt-sensitive hypertension are hallmarks of advanced chronic kidney disease (CKD) and associated with worse outcomes. Dietary sodium (Na
+
) restriction is an accepted intervention, but long-term adherence remains a challenge. Distal diuretics could provide an alternative approach, but they are considered less effective in advanced CKD. Here, we compared both approaches head-to-head.

Methods:
Twenty-six patients with CKD stage 3 or 4 and hypertension were included in this single-center, open-label, randomized cross-over trial (baseline eGFR 39 ± 13 ml/min/1.73 m
2
). Renin-angiotensin inhibitors and diuretics were discontinued 2 weeks prior to interventions and during study period. Subsequently, we compared dietary Na
+
restriction (60 mmol/day) versus amiloride/hydrochlorothiazide (5/50 mg once daily). Both interventions lasted for two weeks and were separated by a 2-week wash-out period. The primary endpoint was 24h systolic blood pressure (SBP).

Results:
Urinary Na
+
excretion was successfully lowered with dietary Na
+
restriction (160 ± 66 to 64 ± 37 mmol/day,
p
< 0.01), and remained similar with diuretics (154 ± 47 to 153 ± 63 mmol/day,
p
= 0.95). Dietary Na
+
restriction lowered 24-hour SBP (134 ± 12 to 129 ± 14 mmHg,
p
< 0.05), while diuretics had a greater effect (138 ± 12 to 124 ± 13 mmHg,
p
< 0.01 for within and between interventions). Both maneuvers significantly lowered indices of fluid overload, including body weight (-1.6 ± 1.1 kg with dietary Na
+
restriction and -1.9 ± 1.5 kg with diuretics), NT-pro-BNP (median -10 and -7 pmol/L), and overhydration as assessed by bioimpedance (-0.6 ± 0.6 and -1.3 ± 0.7 L). Both interventions also lowered eGFR (-2 ± 4 and -5 ± 5 ml/min/1.73 m
2
, p<0.05 for both) and showed a trend towards albuminuria reduction (median -5 mg/day and -20 mg/day). The reduction in overhydration and eGFR was greater with diuretics than with dietary Na
+
restriction (
p
< 0.05).

Conclusions:
Distal diuretics and dietary Na
+
restriction effectively lower blood pressure in CKD 3 and 4 in the absence of renin-angiotensin inhibitors. Both interventions also lower indices of fluid overload. Diuretics produce greater effects than dietary Na
+
restriction. These beneficial effects may outweigh the (hemodynamic) reduction in eGFR.
Abstract 056: Knockout of Dual-Specificity Protein Phosphatase 5 Protects Against Hypertension Induced Chronic Kidney Disease
Authors: Zhang Chao , He Xiaochen , Wang Shaoxun , Roman Richard J , Booz George , Fan Fan
Published: December 2018

Dual-specificity protein phosphatase 5 (Dusp5) is a member of serine-threonine phosphatase family that regulates intracellular signal transduction by dephosphorylating ERK1/2. We previously generated Dusp5 zinc-finger knockout (KO) rats and found that KO of Dusp5 enhances myogenic response of middle cerebral artery and autoregulation of cerebral blood flow. This study investigated whether Dusp5 KO also improves renal hemodynamics and protects against hypertension-induced chronic kidney disease (CKD). Renal tissue expression of Dusp5 was decreased and levels of phosphorylated ERK1/2 (p-ERK1/2) and p-PKC enhanced in KO rats. Blood pressure increased similarly to 180 mmHg in both WT and Dusp5 KO rats treated with DOCA/salt. KO of Dusp5 enhanced autoregulation of renal blood flow (RBF increased by 12.1 ± 4.1% vs. 32.7 ± 4.7% when MAP increased from 100 to 180 mmHg, p<0.05) and reduced renal vascular remodeling compared with WT rats (0.64±0.03 vs. 0.94±0.06 wall-to-lumen ratio, p<0.05). Improvement in renal hemodynamics in hypertensive Dusp5 KO vs. WT rats was associated with decreased proteinuria (226.71 ± 23.82 vs. 337.62 ± 30.41 mg/day, p<0.05) and protein cast formation in the renal corticomedullary region (1.01 ± 0.17% vs. 2.4 ± 0.51%, p<0.05). The degree of glomerular injury was reduced (2.22 ± 0.04 vs. 3.12 ± 0.04, p<0.05) and nephrin expression was greater in hypertensive Dusp5 KO rats vs. WT rats. Hypertension-induced renal fibrosis was attenuated in Dusp5 KO rats (5.32 ± 0.6% vs. 9.90 ± 0.7%, p<0.01) in association with decreased MCP-1 expression, reduced ED-1
+
macrophage infiltration, down-regulated TGF-β1 expression, and attenuated fibrosis-related epithelial-mesenchymal transition (EMT) in the kidney (decreased expression of α-SMA and vimentin, and increased expression of E-cadherin). In conclusion, these results indicate that KO of Dusp5 protects against hypertension-induced proteinuria and renal fibrosis by enhancing renal hemodynamics and reducing vascular remodeling, glomerular injury, macrophage infiltration, TGF-β1 expression and EMT in the kidney. Thus, targeting Dusp5 may offer a novel approach for treating or preventing hypertension-induced CKD.
Abstract 062: Renal Hydrogen Peroxide Prevents Salt-Sensitive Hypertension
Authors: Cuevas Santiago , Asico Laureano D , Jose Pedro A , Konkalmatt Prasad R
Published: December 2018

C57Bl/6 and BALB/c are different in the sensitivity of their blood pressure (BP) to NaCl. High NaCl diet increases BP in C57Bl/6J but not BALB/c mice. However, C57Bl/6J mice are less prone to hypertension-induced renal injury than other mouse strains. The goal of this study was to determine the role of H
2
O
2
in salt-sensitive hypertension. Basal renal levels of reactive oxygen species, including H
2
O
2,
were higher in BALB/c renal proximal tubule cells (RPTC-BALB/c) than RPTCs from C57Bl/6J mice (RPTC-C57Bl/6J) (60.8 ± 5 % vs 41.8 ± 12 %, n=8, P<0.03). Incubation media with 170 mM NaCl (HS) increased H
2
O
2
production in RPTC-BALB/c but not in RPTC-C57Bl/6J, compared with RPTCs incubated in low (90 mM) or normal (145 mM) NaCl (+68±43%, 90 vs 170 mM, n=7, P<0.05). H
2
O
2
(10 μM) treatment of the basolateral side of RPTC-BALB/c in Transwells increased intracellular Na
+
1.62-fold that of vehicle-treated cells (n=4, P<0.05). Over-expression of catalase, abrogated the H
2
O
2
-induced increase in intracellular Na
+
in RPTC-BALB/c. Over-expression of catalase in the kidneys of BALB/c mice on normal (0.9%) NaCl diet did not alter their SBP. However, on high (4%) NaCl diet, SBP was increased in catalase over-expressing mice, relative to vehicle-treated controls (98±1.1 vs 112±1.4 mm Hg, n=3, P<0.05). Decreasing H
2
O
2
by overexpression of catalase predisposes BALB/c mice to salt-sensitive hypertension, suggesting that high salt-induced H
2
O
2
negatively regulates renal sodium transport and provides resistance to salt-induced hypertension.
Abstract 067: Mechanism of Action of 8-Aminoguanine on Renal Excretory Function
Authors: Jackson Edwin K , Mi Zaichuan , Kleyman Thomas R , Cheng Dongmei
Published: December 2018

The endogenous purines 8-aminoguanosine and 8-aminoguanine (8-AG) are K
+
-sparing natriuretics that increase glucose excretion and attenuate salt-induced hypertension. Most effects of 8-aminoguanosine are not direct, but require conversion in the systemic circulation to 8-AG (i.e., 8-aminoguanosine is a prodrug/prohormone). However, the mechanism of action by which 8-AG affects renal excretory function is unknown and is the subject of this investigation. Because 8-AG has structural similarities with inhibitors of epithelial Na
+
channels (ENaC), Na
+
/H
+
exchangers (NHE), and adenosine A
1
receptors, we examined the effects of 8-AG on amiloride-sensitive ENaC activity in mouse collecting duct cells, on intracellular pH of human renal proximal tubule epithelial cells, and on in vivo (in rats) pharmacological responses to 2-chloro-N
6
-cyclopentyladenosine (A
1
-receptor agonist). 8-AG did not block ENaC, NHE, or A
1
receptors. Because Rac1 enhances activity of mineralocorticoid receptors and some guanosine analogues inhibit Rac1, we examined the effects of 8-AG on Rac1 activity in mouse collecting duct cells. Rac1 activity was significantly (
P
=0.024) inhibited by 8-AG (30 μM; from 2.5 ± 0.7 to 1.7 ± 0.7 arbitrary units). Because 8-AG is an inhibitor of purine nucleoside phosphorylase (PNPase; metabolizes inosine to hypoxanthine and guanosine to guanine), we compared the renal effects (in rats) of approximately equipotent intravenous doses of 8-AG (33.5 μmol/kg) vs. 9-deazaguanine (9-DG; 67 μmol/kg; PNPase inhibitor). 8-AG and 9-DG induced similar increases in urinary Na
+
(μmol/30 min; 8-AG, from 4.4 ± 2.0 to 38 ± 17; 9-DG, from 5.6 ± 3.3 to 34 ± 8.6) and glucose (μg/30 min; 8-AG, from 31 ± 17 to 225 ± 77; 9-DG, from 6.9 ± 3.9 to 144 ± 81) excretion. Intravenous 8-AG increased urinary excretion of guanosine and inosine (PNPase substrates), yet decreased excretion of guanine and hypoxanthine (PNPase products). 8-AG reduced K
+
excretion (μmol/30 min; 8-AG, from 29 ± 6.6 to 5.4 ± 1.7) whereas 9-DG did not. However, the Rac1 inhibitor Nsc23766 (9.4 μmol/kg) mimicked the effects of 8-AG on K
+
excretion (μmol/30 min; from 40 ± 7.1 to 18 ± 6.5). Conclusion: Likely 8-AG increases Na
+
and glucose excretion by blocking PNPase and decreases K
+
excretion by inhibiting Rac1.
Abstract 076: All Cause Mortality is Higher for Patients Who Have Bigger Blood Pressure Drops on Antihypertensive Therapy
Authors: Kostis John B , Lin Chun Pang , Cabrera Javier , Blickstein Daniel , Cosgrove Nora M , Kostis William J
Published: December 2018

Objectives:
In the Systolic Blood Pressure Intervention Trial (SPRINT) patients were randomized to the intensive blood pressure group targeting systolic blood pressure (SBP) less than 120 mm Hg or to the standard group targeting SBP less than 140 mm Hg. Here we present data on the effect of SBP drop between randomization and after 3 months of treatment in 8919 patients.

Methods:
We evaluated the association of SBP drop (SBP at randomization minus SBP after 3 months of treatment) on all-cause mortality until the end of the study (approximately 1090 days after the 3-month visit). Logistic regression of all-cause death as affected by the blood drop, age, gender, SBP at 3 months, diastolic BP at 3 months and randomization group was performed

Results:
Bigger SBP drop was associated with higher all-cause mortality (black line in the lower figure, p=0.0347) regardless of randomization to intensive (red) or standard (green) group and after adjustment for the other factors shown in the bottom figure. Mortality was associated with age (p>0.0001), male gender (p>0.0001), SBP at 3 months (p=0.0031), and randomization to intensive treatment (p=0.0269). In addition, patients receiving more than 1 drug were more likely to die (p=0.0179).

Conclusion:
In SPRINT, for a given achieved blood pressure patients with bigger SBP drop from baseline had higher all-cause mortality.