bluuebunny/crossref_metadata_2025 huggingface dataset:
Apathy in Alzheimer’s Disease Correlates with the Dopamine Transporter Level in the Caudate Nuclei
Authors: Udo Niki , Hashimoto Naoki , Toyonaga Takuya , Isoyama Tomoyuki , Oyanagi Yuka , Narita Hisashi , Shiga Tohru , Nakagawa Shin , Kusumi Ichiro
Published: September 2020

Introduction: Apathy is a common neuropsychiatric symptom in patients with Alzheimer’s disease (AD). The striatal binding potential (BP) of 123I-FP-CIT (N-δ-fluoropropyl-2β-carbomethoxy-3β-[4-iodophenyl]tropane) single-photon emission computed tomography (SPECT) is correlated with the degree of apathy in patients with Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). This study aimed to determine if dopaminergic activity in the basal ganglia is associated with the development of apathy in AD. Methods: Nineteen subjects with AD were included and underwent 123I-FP-CIT-SPECT. Patients with other types of dementia as a comorbidity, those taking antidepressants, and those with overt parkinsonism were excluded. Apathy was assessed using the Apathy Evaluation Scale Informant-Japanese version (AES-I-J). SPECT images were overlaid with images in striatal regions of interest (ROIs), and the SPECT values in these regions were counted. The relationship between BP values and AES-I-J scores was investigated using Spearman’s rank correlation coefficient. Results: Significant inverse correlations were observed between BP values and AES-I-J scores in the left caudate nucleus and there was a marginally significant inverse correlation in the right caudate nucleus. Conclusion: The pathological basis of apathy might be the impairment of the dopaminergic nervous system. Further studies on more subjects with AD, healthy controls, and patients with PD and DLB are needed.
Representation of Older Latinxs in Cohort Studies at the Rush Alzheimer’s Disease Center
Authors: Marquez David X. , Glover Crystal M. , Lamar Melissa , Leurgans Sue E. , Shah Raj C. , Barnes Lisa L. , Aggarwal Neelum T. , Buchman Aron S. , Bennett David A.
Published: September 2020

The Rush Alzheimer’s Disease Center (RADC) conducts 5 harmonized prospective clinical-pathologic cohort studies of aging – with 1 study, the Latino Core, focused exclusively on Latinxs, 2 studies consisting of mostly non-Latinx whites, and 2 studies of mostly non-Latinx blacks. This paper contextualizes the Latino Core within the other 4 harmonized RADC cohort studies. The overall aim of the paper is to provide information from the RADC, so that researchers can learn from our participants and procedures to better advance the science of Alzheimer’s disease and related dementias in Latinxs. We describe an annual clinical evaluation that assesses risk factors for Alzheimer’s dementia among older adults without known dementia at enrollment. As all RADC cohort studies offer brain donation as a part of research participation, we discuss our approach to brain donation and subsequent participant decision-making among older Latinxs. We also summarize baseline characteristics of older Latinxs across the 5 RADC cohort studies in relation to the baseline characteristics of non-Latinx blacks and non-Latinx whites. Finally, we outline challenges and considerations as well as potential next steps in cognitive aging research with older Latinxs.
Cell-Free DNA Testing: What Is the Reason Why High-Risk Women Choose It?
Authors: Benítez-Quintanilla Leticia , Pauta Montse , Matas Isabel , Madrigal Irene , Borrell Antoni
Published: September 2020

Objective: The aim of the study wasto describe the past medical history, sociodemographic, and pregnancy characteristics of women at high risk for aneuploidy and to determine which factors are related to her choice of cell-free DNA (cfDNA) testing instead of invasive diagnostic testing. Methods: We conducted a prospective descriptive study including pregnant women from the Western Barcelona public health area at high risk for fetal aneuploidy, defined as a trisomy 21 or 18 risk between 1/10 and 1/250 at the combined first-trimester or at the second-trimester biochemical screening. During 1 year (December 2018 to November 2019), these women were asked to fill in a confidential questionnaire about her past medical history, demographic and pregnancy characteristics, and her opinion about termination of the pregnancy after a counseling consultation with a maternal-fetal medicine specialist in which advantages and disadvantages of both testing methods, cfDNA or diagnostic testing, were discussed. Logistic regression analysis was used to determine which factors were related with cfDNA uptake. Results: During the study period, 82 pregnant women filled the questionnaire. The median maternal age was 39.6 years (interquartile range [IQR] 37.3–40.9 years), and 73 (89%) of them were 35 years or older. Forty-three (52%) women opted for cfDNA testing, while 39 (48%) chose invasive diagnosis. In a logistic regression analysis, the use of assisted reproductive techniques (OR 13.03; 95% CI: 1.47–115.56; p = 0.021) and Latin American origin (OR 6.66; 95% CI 1.73–25.66; p = 0.006) were shown to be related to a higher cfDNA uptake. In contrast, nonreligious women (OR 0.21; 95% CI: 0.06–0.72; p = 0.013) and a favorable opinion about termination of pregnancy (OR 0.23; 95% CI: 0.06–0.92; p = 0.037) were related with a lower uptake. Conclusion: Half of the pregnant women at high risk for fetal aneuploidy opted for cfDNA testing. The main reason to choose cfDNA was avoiding the risk of pregnancy loss. Women using assisted reproductive techniques and those of Latin American origin preferred cfDNA testing, while nonreligious women and those with a favorable opinion on termination pregnancy preferred invasive testing.
The Potential of Immersive Virtual Reality for Cognitive Training in Elderly
Authors: Bauer Anna Cornelia Maria , Andringa Gerda
Published: September 2020

The number of elderly is growing rapidly, including those that struggle with cognitive decline and, consequently, activities of daily living. Developing interventions that slow down cognitive decline would greatly benefit the autonomy of these elderly, as well as their caretakers. Virtual reality (VR) is an immersive and interactive human-computer interface with real-time simulation that is suggested to be a promising tool to improve cognitive functioning. This literature review discusses the features of immersive VR, including its opportunities and limitations, that are of special relevance for improving cognition in elderly. First, the high flexibility of VR allows for personalized and safe training of potentially harmful situations and isolated aspects of tasks. Second, VR’s dynamic and real-time feedback on performance provides a labor-extensive tool for caretakers in elderly care. Third, the acquisition of high resolution data enables the exposure of subtle changes over time, relevant for detecting the nature and extent of cognitive changes in elderly, including those with dementia. Fourth, immersive VR has been related to cybersickness. Finally, VR is immersive and enables the perception and expression of emotions, motor behaviors, and multiple senses. Aged subjects are found to have sparing of emotional learning and show increased reliance on multisensory integration for learning. Moreover, they experience high levels of flow, motivation, and presence in VR setups. Despite the clear potential of immersive VR, the studies available are small scale and have not been replicated. The digital illiteracy of elderly and healthcare personnel form an additional barrier for implementation. Hence, while replication of outcomes and standardization of VR interventions is required before it can be used in standard care, VR may provide a particularly effective tool for training cognition in elderly.
Trigeminal Neuralgia Secondary to Meningiomas and Vestibular Schwannoma Is Improved after Stereotactic Radiosurgery: A Systematic Review and Meta-Analysis
Authors: Peciu-Florianu Iulia , Régis Jean , Levivier Marc , Dedeciusova Michaela , Reyns Nicolas , Tuleasca Constantin
Published: September 2020

Introduction: Trigeminal neuralgia (TN) secondary to tumors is encountered in up to 6% of patients with facial pain syndromes and is considered to be associated with tumors affecting the trigeminal nerve pathways. The most frequent are meningiomas and vestibular schwannomas (VS). Stereotactic radiosurgery (SRS) has emerged as a valuable treatment, with heterogeneity of clinical results. We sought to review the medical literature on TN treated with SRS for meningiomas and VS and investigate the rates of improvement of TN symptoms. Methods: We reviewed articles published between January 1990 and December 2019 in PubMed. Pain relief after SRS, the maintenance of pain relief, and TN recurrence and complications were evaluated with separate meta-analyses, taking into account the data on individual patients. Results: Pain relief after SRS was reported as Barrow Neurological Institute (BNI) pain intensity scores of BNI I in 50.5% (range 36–65.1%) of patients and BNI I–IIIb in 83.8% (range 77.8–89.8%). There was no significant difference in series discussing outcomes for tumor targeting versus tumor and nerve targeting. Recurrences were described in 34.7% (range 21.7–47.6; tumor targeting). Maintenance of BNI I was reported in 36.4% (range 20.1–52.7) and BNI I–IIIb in 41.2% (range 29.8–52.7; tumor targeting series). When both the nerve and the tumor were targeted, only 1 series reported 86.7% with BNI I–IIIb at last follow-up. Complications were encountered in 12.6% (range 6.3–18.8; tumor targeting series) of patients; however, they were much higher, as high as 26.7%, in the only study reporting them after targeting both the nerve and the tumor. The most common complication was facial numbness. Conclusion: SRS for TNB secondary to benign tumors, such as meningiomas and VS, is associated with favorable clinical course, but less favorable than in idiopathic TN. There was, however, heterogeneity among reports and targeting approaches. Although targeting both the nerve and the tumor seemed to achieve better long-term results, the rate of complications was much higher and the number of patients treated was limited. Future clinical studies should focus on the standard reporting of clinical outcomes and randomization of targeting methods.
Can Psychological Resilience Protect the Mental Health of Healthcare Professionals during the COVID-19 Pandemic Period?
Authors: Bahar Aynur , Koçak Hatice Serap , Samancıoğlu Bağlama Sevgin , Çuhadar Döndü
Published: September 2020

It is important to protect the mental health of healthcare employees who are facing the difficult experience of a pandemic. There are proofs indicating that the state of mental well-being is related with the levels of psychological resilience. It may be important for reducing the psychological issues and emotions of burnout in healthcare professionals by increasing their psychological resilience levels during this process in which disease anxiety and fear of death develop. The purpose of this review study was to attract attention to the mental issues and psychological resilience of healthcare professionals who have the closest contact with the patients.
Referral Criteria to Palliative Care for Patients With Heart Failure
Authors: Chang Yuchieh Kathryn , Kaplan Holland , Geng Yimin , Mo Li , Philip Jennifer , Collins Anna , Allen Larry A. , McClung John A. , Denvir Martin A. , Hui David
Published: September 2020

Background:

Patients with heart failure have significant symptom burden, care needs, and often a progressive course to end-stage disease. Palliative care referrals may be helpful but it is currently unclear when patients should be referred and by whom. We conducted a systematic review of the literature to examine referral criteria for palliative care among patients with heart failure.

Methods:

We searched Ovid, MEDLINE, Ovid Embase, and PubMed databases for articles in the English language from the inception of databases to January 17, 2019 related to palliative care referral in patients with heart failure. Two investigators independently reviewed each citation for inclusion and then extracted the referral criteria. Referral criteria were then categorized thematically.

Results:

Of the 1199 citations in our initial search, 102 articles were included in the final sample. We identified 18 categories of referral criteria, including 7 needs-based criteria and 10 disease-based criteria. The most commonly discussed criterion was physical or emotional symptoms (n=51 [50%]), followed by cardiac stage (n=46 [45%]), hospital utilization (n=38 [37%]), prognosis (n=37 [36%]), and advanced cardiac therapies (n=36 [35%]). Under cardiac stage, 31 (30%) articles suggested New York Heart Association functional class ≥III and 12 (12%) recommended New York Heart Association class ≥IV as cutoffs for referral. Prognosis of ≤1 year was mentioned in 21 (21%) articles as a potential trigger; few other criteria had specific cutoffs.

Conclusions:

This systematic review highlighted the lack of consensus regarding referral criteria for the involvement of palliative care in patients with heart failure. Further research is needed to identify appropriate and timely triggers for palliative care referral.
CD4
+
T-Cell Endogenous Cystathionine γ Lyase–Hydrogen Sulfide Attenuates Hypertension by Sulfhydrating Liver Kinase B1 to Promote T Regulatory Cell Differentiation and Proliferation
Authors: Cui Changting , Fan Jinghui , Zeng Qiang , Cai Junyan , Chen Yongzeng , Chen Zhenzhen , Wang Wenjie , Li Shuang yue , Cui Qinghua , Yang Jichun , Tang Chaoshu , Xu Guoheng , Cai Jun , Geng Bin
Published: September 2020

Background:

Hydrogen sulfide (H
2
S) has antihypertension and anti-inflammatory effects, and its endogenous-generation key enzyme cystathionine γ lyase (CSE) is expressed in CD4
+
T cells. However, the role of CD4
+
T-cell endogenous CSE/H
2
S in the development of hypertension is unclear.

Methods:

Peripheral blood lymphocytes were isolated from hypertensive patients or spontaneously hypertensive rats, then H
2
S production and expression of its generation enzymes, cystathionine β synthase and CSE, were measured to determine the major H
2
S generation system changes in hypertension. Mice with CSE-specific knockout in T cells (conditional knockout, by CD4
cre
mice hybridization) and CD4 null mice were generated for investigating the pathophysiological relevance of the CSE/H
2
S system.

Results:

In lymphocytes, H
2
S from CSE, but not cystathionine β synthase, responded to blood pressure changes, supported by lymphocyte CSE protein changes and a negative correlation between H
2
S production with systolic blood pressure and diastolic blood pressure, but positive correlation with the serum level of interleukin 10 (an anti-inflammatory cytokine). Deletion of CSE in T cells elevated BP (5–8 mm Hg) under the physiological condition and exacerbated angiotensin II–induced hypertension. In keeping with hypertension, mesenteric artery dilation impaired association with arterial inflammation, an effect attributed to reduced immunoinhibitory T regulatory cell (Treg) numbers in the blood and kidney, thus causing excess CD4
+
and CD8
+
T cell infiltration in perivascular adipose tissues and kidney. CSE knockout CD4
+
T cell transfer into CD4 null mice, also showed the similar phenotypes’ confirming the role of endogenous CSE/H
2
S action. Adoptive transfer of Tregs (to conditional knockout mice) reversed hypertension, vascular relaxation impairment, and immunocyte infiltration, which confirmed that conditional knockout–induced hypertension was attributable, in part, to the reduced Treg numbers. Mechanistically, endogenous CSE/H
2
S promoted Treg differentiation and proliferation by activating AMP-activated protein kinase. In part, it depended on activation of its upstream kinase, liver kinase B1, by sulfhydration to facilitate its substrate binding and phosphorylation.

Conclusion:

The constitutive sulfhydration of liver kinase B1 by CSE-derived H
2
S activates its target kinase, AMP-activated protein kinase, and promotes Treg differentiation and proliferation, which attenuates the vascular and renal immune-inflammation, thereby preventing hypertension.
Abstract 12: The Etiology Of Inverse Salt Sensitivity Of Blood Pressure: Mirna-485-5p Binds To The Dopamine Type 2 Receptor (d
2
R) Snp Rs6276 And Decreases D
2
R Expression
Authors: Gildea John J , Xu Peng , Schiermeyer Katherine , Yue Wei , Carey Robert M , Jose Pedro A , Felder Robin A
Published: September 2020

Inverse salt sensitivity is the paradoxical increase in blood pressure of individuals to a low sodium diet. rs6276, a single nucleotide polymorphism found in the 3’ untranslated region of the D2R gene (DRD2), which is associated with decreased expression and is also associated with the inverse salt sensitive phenotype (ISS). Urine derived renal proximal tubule cells grown from ISS participants with homozygous rs6276 SNPs vs salt resistant (SR) wild type for rs6276 SNPs have decreased expression of D2R as measured by receptor binding studies using BodipyFL-Spiperone (100 nM for 2 hrs, -36.9% ± 2.6% reduction in ISS-10 vs SR-6, n=5, p<0.01). miRNA-485-5p potentially binds to the rs6276 SNP in the 3’ UTR site and therefore could be a member of a newly identified classification of SNPs called miRSNPs. We transfected a miRNA-485-5p miRNA mimic and a miRNA blocker (20 nM for 72 hrs) to determine the effect on D2R expression on both wild type and homozygous variant SNP participant cell lines. Transfection of mir-485-5p only alters the expression of D2R in the ISS cell lines with SNPs (52619 ± 2001 RFU ISS control miRNA vs 69496 ± 2108 RFU ISS-10 miRNA blocker and vs 30434 ± 1824 RFU ISS-10 miRNA mimic, n=9, p<0.01, one-way ANOVA). The miRNA-485-5p blocker was able to return the D2R expression levels back to levels found in SR cells. Further studies are necessary to determine if the miRNA-485-5p mimic enhances and miRNA-485-5p blocker reverses any of the ISS cell phenotypes identified.
Abstract 5: White Coat Hypertension Stability In Children And Adolescents: Pediatric Nephrology Research Consortium Study
Authors: Miyashita Yosuke , HANEVOLD Coral , Faino Anna , Scher Julia , Lande Marc B , Yamaguchi Ikuyo , Hernandez Joel , Acosta Alisa , Weaver Donald J , Thomas Jason , Kallash Mahmoud , Ferguson Michael A , Patel Ketan N , South Andrew , Kelton Megan , Flynn Joseph T
Published: September 2020

There is no pediatric data on whether white coat hypertension (WCH) is a precursor of sustained HTN. The objective of this study was to determine diagnosis changes on follow-up ambulatory blood pressure monitoring (ABPM) in children and adolescents diagnosed with WCH on their initial ABPM and to assess for predictive factors of progression to HTN. Retrospective review was conducted at 11 centers to identify patients with WCH diagnosed by ABPM and had repeat ABPM at least 6 months after the first study. Subjects with secondary HTN, on antihypertensive medication, and diabetes mellitus were excluded. Patients with ADHD were included in the study if medications were stable. Chart review included associated risk factors such as BMI, obstructive sleep apnea, and family history of HTN. ABPM phenotype was determined using the 2014 AHA guidelines. The association between abnormal ABPM diagnosis on follow-up and ABPM index and blood pressure load variables was assessed using univariable generalized linear mixed effect models. Significant ABPM index and load variables (based on p < 0.15) were subsequently added to a multivariable model with the following pre-specified covariates: gender, family history of HTN, age, BMI z-score, ADHD, and interval time between ABPMs. One hundred and one patients met criteria for inclusion with a median age of 14 years (80% males) and median interval time of 14 months (range: 6 – 55 months). On follow-up ABPM, 18% and 32% of patients demonstrated HTN and prehypertension respectively (18 and 32 of 101, respectively). In univariable modeling, awake and nocturnal systolic BP index ≥ 0.9 on the first ABPM were found to be significantly associated with progression to abnormal ABPM [unadjusted OR (95% CI) awake: 4.3 (1.2 – 14.6); nocturnal: 3.2 (1.0 – 10.1)]; however, these associations were not significant after adjusting for pre-specified covariates [adjusted OR (95% CI) awake: 2.7 (0.7-10.4); nocturnal: 2.6 (0.7 – 9.2)]. Approximately half of children and adolescents first diagnosed with WCH progressed to an abnormal ABPM phenotype on follow-up, suggesting that longitudinal follow-up with ABPM is indicated in pediatric WCH patients. We were unable to identify ABPM findings that might predict a higher risk for progression.
Abstract MP02: Sox6 Ablation In Renin Expressing Cells Protects Mice Against Hypertension And Kidney Injury
Authors: Saleem Mohammad , Barturen Pierina , Saavedra Luz A , Gomez Jose A
Published: September 2020

Introduction:
The Renin angiotensin aldosterone system (RAAS) is implicated in renal artery stenosis (RAS) and renovascular hypertension. RAS or renal artery occlusion is an intractable problem affecting about 6% of people over 65 and up to 40% of the people with coronary or peripheral vascular disease in the United States. Renin being the rate limiting enzyme in RAAS is considered the key driver of RAS. The mechanism of renin regulation during RAS is still elusive and warrants further investigation. Here we studied the function of the transcription factor Sox6 in the renin regulation using a new knockout mouse model during RAS.

Methods:
We used a mouse model in which Sox6 is knockout specifically in renin expressing cells (Sox6 KO). Using these mice, we developed a modified 2-kidney 1-clip (2K1C) Goldblatt model to constrict right renal artery to induce RAS. Two weeks after surgery, renin, prorenin, prorenin receptor (PRR), and N-GAL expressions were measured using Western blot. Blood pressure was measured using tail-cuff method. Creatinine clearance was measured in urine using a colorimetric assay.

Results:
Comparing Sox6 KO with the Sox6 wild type littermates, we found that Sox6 KO mice exhibit lower expression of renin (0.36 vs. 0.45, SEM= 0.11 n= 11-15, P<0.01) and prorenin (1.25 vs. 2.07, SEM=0.30, n=11-15, P<0.05). Sox6 KO mice were protected against renovascular hypertension (SBP, 114.5 vs. 131.1, SEM=5.31 n=13-15, P<0.01), and kidney injury during RAS. Furthermore, we found that the levels of creatinine clearance were preserved in Sox6 KO mice compared to WT littermates (2372 vs. 1341, SEM=342.3, n=4-5, P<0.05) during RAS. The levels of the kidney injury marker N-GAL were significantly lower in KO mice compared to WT littermates (1.3 vs. 2.7, SEM=0.38, n=6-8, P<0.01). Similarly, PRR receptor expression were significantly lower in KO compared to WT (1.23 vs. 0.72, SEM=0.33, n=2-5, P<0.01) during RAS.

Conclusions:
Our results show that knocking out Sox6 in renin expressing cells inhibits renovascular hypertension, renin, prorenin, PRR, and N-GAL expression, and preserve creatinine clearance induced by RAS. These results suggest that Sox6 has a new function in hypertension and kidney injury induced by RAS.
Abstract MP03: Immunophenotyping A Heart Failure With Preserved Ejection Fraction (HFpEF) Mouse Model With Cellular Indexing Of Transcriptomes And Epitopes (CITE)-seq
Authors: Smart Charles D , Agrawal Vineet , Hemnes Anna R , Madhur Meena S
Published: September 2020

Deoxycorticosterone acetate (DOCA)-salt is a common hypertension model in mice and has recently been used to study heart failure with preserved ejection fraction (HFpEF) in rats. Our goal was to validate DOCA-salt as a mouse model of HFpEF and determine how DOCA-salt alters the cardiac immunological landscape to identify novel therapeutic targets for this disease. DOCA-salt mice underwent uninephrectomy, implantion of a DOCA pellet, and supplementation of the drinking water with 1% NaCl water for three weeks. Control mice underwent a sham procedure and received normal water. Compared to control mice, DOCA-salt mice exhibited elevated systolic BP, increased heart weight to body weight ratios (5.6 vs 7.1), increased lung wet to dry weight ratios (4.4 vs 4.8) indicative of pulmonary congestion, and decreased time to exhaustion upon treadmill exercise testing (23.0 vs. 18.5 seconds). On conscious echocardiography, DOCA-salt mice exhibited a preserved ejection fraction. Invasive hemodynamic studies revealed an increased tau constant (5.7 vs 8.2) and increased end-diastolic pressures in DOCA-salt mice (1.7 vs 2.6), consistent with diastolic dysfunction. CITE-seq, a novel technique to obtain transcriptomic and surface marker expression on single cells, was performed on a total of 4,359 and 7,600 cells sorted live CD45+ leukocytes from four sham and four DOCA-salt left ventricles, respectively. Unsupervised computational analysis revealed 29 clusters of immune cells. Six clusters containing natural killer, T lymphocyte and myeloid cell populations were overrepresented and five B cell clusters were underrepresented in DOCA-salt samples. Differential expression analysis of CD11b+CD64+ cardiac macrophages revealed transcriptional changes between groups with 146 significantly upregulated and 111 downregulated genes. Gene set enrichment analysis showed upregulation of leukocyte migration, response to type I interferon, and cytokine-mediated signaling pathways in DOCA-salt macrophages. In conclusion, the DOCA-salt mouse model recapitulates key features of HFpEF including diastolic dysfunction with preserved ejection fraction, cardiac hypertrophy, and pulmonary congestion and is associated with an altered cardiac immune cell profile.
Abstract MP06: Kinin B1 Receptor Mediates Orexin System Hyperactivity In Salt-sensitive Hypertension
Authors: Parekh Rohan U , Abdel-rahman Abdel A , Sriramula Srinivas
Published: September 2020

Hyperactivity of the orexin system contributes to several animal models of hypertension and enhances arginine vasopressin (AVP) release. We previously reported higher neuronal kinin B1 receptor (B1R) expression and brain AVP levels in hypertensive mice. However, the role of B1R and its interaction with orexin system in neurogenic hypertension have not been studied. In the present study, we tested the hypothesis that kinin B1R contributes to hypertension by upregulation of orexin-AVP signaling in the brain. Deoxycorticosterone acetate (DOCA)-salt treatment (1 mg/g body weight DOCA, 1% saline in drinking water, 3 weeks) of wild-type (WT) male mice produced a significant increase in mean arterial pressure (MAP; radio-telemetry) (138 ±3 mmHg, n=8, p<0.01) that was blunted in B1R knockout mice (121±2 mmHg,
P
<0.05 vs. WT+DOCA). In WT mice, DOCA-salt, compared to vehicle, increased mRNA levels of orexin receptor 1 (2.5 fold, n=9, p<0.001), orexin receptor 2 (3 fold, n=9, p<0.001) and AVP (3 fold, n=9, p<0.01) in the hypothalamic paraventricular nucleus (PVN), and these DOCA-salt evoked effects were attenuated in B1RKO mice. Similarly, DOCA-salt evoked increases in protein expression of orexin receptor 1 and 2 in the hypothalamic PVN of WT mice were attenuated by 25±5% and 33±5% (p<0.05), respectively, in B1RKO vs WT+DOCA mice. Furthermore, DOCA-salt treatment increased plasma AVP levels in WT mice compared to vehicle treated mice (13.69±1.1 vs. 47.86±8.7 pg/ml, p<0.05), but not in B1RKO mice. Together, these data provide novel evidence that kinin B1R plays an important role in mediating DOCA-salt induced hypertension possibly via upregulating the orexin-AVP signaling in the brain.
Abstract MP08: Testosterone Contributes To Renal Necrosis In Male Spontaneously Hypertensive Rats (SHR).
Authors: Abdelbary Mahmoud , Gillis Ellen E , Sullivan Jennifer C
Published: September 2020

We previously published a sex difference in renal necrosis in SHR with males having a maturation induced increase in renal necrosis that is absent in females. Testosterone is known to drive an increase both in blood pressure (BP) with maturation in male SHR and necrosis of renal tubular epithelial cell in vitro. In the current study we tested the hypothesis that testosterone underlies the maturation induced increase in renal necrosis in male SHR. At 4 weeks of age, male SHR were randomly assigned to either sham or gonadectomy (ORX) groups (n=3). To control for the influence of high BP on renal necrosis, a third group was subjected to a sham surgery and treated with the anti-hypertensive medications hydrochlorothiazide (HCTZ; 55mg/kg/day) and reserpine (Res; 4.5 mg/kg/day) in drinking water starting at 9 weeks of age (n=4) to prevent age-related increases in BP. At 8 weeks of age, telemeters were implanted in all groups followed by a recovery for 1 week before BP was recorded. A separate set of rats were randomly assigned to Sham (n=3), ORX (n=4), or HCTZ/Res (n=4) and subjected to the exact same procedures as the previous set except for telemetry implantation. All rats were euthanized at 13 weeks of age and kidneys were collected for the quantification of renal necrosis using flow cytometric analysis of 7AAD
+
cells. Data were analyzed using one-way ANOVA and presented as mean ± standard error. BP was significantly lower in ODX and HCTZ/Res treated groups compared to sham (mean arterial blood pressure (mmHg): Sham= 139±2; HCTZ/Res= 117±3; ODX= 126±2; p=0.002; n=3-4). Renal necrosis was also significantly less in ORX rats, but not altered in HCTZ/Res treated groups compared to sham (renal necrosis expressed as % total gated kidney cells: Sham= 6±0.3%; HCTZ/Res=5±0.4%; ODX= 4±0.4%; P=0.003; n=6-7). Testosterone contributes to maturation induced increase in renal necrosis in male SHR.
Abstract MP09: Sex Differences And Development Of Advanced Diabetic Nephropathy In Type 2 Diabetic Nephropathy Rats
Authors: Spires Denisha , Palygin Oleg , Levchenko Vladislav , Khedr Sherif , Nikolaienko Oksana , Klemens Christine A , Staruschenko Alexander
Published: September 2020

Diabetic kidney disease (DKD) is a severe complication of diabetes, which causes an increased risk of cardiovascular diseases and end-stage renal failure. Recent clinical data have demonstrated distinct sexual dimorphisms in the pathogenesis of DKD in humans, which impacts both severity- and age-related risk factors. A type 2 diabetic nephropathy (T2DN) rat model characterized by spontaneous development of an advanced form of diabetic nephropathy (DN) was used here to study sexual dimorphisms in the development of type 2 diabetes with DN. Male and female T2DN rats at late stages of the disease were used to evaluate hyperglycemia, renal injury, and kidney function. During late stage DKD (>46 weeks), glucose tolerance tests (GTT) revealed higher glucose levels in males (378 ± 19 vs. 183 ± 48 mg/dL) compared to females. This was accompanied by pathological changes in kidney function including urinary nephrin shedding, albuminuria (11.8 ± 5.7 vs. 0.98 ± 0.64 Alb/Cre ratio), and glomerular damage. To test the role of the endocrine environment in the pathophysiology of type 2 diabetes with DKD, we performed gonadectomies on male and female T2DN rats at 9 to 10 weeks of age, and animals were monitored until the full development of DKD (>46 weeks). All T2DN rats (intact and gonadectomized) maintained their diabetic phenotype, which was verified by higher end point blood glucose levels following a GTT (intact vs gonadectomized, male and female, respectively; 404 ± 21 vs 466 ± 32 and 264 ± 20 vs 291 ± 25 mg/dL). Based on kidneys to body weight ratios, gonadectomized male T2DN rats had a significant reduction in kidney hypertrophy (intact vs gonadectomized; males and females, respectively: 9.9 ± 0.2 vs 7.4 ± 0.2 and 7.7 ± 0.2 vs 7.0 ± 0.2 ratio). Moreover, FITC-inulin based GFR measurements revealed gonadectomized males had improved GFRs, whereas the GFRs of gonadectomized females rats were worsened (7.5 ± 1.5 vs. 4.1 ± 0.7 for male and 4.1 ± 0.2 vs. 7.3 ± 1.3 for female μg/mL/min; gonadectomy vs intact, correspondingly). In conclusion, male T2DN rats develop more severe DKD compared to age-matched females, and this phenotype is partially attenuated by the absence of sex hormones in males and exacerbated by the absence of hormones in females.
Abstract MP36: Effects Of Intensive Blood Pressure Treatment On Orthostatic Hypotension: An Individual-level Meta-analysis
Authors: Juraschek Stephen P , Hu Jiun-Ruey , Cluett Jennifer , Ishak Anthony , Mita Carol , Lipsitz Lewis , Appel Lawrence J , Beckett Nigel , Coleman Ruth L , CUSHMAN WILLIAM , Davis Barry R , Grandits Greg , Holman Rury R , Miller Edgar R , Peters Ruth , Staessen Jan A , Taylor Addison , Thijs Lutgarde , Wright Jackson T , Mukamal Kenneth J
Published: September 2020

Background:
Intensive blood pressure (BP) treatment reduces the risk of cardiovascular disease, but there are ongoing concerns that it also might be harmful by increasing the risk of orthostatic hypotension (OH). However, individual trials have been inconclusive.

Methods:
In this individual participant data meta-analysis, we systematically reviewed MEDLINE, EMBASE, and CENTRAL databases through October 7, 2019 for randomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) on measured OH. OH was defined as a drop in SBP ≥20 mmHg or DBP ≥10 mmHg after changing positions from seated to standing. Ultimately, five trials of BP treatment goal were identified. Effects were examined overall and in subgroups of baseline characteristics, including diabetes, standing BP pre-randomization (<110 vs ≥110 mm Hg), and pre-randomization OH.

Results:
There were 18,466 participants with 127,998 follow-up visits. Most trials demonstrated low risk of bias with minimal heterogeneity of effects across trials (

I
2

= 0.0%). Intensive BP treatment significantly lowered risk of OH (OR 0.93; 95% CI: 0.86, 0.99). Effects were strongest among adults without diabetes (OR 0.90 vs 1.10;
P
-interaction = 0.015) and adults with lower standing SBP (OR 0.66 for <110 mmHg vs 0.96 for ≥110 mmHg;
P
-interaction = 0.02). Effects did not differ by pre-randomization OH (
P
-interaction = 0.80). In sensitivity analyses that included 4 additional placebo-controlled trials, overall and subgroup findings were unchanged (
Figure
).

Conclusion:
OH prior to or in the setting of more intensive BP treatment should not be viewed as a reason to avoid or to de-escalate treatment for hypertension.
Abstract MP39: Autophagy Regulates β-hydroxybutyrate Synthesis To Prevent High-salt Induced Vascular Damage
Authors: McCarthy Cameron G , CHAKRABORTY Saroj , Singh Avinash , Schreckenberger Zachary J , Mell Blair , Wenceslau Camilla F , Joe Bina
Published: September 2020

Overconsumption of dietary salt is unequivocally linked with end organ damage. We have recently observed that a high salt (HS) diet induces liver dysfunction in the form of impaired synthesis of ketone body, β-hydroxybutyrate (βOHB), in Dahl salt-sensitive rats. However, the molecular mechanisms as to why βOHB is decreased after consuming a HS diet remains unknown, as well as if it contributes to vascular dysfunction. We hypothesized that a HS diet (2%) for 8 weeks would decrease systemic levels of βOHB in Dahl salt-resistant (R) rats and this would be associated with endothelial dysfunction. Furthermore, reconstitution of βOHB bioavailability by giving 1,3-Butanediol (1,3-BD; 20%
v/v
) in the drinking water would improve endothelial function in HS fed Dahl R. As hypothesized, a HS diet decreased serum concentration (mM) of βOHB [Low salt (LS), non-fasting (NF): 0.31±0.02 vs. fasting (F): 0.96±0.04*; HS, NF: 0.33±0.02 vs. F: 0.77±0.04*#, *p<0.05 vs. NF, #p<0.05 vs. LS-F]. A HS diet decreased the sensitivity of isolated mesenteric resistance arteries (MRA) to acetylcholine (ACh), and 1,3-BD treatment prevented this endothelial dysfunction (LogEC50, Dahl R-LS: -7.35±0.05 vs. Dahl R-HS: -7.19±0.07* vs. Dahl R-HS+1,3-BD: -7.42±0.10, p<0.05). Furthermore, when MRA were incubated with indomethacin, only Dahl R-HS presented with a decreased sensitivity to ACh (LogEC50, HS: -7.19±0.07 vs. HS+indomethacin: -7.66±0.08*, p<0.05), indicating that 1,3-BD treatment decreased cyclooxygenase-induced vascular inflammation (LogEC50, 1,3-BD -7.42±0.10 vs. 1,3-BD +indomethacin: -7.61±0.09, p>0.05). Evolutionarily, autophagy functions to mobilize nutrients in times of starvation, including ketone bodies such as βOHB. Therefore, we hypothesized that inhibition of autophagy would decrease βOHB. Treatment with lysosomal alkalizer chloroquine (CQ), impeded the starvation-induced increase in βOHB (NF: 0.38±0.02 vs. F: 1.11±0.09* vs. F+CQ: 0.78±0.19*#, *p<0.05 vs NF, # p<0.05 vs F). In summary, these data reveal that a HS diet decreases liver-derived βOHB, independent of high blood pressure, and is protective against HS-induced vascular damage. We suggest that autophagy could be a novel mechanism underlying the vascular protective effects of βOHB.
Abstract MP40: Hiv Impairs Endothelial Function And Elevates Blood Pressure Via Tnfa Dependent Mechanisms In Male And Female Mice.
Authors: Kress Taylor , Belin De Chantemele Eric J , Faulkner Jessica L , Bruder do Nascimento Thiago
Published: September 2020

HIV is a major health concern with over 37 million individuals worldwide living with HIV. The onset of combination antiretroviral therapy (cART) patients with HIV (PWH) live longer but exhibit accelerated development of cardiovascular disease. Clinical evidence indicates that 35% of PWH exhibit hypertension, however, the etiopathology is still ill-defined. We plan to take advantage of a transgenic mouse model (Tg26) that mimics patients with a repressed virus, to test the hypothesis that viral infection independent of cART induces endothelial dysfunction and hypertension via a TNF-α mediated mechanism. Vascular reactivity was analyzed via wire myography and blood pressure (BP) recorded via radio-telemetry. Results showed that viral infection impaired aorta endothelium-dependent relaxation as reflected by a decrease in acetylcholine-mediated relaxation in both Tg26 mice (P<0.05) which was ameliorated with the NOX 1/4 inhibitor GKT 137831. Smooth muscle cell-dependent relaxation (SNP) and contractility to phenylephrine and KCl remained intact in Tg26 mice. Viral infection increased systolic, diastolic, and mean arterial pressure (MAP: male: WT=112.3±1.3 vs Tg26=121.9±4.0 mmHg/ female: WT=110.6±3.01/ Tg26=120.3±6.9 mmHg) and elevated heart rate (HR) in both sexes (p<0.05). We used atropine, propranolol, and hexamethonium in WT and Tg26 mice to investigate the contribution of the autonomic nervous system to hypertension. HR responses to both atropine (Female: +5.07±2.8% vs. male +4.3±5.4% of baseline) and propranolol (Female: 19.9±6.1% vs. male 12.0±4.3%) revealed no significance or sex differences in WT mice and no effects of viral infection on autonomic control of heart rate in Tg26 mice. BP responses to hexamethonium revealed no effect of sex or viral infection, supporting a limited contribution of the autonomic nervous system to hypertension in Tg26 mice. However, we found that TNFα inhibition with etanercept reduced mean arterial pressure in Tg26 mice to the level of the WT mice (WT=112.3±1.3, Treated=110.1±0.185) and improved endothelial function. These data indicate that HIV infection contributes to cardiovascular disease via inducing endothelial dysfunction and hypertension via NOX and TNFα-dependent mechanisms respectively.
Abstract MP45: Prorenin Induces Intracellular Signaling And Reactive Oxygen Species In The Brainstem
Authors: Nakagawa Pablo , Donato Silva Sebastiao , Gomez Javier , Grobe Justin L , Sigmund Curt D
Published: September 2020

The activation of the brain renin angiotensin system (RAS) is required for the blood pressure (BP) elevation in models of neurogenic hypertension (HT). However, it remains unclear whether the expression of prorenin and its binding to prorenin receptor (PRR) in particular brain regions is required for the activation of the brain RAS. Compelling new evidence indicates that renin is expressed in the proximity of the rostral ventrolateral medulla (RVLM) and the nucleus ambiguous within the brainstem where RAS genes including PRR, angiotensinogen, and angiotensin receptors were also detected. Thus, we hypothesized that prorenin acts within the brainstem to induce extracellular signal-regulated kinases (ERK1/2) phosphorylation and generation of reactive oxygen species (ROS) resulting in BP elevation through a PRR-dependent mechanism. Neonatal brainstem neurons obtained from mice at postnatal day 1-3 were cultured and subsequently incubated in presence of recombinant prorenin (rProrenin; 100 nM) or vehicle. rProrenin increased the ratio of phosphorylated-to-total ERK1/2 from 0.7±0.1 A.U. at baseline to 1.0±0.1 A.U. at 30 min (54% increase; p=0.004; n=7) and 1.3±0.1 A.U. at 60 min (102% increase; p<0.0001; n=7). Both PRO20, a PRR blocker, and Ro-31, a protein kinase C inhibitor, abrogated prorenin-induced ERK1/2 phosphorylation, suggesting a PRR-dependent component to this response. Treatment with rProrenin increased NADPH oxidase activity by 47.2±9.5 % compared to vehicle control (p<0.05, n=5). RVLM-targeted stereotactic microinjection of glutamate, rProrenin, or Ang II, but not vehicle, induced an acute BP elevation in isoflurane-anesthetized C57BL/6J mice. Moreover, preliminary data indicate that RVLM-targeted ablation of PRR in PRR-flox mice attenuates the pressor response to deoxycorticosterone (DOCA)-salt in females (WT=132±3 vs KO=120±3 mmHg; p<0.05; n=3-4), but not males (n=5-8), during the first week on DOCA-salt treatment. There was no difference in BP during the 2
nd
and 3
rd
week of DOCA-salt. We conclude that prorenin induces PRR-mediated downstream signaling involving ERK1/2 phosphorylation and generation of ROS in brainstem neurons, which might contribute to BP elevation in neurogenic HT in sex-dependent manner.
Abstract MP48: EGF Regulates VSMC Migration And Proliferation Through Crosstalk Between TRPM7 And EGFR
Authors: Rios Francisco J , Zou ZhiGuo , Neves Karla B , Alves-lopes Rheure , Ling Jiayue , Baillie George G , Gao Xing , Fuller Will , Camargo Livia L , Gudermann Thomas , Chubanov Vladimir , Montezano Augusto C , Touyz Rhian M
Published: September 2020

Epidermal growth factor (EGF), signals throught the EGF receptor (EGFR) and plays an important role in the pathogenesis of vascular remodeling. Transient receptor potential melastatin 7 (TRPM7) is a channel bound to a kinase domain important for Mg
2+
, Zn
2+
and Ca
2+
homeostasis. Cancer patients treated with EGFR inhibitors develop hypomagnesemia, suggesting a relationship between EGFR and TRPM7. Here we investigated the role of TRPM7 in EGF signaling in vascular smooth muscle cell (VSMC) from humans (hVSMC) and rats (rVSMC). VSMCs were stimulated with EGF (50ng/ml) for 5min and 24h with/without pretreatment of gefitinib (1μM), PP2 (10μM), 2APB (30μM) and NS8593 (40μM), inhibitors of EGFR, c-Src kinase and TRPM7 respectively. Aortas were isolated from wild type (WT), TRPM7-deficient (TRPM7
+/Δkinase
) and kinase-dead (TRPM7
R/R
) mice. Protein expression was assessed by immunoblotting. Ca
2+
and Mg
2+
were assessed using Cal-520 and Mg-green probes respectively. EGFR/TRPM7 interaction was investigated by proximity ligation assay (PLA), immunoprecipitation and confocal microscopy. VSMC migration and proliferation were examined by wound healing and CFSE proliferation assays. In hVSMC and rVSMC, EGF increased TRPM7 expression (47%) and phosphorylation (21%), (p<0.05); effects abolished by gefitinib and PP2. EGF-induced Mg
2+
and Ca
2+
influx was attenuated by gefitinib (4% and 8% respectively), NS8593 (5% for Mg
2+
) and 2-APB (6% and 13% respectively). EGF enhanced ERK1/2 phosphorylation (3-fold) through c-Src, EGFR and TRPM7, p<0.05. Cell migration (26%) and proliferation (17%) were enhanced by EGF, and reduced by inhibitors of EGFR, TRPM7 and ERK1/2, p<0.05. EGF induced TRPM7-EGFR interaction (51%), which was reduced by gefitinib (34%) and PP2 (25%). VSMC from TRPM7
+/Δkinase
showed reduced EGFR expression (73%), phospho-c-Src (22%), and phospho-ERK1/2 (90%). Aortas from TRPM7
R/R
exhibited reduced phospho-EGFR (63%) and phospho-ERK1/2 (36%). Vessels from TRPM7
+/Δkinase
showed reduced wall thickness (35%). Our findings demonstrate that interaction between EGFR/TRPM7 is a key process underlying EGF-induced VSMC migration and growth. This novel EGF-c-Src-EGFR-TRPM7 pathway may play an important role in vascular remodeling.
Abstract P008:
Sex Differences In The Development Of Diabetic Kidney Disease And Salt Sensitivity In Db/db Mice
Authors: Veiras Luciana C , Shen Justin Z , Bernstein Ellen A , Okwan-Duodu Derick , Khan Zakir , Cao Duoyao , Dominici Fernando P , Bernstein Kenneth E , Giani Jorge F
Published: September 2020

Introduction:
Clinical studies show that men have higher risk than premenopausal women for the development of diabetic kidney disease. However, the mechanisms behind the sexual dimorphism associated with renal injury and salt sensitivity during diabetes remain unknown.

Methods:
7-month-old male and female diabetic (db/db) and non-diabetic (db/+) mice received either a high-salt (HS, 4% NaCl w/w) or a control (0.7% NaCl w/w) diet for 4 weeks (n=6). Mean arterial pressure (MAP) was measured by telemetry. A subgroup of male mice was exposed to HS and the anti-inflammatory drug mycophenolate mofetil (MMF, 30 mg/Kg/day, IP). At the end, mice were euthanized, and kidneys were preserved to assess renal sodium transporters and inflammation.

Results:
Male db/db mice display hypertension when exposed to HS whereas female db/db mice remain normotensive during the whole treatment (MAP: 125±7 vs. 103±3 mmHg, P<0.05). Hypertension in male db/db mice was associated with an improper suppression of key sodium transporters: NKCC2 and ENaC. Renal angiotensin II and plasma aldosterone were suppressed after HS in all experimental groups negating a role of these hormones in sodium transporters dysregulation and salt sensitivity. Compared to females, male db/db mice show higher levels of proinflammatory cytokines (IL-1β: 2.3-fold, IL-6: 1.7-fold and TNFα: 2.3-fold, P<0.05 by ELISA) and more leucocyte infiltration (CD45+ cells: 1.6-fold, P<0.05 by flow cytometry) in the kidney. Blocking inflammation with MMF reduced NKCC2 and ENaC expression in response to HS and prevented salt sensitivity in male db/db mice (MAP: 105±10 mmHg).

Conclusion:
Renal inflammation in male, but not in female, db/db mice induces salt-sensitive hypertension by preventing the suppression of key sodium transporters in response to HS. Thus, we provide a mechanistic explanation of the sexual dimorphism associated with the development of salt sensitivity during diabetes.