bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P213: Furosemide-mediated Suppression Of
P
38 MAPK Signaling Abrogates Cholinergic-mediated Salt Sensitive Hypertension In Young Spontaneously Hypertensive Rats
Authors: Raikwar Nandita , Maiers Trever , Hohmann Holly , Ryan Alan , Snyder Peter , Harwani Sailesh
Published: August 2021

Hypertension is a major cause of premature death worldwide. Inflammatory macrophages play a key role in the pathogenesis of hypertension. Our lab has observed that nicotinic acetylcholine receptors (nAChR) activation potentiates salt-sensitive hypertension in Spontaneously Hypertensive Rats (SHR). Cholinergic receptor activation causes infiltration of CD68
+
macrophages into the renal cortex/medulla junction and results in enhanced expression of renal sodium-potassium chloride cotransporter (NKCC2). To determine whether or not NKCC2 plays a role in the activation of inflammatory pathway furosemide, a selective pharmacologic blocker of NKCC2, was used to block NKCC2 expression in SHR in current study. Young pre-hypertensive SHR, receiving nicotine infusion (15mg/kg/day), were fed HSD (4% NaCl) and treated with either saline or furosemide (20mg/kg/day) intraperitoneal injections. There was a 16% increase (158.5±7.3 mmHg to 183.6±7.0 mmHg) in the systolic blood pressure in SHR that received saline injections, compared to no increase in SHR that received furosemide (155±6.0 mmHg to 148±3.6 mmHg) (p<0.0016). There was over a two-fold increase in fractional excretion of sodium (FENa, p=0.03) in the furosemide group, compared to saline controls. Although furosemide injections did not alter renal NKCC2 expression, there was nearly 50% reduction in phosphorylated p38 MAPK (p=0.0002) and a 25% decrease in renal infiltration of inflammatory CD68
+
macrophages in SHR receiving furosemide injections, compared to saline controls. Interestingly, there was also a significant reduction in urinary albumin in response to furosemide injections (14.7±5.7 control vs 3.3±0.9 furosemide, p=0.027). Based on these findings, we conclude that furosemide results in cessation of the development of hypertension via interruption of a p38-MAPK dependent inflammatory pathway.
Abstract P215: Treatment With Il-17 Inhibitors Is Not Associated With A Change In Blood Pressure In Human Subjects: A Retrospective Cohort Study
Authors: Tsai Peihsuan , Gilroy Daniel , Le Thu H , Drury Erika R
Published: August 2021

Background:
Recent evidence suggests IL-17 contributes to the pathogenesis of autoimmune, inflammatory, and cardiovascular diseases. It has been demonstrated
in vivo
that IL-17 is critical for the maintenance of angiotensin II-induced hypertension (HTN) and vascular dysfunction. We aim to determine if IL-17 inhibitors (IL-17I) have direct effects on blood pressure (BP) in human subjects.

Method:
We conducted a single-center retrospective cohort study of patients who had been treated with an IL-17I (ixekuzumab or secukinumab) for psoriasis (P) or psoriatic arthritis (PA). Aggregated data in a 3 month window at 3-months prior to initiation of the IL-17I (baseline) and at 3, 6, and 12 months after initiation were analyzed using paired t-test. Wilcoxon non-parametric test was used if normality test failed. Pre-existing HTN was defined by ICD-coding. Unique antihypertensive medication was defined as number of unique class of BP prescription filled within a specified 3-month windows.

Results:
We identified 307 patients who had been treated with IL-17I. We included 103 patients who had BP data in all above specified time windows. The mean age was 47 ± 13 years, 39 (38%) were men, 68 (66%) had HTN, and 23 (22%) had diabetes. Among all patients, mean baseline BP was 129/76 mmHg. There was no significant change in systolic or diastolic BP (SBP or DBP, respectively) at 3 months (129/76 mmHg) or 6 months (130/76 mmHg). There was a trend of increased BP at 12 months (131/77 mm Hg), reaching significance only for DBP (p = 0.048). When stratified by pre-existing HTN, there was no significant change in SBP or DBP at any time point. The number of unique prescribed BP medication was 0.45 at baseline, and significantly increased to 0.68 (p= 0.027), 0.87 (p=0.006), and 0.83(p=0.004) at 3-,6-, and 12-month respectively, suggesting patients required more antihypertensive therapy while on IL-17I.

Conclusion:
IL-17I use for P or PA was not associated with a significant change in BP over 1 year of treatment. This could be confounded by an increase in the number of unique BP medications prescribed which implies a rise in BP. This could be due to IL-17I therapy or other factors such as age. A prospective study is needed to better evaluate the effects of IL-17 inhibition on BP.
Abstract P228: RhoBTB1 Is Expressed In Placental Syncytiotrophoblast Cells
Authors: Livergood M. Christine , Opichka Megan , Gomez Javier , Grobe Justin L , McIntosh Jennifer , Sigmund Curt D
Published: August 2021

Preeclampsia is a pregnancy-specific disorder of hypertension and end-organ dysfunction that poses serious clinical problems for women and their offspring that extend beyond the peripartum period. Abnormal placentation is at the core of preeclampsia. PPARγ-deficient mice exhibit numerous placental defects including malformation of the labyrinth zone, lack of infiltration of fetal blood vessels, and rupture of maternal blood sinuses, suggesting that PPARγ is a critical regulator of placental development and possibly function. Rho-related BTB domain-containing protein 1 (RhoBTB1) is a PPARγ target gene which controls the level of cGMP in vascular smooth muscle cells by functioning as an adaptor delivering phosphodiesterase 5 (PDE5) to the Cullin-3 ubiquitin ligase complex. Analysis of gene expression databases revealed that placenta is among the tissues with the highest level of RhoBTB1 expression. Thus, we examined if the level or cell-specificity of RhoBTB1 expression was altered in preeclampsia. Placental samples were obtained from the Medical College of Wisconsin Maternal Research Placenta and Cord Blood Bank. We examined placentas from term healthy (n=3), preterm non-preeclamptic (n=2), term preeclamptic (n=2) and preterm preeclamptic (n=2) pregnancies. RNAscope in situ hybridization was used to qualitatively evaluate expression of RhoBTB1 and several placental markers. Our results reveal that RhoBTB1 co-localizes with CYP19A1, a gene encoding cytochrome P450 enzyme, a target specific to the syncytiotrophoblast cell layer in the placenta. Expression of RhoBTB1 was not co-localized with platelet-endothelial cell adhesion molecule-1 (PECAM) or with melanoma cell adhesion molecule (MCAM), both endothelial cell markers. These results indicate that RhoBTB1 is specifically expressed in the syncytiotrophoblast cell layer in human placentas. This finding persisted in preterm and preeclamptic placental samples. These data compel us to assess the functional significance of placental RhoBTB1 using conditional knockout and a conditional activatable RhoBTB1 models. Further investigative work is being done to determine if placental RhoBTB1 expression is altered based on ethnic and racial differences.
Abstract P234: Hypertensive Disorders Of Pregnancy And Increased Levels Of Cardiac Troponin I After Delivery
Authors: Kato Takao , Muta Eri , Inoko Moriaki
Published: August 2021

Background:
Cardiovascular functions and hemodynamics dramatically change during pregnancy such as cardiac output, expanded blood volume, reduced systematic vascular resistance, and heart chamber enlargement. Hypertensive disorders of pregnancy (HDP) may affect the cardiac load during pregnancy; however, the data about plasma concentration of cardiac troponin in pregnant women with HDP is very limited.

Methods:
We prospectively collected data of 751 pregnant women between 2012 and 2013 in Japanese general hospital. We analyzed laboratory data and echocardiographic findings after delivery. The elevated cTnI was defined as >0.015 ng/mL because the normal population have serum cTnI of less than 0.015 ng/mL in this assay.

Results:
The HDP were observed in 32 patients; the elevated cTnI was observed 40 patients. The age of patients with HDP (33.7 ±4.3 years) was not different from that of those without HDP (33.3 ± 5.0 years). The brain natriuretic peptides levels were not different between those with and without HDP. The proportion of elevated cTnI was higher in those with HDP (21.8%) than those without (3.6%, P<0.0001). After adjusting for confounders, the risk of elevated cTnI in those with HDP relative to those without HDP remained significant (odds ratio 4.52, 95% confidence interval 1.45-14.5). There were no women with reduced left ventricular ejection fraction.

Conclusions:
HDP was associated with elevated cTni, suggesting myocardial microinjury might occur more frequently in those with HDP.
Abstract P238: Regulation Of G Protein-coupled Receptor Kinase 4 Expression By Serum In Breast Cancer And Renal Proximal Tubule Cells
Authors: Yue Wei , Xu Peng , Gildea John J , Felder Robin A
Published: August 2021

G protein-coupled receptor kinase 4 (GRK4) is a member of the GRK family which play critical role in regulation of the function of G protein-coupled receptors. Our previous studies have shown that GRK4 not only plays a role in regulating sodium excretion in renal proximal tubule cells but also acts as a stimulator on proliferation of breast cancer cells. Uncontrolled proliferation is a characteristics of cancer cells and GRK4 is upregulated in breast cancer cells. We hypothesized that expression of GRK4 may be regulated differently in cancer and non-cancer cells. To test this hypothesis, expression of GRK4 in response to serum was compared in breast cancer cells and renal proximal tubule cells by Western analysis. In three breast cancer cell lines serum withdrawal caused rapid reduction in the levels of GRK4 which occurred as early as 15 min. GRK4 levels correlated with the concentrations of serum added to the culture media. To determine if growth factors were a critical element for maintaining GRK4 levels in the cells, EGF (10-20 ng/ml) was added to serum free medium for 24 h. There was no increase in GRK4 levels in the cells treated with EGF compared with the serum starvation control. Similarly, serum withdrawal (16 h) led to 40-80% decrease of GRK4 levels in renal proximal tubule cells even in the presence of EFG supplement. Serum feeding for 30 min after starvation dramatically increased the levels of GRK4 in both breast cancer cells and RPTC which exceeded the steady state levels. This rapid recovery of GRK4 protein do not need de novo protein synthesis because pretreatment of the cells with protein synthesis inhibitor, cycloheximide (10 μg/ml, 24 h), did not prevent this event. Expression of GRK2, another member of the GRK family, was not affected by serum starvation. Our results have shown that GRK4 is very sensitive to serum concentration in breast cancer cells as well as in RPTC. Preliminary studies suggest that rapid protein degradation rather than shutting down the protein synthesis plays a major role in this kind of GRK4 regulation. The biological significance of serum regulation of GRK4 in cancer and non-cancerous cells needs further investigation.
Abstract P244: Scleroderma Renal Crisis Among Systemic Sclerosis Patients; A Large Cohort Study From The United States National Emergency Department Database.
Authors: Uddin Mohammed , Mir Tanveer , Shafi Obaid , Tahir Hamza , Surapaneni Sarvani , Laharwal Mehak , Hans Aakash , Sheikh Shoaib , Hammad Ali , Qureshi Waqas
Published: August 2021

Background:
Literature regarding trends for incidence and mortality of Scleroderma renal crisis (SRC) in systemic sclerosis (SSc) within the United States (US) emergency departments (ED) is limited.

Objective:
To study the trends for incidence and mortality of SRC among SSc patient encounters within the US EDs.

Methods:
Data from the national emergency department sample (NEDS) constitutes 20% sample of hospital-owned EDs and in-patient sample in the United States. All ED encounters were included in the analysis. Major complications related to each ED encounter were obtained by using ICD codes. A Linear p-trend was used to assess the trends.

Results:
Of the total 180,435 ED encounters with a diagnosis of SSc in NEDS for the years 2009-2014, 771 (4.27/1,000) (mean age of 59.6 ± 15.5 years, 75.4% females) patients were recorded with SRC. A total of 32 (4.1%) patients had died during these ED hospital encounters. The SSc with SRC subgroup was associated with higher rates of life-threatening complications when compared to SSc without the SRC subgroup. Cerebrovascular complications include acute ischemic stroke 44 (5.6%). Cardiac complications include new-onset atrial fibrillation 62 (8%), conduction block 13 (1.6%) and acute onset heart failure 186 (24.1%). Other complications include pulmonary arterial hypertension 122 (15.8%), respiratory failure 212 (27.5%), and deep vein thrombosis 36 (4.7%). The yearly trend for the incidence of SRC every 1,000 ED SSc encounters in the United States increased over the study years from 2.11/1,000 in 2009 to 5.79/1,000 in 2014 (linear p-trend 0.002). The yearly trend for the mortality related to SRC in the United States remained steady over the study years 2009-2014 (linear p-trend 0.3187).

Conclusion:
SRC is a relatively rare medical emergency among patients with SSc. Although there has been a significant rise in the incidence of SRC among SSc patients over the study years, mortality rates had remained steady. Proper management of the underlying risk factors can prevent the development of SRC and associated complications.
Keywords:
Systemic sclerosis, Scleroderma renal crisis, pulmonary hypertension, deep vein thrombosis.
Abstract P256: Genetic Determinants Of Blood Pressure Associate With Apparent Treatment Resistant Hypertension
Authors: Breeyear Joseph H , Shuey Megan M , Edwards Todd L , Hellwege Jacklyn
Published: August 2021

Hypertension is estimated to affect more than 49.6% of US adults 20 years and older. Of those individuals with hypertension, more than ten million are classified as apparent treatment resistant hypertensive (aTRH). The attributable risk of uncontrolled hypertension was estimated to be 49% for cardiovascular disease and 62% for stroke. We developed a polygenic risk score (PRS) for systolic (SBP) and diastolic (DBP) blood pressure to examine the association between the genetic determinants of blood pressure and aTRH with the goal of identifying high risk individuals. The meta-analyzed transethnic results of Giri et al., Biobank Japan, and Liang et al. were used to generate a PRS with PRS-CS followed by
p
-value thresholding, and validation in the UK Biobank (n
max
=341,930). Associations were modeled with logistic regression adjusted for age, age-squared, BMI, sex, and ten principal components of ancestry in BioVU’s transethnic population (n
max
=37,978), as well as non-Hispanic Black (n
max
=5,026) and non-Hispanic White (n
max
=28,545) subsets. The SBP PRS was significantly associated with an increased aTRH risk in the non-Hispanic White subset (1.08 (1.04 - 1.12),
p
= 0.00037) and transethnic (1.08 (1.04 - 1.13),
p
= 0.00020) populations, but not the non-Hispanic Black subset. The DBP PRS was not associated with aTRH in any population. Our findings present evidence that individuals with a higher genetic predisposition towards hypertension are at higher risk of aTRH. By integrating polygenic risk scores and clinical covariates in prediction of aTRH, individuals’ therapeutic regimens may be tailored to help maintain stable blood pressures, therefore reducing their risk of comorbidities.
Abstract P262: Spike Protein 1 Of Sars-cov-2 Increases Interferon Stimulated Genes And Induces An Immune/inflammatory Responses In Human Endothelial Cells.
Authors: Rios Francisco J , Montezano Augusto C , Camargo Livia L , Lopes Rheure A , Aranday-Cortes Eihu , McLauchlan John , Touyz Rhian M
Published: August 2021

Introduction:
Interferon (IFN) alpha (IFNα) and lambda3 (IFNL3) constitute the first line of immunity against SARS-CoV-2 infection by increasing interferon-stimulated genes (ISGs). IFNs influence the expression of angiotensin-converting enzyme 2 (ACE2), the receptor for S-protein (S1P) of SARS-CoV-2. Here we hypothesized that in human microvascular endothelial cells (EC) IFNL3 and IFNα influence ACE2 and immune/inflammatory responses mediated by S1P.

Methods:
EC were stimulated with S1P of SARS-CoV-2 (1 μg/10^6 cells), IFNα (100 ng/mL) or IFNL3 (100 IU/mL). Because ACE2, metalloproteinase domain 17 (ADAM17) and type II transmembrane serine protease (TMPRSS2) are important for SARS-CoV-2 infection, cells were treated with inhibitors of ADAM17 (marimastat, 3.8nM and TAPI-1, 100nM), ACE2 (MLN4760, 440pM), and TMPRSS2 (camostat, 50μM). Expression of ISGs (ISG15, IFIT1, and MX1) was investigated by real-time PCR (5h) and protein expression by immunoblotting (24h).

Results:
EC stimulated with S1P increased expression of ISGs: ISG15 (2 fold), IFIT1 (6 fold), MX1 (6 fold) (n=12, p<0.05). EC exhibited higher responses to IFNα (ISG15: 16 fold, IFIT1: 21 fold, MX1: 31 fold) than to IFNL3 (ISG15: 1.7 fold, IFIT1: 1.9 fold, MX1: 1.7 fold) (p<0.05). S1P increased gene expression of IL-6 (1.3 fold), TNFα (6.2 fold) and IL-1β (3.3 fold), effects that were maximized 100% by IFNα. Only marimastat inhibited S1P effects. IL-6 was increased by IFNα (1230 pg/mL) and IFNL3 (1124 pg/mL) vs control (591pg/mL). IFNα increased expression of ACE2 (75 kDa) (63%), ADAM17 (36%), and TMPRSS2 (65%). This was associated with increased phosphorylation of Stat1 (134%), Stat2 (102%), ERK1/2 (42%). Nitric oxide production and eNOS phosphorylation (Ser1177) were reduced by IFNα and (40%) and IFNL3 (40%).

Conclusions:
In human microvascular endothelial cells, S1P, IFNα and IFNL3 induced an immune response characterized by increased expression of interferon-stimulated genes and IL-6 production, processes that involve ADAM17. Inflammation induced by S1P was amplified by IFNα. Our novel findings demonstrate that S1P induces an endothelial immune/inflammatory response that may be important in endotheliitis associated with COVID-19.
Abstract P264: Protective Effects Of Angiotensin II Inhibitors In Lebanese SARS-COV2 Hospitalized Patients
Authors: Abdulhai Farah , Fares Souha , Mekary Wissam , Habeichi Nada J , Massoud Gaelle P , Refaat Marwan M , Zouein Fouad A
Published: August 2021

Introduction:
SARS-CoV2 leads to increased Angiotensin II resulting in worsened cardiovascular disease (CVD) outcome and prognosis. ACEIs and ARBs prescribed drugs could be a crucial player in SARS-COV2 prognosis, owing that ACE2 is one SARS-CoV2 binding site and that ACE2 expression in the cardiovascular system is markedly elevated following the treatment with ACEIs and ARBs.

Hypothesis:
We hypothesized that hospitalized SARS-COV2 Lebanese patients with varying stages of heart failure (A through C) taking ACEIs or ARBs will exhibit an overall better cardiovascular prognosis than control patients with comparable demographics but on other cardiovascular medications.

Method:
Lebanese patients (N=66) classified as heart failure A-C and admitted to AUBMC for SARS-CoV2 infection were recruited as a part of an ongoing clinical study. Patients were assigned to the control group (No ACEIs or ARBs) or the study sample group (on ACEIs or ARBs). Baseline characteristics including cardiovascular, inflammatory, respiratory and overall outcomes were collected from the patients’ medical charts and analyzed. Unadjusted associations on recruited patients are presented here. Adjusted analyses will be performed when a total of 200 patients is reached.

Results:
The average age of patients was 69±12.42. The total average weight was 84.24±15.59 Kg and significantly higher in ACEIs/ARBs group (p=0.032). Most patients were males (48 of 66) and patients on ACEIs/ARBs medication were 38 of 66. Heart failure stage, systolic and diastolic blood pressures and heart rate were comparable on presentation between patients on ACEIs/ARBs and controls. Unadjusted analysis showed a significantly higher percentage of death (p=0.024), mechanical ventilation (p=0.05), and elevated troponin (p=0.03) in the control group. A trend towards higher percentage of elevated NT-ProBNP and high levels of peak IL-6 were observed in the control group (p = 0.088 and p=0.076 respectively). All patients had elevated CRP on admission. SARS-CoV2 treatments were comparable between the two groups.

Conclusion:
Higher mortality and worsened prognosis were observed in the control groups when compared to the ACEIs/ARBs group. Ongoing recruitment is currently underway to perform adjusted analyses.
Abstract P272: Mechanisms By Which Aldosterone And Insulin Stimulate Endothelial Cell Sodium Currents.
Authors: Yang Yan , Zhang Liping , Parrish Alan , Jia Guanghong , Aroor Annayya , Sowers James R , Hill Michael A
Published: August 2021

Aldosterone and insulin are known to increase the activity of the epithelial Na
+
channel (ENaC) in tubular epithelial cells through multiple mechanisms involving both transcriptional and post-transcriptional events. Such studies have implicated a key role for serum and glucocorticoid-stimulated kinase 1 (SGK-1) in determining ENaC activity. Comparatively less information is available regarding such regulation of the endothelial cell (EC) Na+ channel (EnNaC). The importance of such knowledge relates to prior studies having shown that EnNaC contributes to cardiovascular stiffening in states of hyperaldosteronism and hyperinsulinemia/insulin resistance. We hypothesized that aldosterone and insulin converge on SGK-1 to increase EnNaC activity. To determine how EnNaC is affected by insulin and aldosterone pulmonary ECs were isolated from wild-type mice and global SGK-1 deficient mice and held under conditions of short-term tissue culture. ECs were subsequently exposed to aldosterone (10 nM), insulin (100 nM) or DMSO control for 24 hr and whole cell EnNaC currents measured by patch clamp. Both chronic aldosterone and insulin increased Na
+
currents in ECs from wild-type mice, while in cells from SGK-1-/- mice the response to aldosterone was significantly blunted. However, insulin continued to increase EnNaC activity in SGK-1-/- mice. Acute insulin treatment (10 mins) showed a concentration-dependent (10 – 100 nM) increase in EC Na
+
currents in both SGK+/+ and SGK-/- mice which was prevented by PI3 kinase inhibition with LY294002 (30 uM). Thus, in ECs aldosterone-mediated activation of EnNaC is dependent on SGK-1 while insulin exerts a stimulatory effect via PI3 kinase, even in the absence of SGK-1.
Abstract P276: A High Sodium Diet Reduces Cutaneous Microvascular Function In Normotensive Individuals With Salt Sensitive Blood Pressure
Authors: Patik Jordan C , Stock Joseph M , Romberger Nathan T , Lennon Shannon L , Farquhar William B , Edwards David G
Published: August 2021

Impaired vascular function likely contributes to the association between dietary sodium intake and the development of cardiovascular disease. Using the cutaneous microvasculature as a model, we have previously shown that a high sodium (HS) diet blunts local heating-induced vasodilation in normotensive individuals with salt resistant (SR) blood pressure (BP). However, the effect of a HS diet on the cutaneous microvasculature in normotensive salt sensitive (SS) individuals remains unclear. Therefore, we tested the hypothesis that cutaneous microvascular function is reduced by a HS diet to a greater degree in SS compared to SR individuals. After each 7-day controlled feeding diet (low sodium (LS) = 20 mmol/day; HS = 300 mmol/day), an intradermal microdialysis fiber was inserted in the ventral forearm and perfused with Ringer’s solution. Skin blood flow (SkBF) was continuously monitored via laser Doppler flowmetry and a local heating unit was placed over the fiber and heated to 42°C until SkBF reached a stable plateau. Site-specific maximal SkBF was determined by perfusing 28mM sodium nitroprusside and heating to 43°C. Mean arterial pressure (MAP) was assessed at regular intervals on the contralateral arm and was used to calculate cutaneous vascular conductance (CVC = SkBF / MAP). Subjects wore a 24-hr ambulatory BP monitor and collected their urine on the final day of each diet. Fourteen subjects (9W / 5M, 42 ± 14 yr) whose MAP increased >5 mmHg (Δ8 ± 1 mmHg) on the HS diet were defined as SS and were compared to 14 age- (43± 14 yr) and sex-matched SR subjects (Δ1 ± 3 mmHg). SS and SR had similar MAP at baseline (88 ± 9 vs. 90 ± 8 mmHg, P = 0.88) and urinary sodium excretion was increased similarly across groups by the HS diet (Δ239 ± 104 vs. Δ220 ± 66 mmol / 24 hr, P = 0.20). Cutaneous vasodilation in response to local heating was decreased on the HS diet relative to the LS diet in both SS (Δ-9 ± 9 %CVCmax, P = 0.005) and SR (Δ-9 ± 9 %CVCmax, P=0.005); however, there was not a group x diet interaction (P = 0.99). In contrast to our hypothesis, these results suggest that the deleterious effects of high sodium diets on cutaneous microvascular function are similar in normotensive salt sensitive and salt resistant individuals.
Abstract P283: CCL5 Acts As A Vasoconstrictor On Penetrating Arterioles In The Cerebral Circulation By Enhancing 20-HETE Activity
Authors: Crumpler Reece F , Zhang Huawei , Fang Xing , Wang Shaoxun , Zheng Baoying , Elliot Parker S , Ryu Jane J , Strong Luke , Thomas Kirby N , Fan Fan , Roman Richard J
Published: August 2021

20-HETE is synthesized from arachidonic acid by cytochrome P450 (CYP) enzymes 4A and 4F. Inactivating mutations in the CYP enzymes that produce 20-HETE are associated with hypertension and stroke in man. We previously revealed that inactivating variants of CYP4A/F enzymes are associated with dementia in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NS) population. 20-HETE is involved with sodium regulation in the kidney and is a powerful vasoconstrictor. It was recently discovered that CCL5 and 20-HETE share the same receptor, GPR75. We previously found that 20-HETE constricts and augments the myogenic response (MR) of the middle cerebral artery (MCA) and renal afferent arteriole. However, whether CCL5 has any effect on penetrating arterioles (PAs) and interacts with 20-HETE is unknown. We found that GPR75 is expressed in PAs and pericytes in the brain. CYP4A is also expressed in pericytes and is inversely proportional to levels of GPR75 in the brain. In the present study, we found that 20-HETE contributes to the basal myogenic tone of PAs in SD rats. Administration of HET0016, a 20-HETE synthesis inhibitor, dilated the PA by 34 ± 3% (n = 6) under 10 mmHg perfusion pressure. Administration of WIT003, a 20-HETE agonist, constricted the vessel by 23 ± 4% (n = 6) under the same perfusion pressure. We found that CCL5 also reduced PA diameter by 20 ± 4% (n = 7) in SD rats under 10 mmHg perfusion pressure. Moreover, we compared the response to CCL5 in SS rats that are 20-HETE deficient and SS.CYP4A1 transgenic rats in which 20-HETE production is restored. PAs isolated from SS rats treated with 0.1 nM CCL5 constricted by 9 ± 5% (n = 6) while those treated with 10 nM constricted by 12 ± 3% (n = 6). CCL5 had a greater response in PAs from the SS.CYP4A1 strain, and the diameter of the PAs constricted by 14 ± 2% (n = 5) and 24 ± 5% (n = 5) in response to 0.1 and 10 nM CCL5, respectively. These results demonstrate that CCL5 has a direct effect on PAs similar to 20-HETE that acts via the GPR75 receptor. However, further study is needed to determine how CCL5 and 20-HETE interact to promote vasoconstriction. These studies would help further understand the involvement of 20-HETE in disease and potentially identify novel drug targets.
Abstract T1: Prognostic Value Of 24-hour Ambulatory Blood Pressure And Heart Rate Patterns In Diabetes: A 20-year Longitudinal Analysis Of The Chronic Diabetes Complications And All-cause Mortality In Pisa From 1999 Onwards (CHAMP1ON) Study Cohort
Authors: Chiriacò Martina , Sacchetta Luca , Forotti Giovanna , Leonetti Simone , Nesti Lorenzo , Taddei Stefano , Natali Andrea , Solini Anna , Tricò Domenico
Published: August 2021

Background:
Abnormal circadian blood pressure (BP) patterns and reduced heart rate variability (HRV) are established risk factors for cardiovascular events in diabetic patients. However, studies assessing all-cause mortality associated with altered BP patterns and HRV in diabetes are limited by follow-up periods of less than 10 years.

Methods:
We examined a cohort of 349 patients with type 2 diabetes (
n
=284) or type 1 diabetes (
n
=65) recruited in Pisa (Italy) from 1999 and followed-up for 21 years, all with available 24-hour ambulatory BP and HRV monitoring. Dipping, non-dipping and reverse dipping status were defined as a ≥10% decline, <10% decline, and ≥0.1% increase in average night-time systolic BP (SBP) compared with average daytime SBP, respectively.

Results:
After 6,251 person-years of follow-up (median follow-up 21.0 [14.0-21.0] years, 183 [52%] women, age 57.1±11.9 y, BMI 29.4±5.9 kg/m
2
, HbA1c 8.6±2.1%), a total of 136 (39%) deaths occurred. Compared with dippers (n=166), non-dippers (n=144) and reverse dippers (n=39) showed progressively higher prevalence of cardiac autonomic neuropathy (11%, 16% and 31%, respectively), low HRV (45% vs 53% vs 62%), 24-hour hypertension (40%, 60% and 67%), isolated nocturnal hypertension (5%, 27% and 49%), postural hypotension (14%, 26% and 43%), and lower prevalence of white-coat hypertension (31%, 17% and 13%). Reverse dippers and non-dippers had progressively lower mean overall survival (OS) compared with dippers (16.1±5.3 years, 17.5±5.3 years and 18.6±4.6 years, respectively). Reverse dippers also showed an increased risk of all-cause mortality after adjustment for age, sex, BMI, office SBP, plasma glucose, and diabetes duration and type (HR 2.3 [1.4-3.8]). Patients with low HRV had reduced mean OS than those with high HRV (16.9±5.5 and 18.8±4.4, respectively) but similar adjusted risk (HR 1.3 [0.9-1.9]). No significant interactions emerged between BP patterns, HRV and diabetes type on OS.

Conclusions:
Non-dipping and reverse dipping BP patterns are associated with an increased prevalence of cardiac autonomic neuropathy and reduced survival probability in diabetic patients over a 21-year follow-up, with reverse dipping more than doubling the adjusted risk of all-cause mortality.
Abstract T3: Type 2 Myocardial Infarction Predicts Outcome In Hypertensive Crisis Patients: Nationwide Analysis
Authors: Maraey Ahmed M , Elzanaty Ahmed , Elsharnoby Hadeer R , Salem Mahmoud , Khalil Mahmoud , Younes Ahmed , Elsharnouby Mohamed
Published: August 2021

Background:
Type 2 Myocardial infarction (T2MI) can occur in hypertensive crisis patients. The impact of T2MI in this population is poorly understood due to limited available data.

Objective:
To assess the impact of T2MI on patients admitted to the hospital with hypertensive crisis.

Methods:
We queried National Readmission Database (NRD) of year 2018 for adult patients admitted with a primary diagnosis of hypertensive crisis. Patients were excluded if they had type 1 myocardial infarction (T1MI), septic shock, or bleeding in the index admission. Primary outcome was 90-day readmission due to T1MI. Secondary outcome was in-hospital mortality. Subgroup analysis was done according to urgency and emergency presentation. Multivariate regression was done to account for confounders.

Results:
A total of 101211 patients were included in our cohort of whom 3644 (3.6%) were diagnosed with T2MI and 24471 (24.2%) were readmitted within 90 days of discharge. Of those, 912 (3.7%) were diagnosed with T1MI on readmission. T2MI was independently associated with increased odds of 90-day readmission with T1MI (Adjusted odds ratio (aOR): 2.67, 95% CI [1.91-3.75], P=0.000). T2MI effect was observed in hypertensive urgency, and in hypertensive emergency. T2MI was associated with increased in-hospital mortality in hypertensive urgency population (aOR: 4.21, 95% [1.58-11.25], P=0.004) but not in hypertensive emergency (table 1).

Conclusion:
In hypertensive crisis patients, T2MI was associated with increased 90-day readmission with T1MI. Aggressive management of cardiovascular risk factors and risk stratification should be considered at the time of diagnosis.
Immigration and Multicultural Citizenship in Europe: Insights from the Framework Convention for the Protection of National Minorities
Authors: Jacob-Owens Timothy
Published: August 2021

Multicultural citizenship, a set of group-differentiated rights for minority cultural groups, is now a common feature of most domestic legal systems in Europe. The conventional view, widely reflected in practice, suggests that ‘strong’ rights of this sort should be restricted to so-called ‘historical’ minorities. However, the increasingly long-standing presence of distinct cultural groups of immigrant origin raises the question of whether, and to what extent, the latter should also be granted stronger forms of multicultural citizenship. This article addresses this question by reference to the Council of Europe’s Framework Convention for the Protection of National Minorities, a central pillar of the international minority rights regime in Europe. The article analyses the application of the treaty to immigrant-origin groups in the Czech Republic and the United Kingdom, showing that the scope of protection afforded to such groups is stronger than previously assumed, though less far-reaching as compared to their ‘historical’ counterparts.
Relocating the Prophet’s Image: Narrative Motifs and Local Appropriation of the Zarathustra Legend in Pre- and Early Islamic Iran (Part II - North-West Iran)
Authors: Terribili Gianfilippo
Published: August 2021

From the very beginning of Iranian disciplinary studies, the material concerning Zarathustra’s biography has been analysed in depth, firstly to identify the homeland of the Prophet and then to discuss the historical reality of this authoritative figure. Despite the divergences of opinion, emphasis has always been placed on the reconstruction of the figure of Zarathustra and much less on the socio-cultural context in which the image of the Prophet was cultivated. The present paper represents the second part of a larger work (see Terribili 2020) that aims to reverse this perspective and emphasize those data, which link up narrative variations and extensions with local identities. In fact, variations in geographical setting reveal processes of acculturation through which social groups reinvented the influential image of the Prophet within a familiar horizon. In this respect, the Sasanian period proved pivotal in the formation of both Zoroastrian and Iranian communal identities. In the wake of the first work, this second paper approaches aspects connected to the North-West Iran and Ādurbādagān tradition.
Description of Electrogena sartorii sp. nov., a new representative of the genus Electrogena Zurwerra & Tomka, 1985 (Ephemeroptera: Heptageniidae), from Iran using molecular and morphological data
Authors: MOAZZEN MINA , KEIKHOSRAVI ALIREZA , RASTEGAR-POUYANI ESKANDAR
Published: August 2021

A new species, Electrogena sartorii sp. nov., is described at the larval stage using molecular and morphological data from Iran. In addition, two species; Electrogena gibedede Sroka & Godunko, 2012 and Anapos kugleri (Demoulin, 1973) are recorded from Iran for the first time. Considering the fact that many areas in Iran are not well explored an urgent and complete survey, in particular on the order Ephemeroptera, is needed to uncover the real biodiversity.
New species of Eugryllacris (Orthoptera: Gryllacrididae) from Yunnan, China
Authors: LIU JING , YANG HONGQIANG , LU XIANGYI , BIAN XUN
Published: August 2021

This paper describes one new species from Yunnan, China and reports the complete mitogenome. The new species differs from other species of the genus in markings on the frons and pronotum with 1 pair of black spots. The complete mitochondrial genome (mitogenome) of this new species was sequenced and analyzed using High-Throughput Sequencing. The mitogenome was 15513bp in length, comprising of 37 genes and a control region, and its gene order and location are identical to the ancestral insect mitogenome. The protein-coding genes (PCGs) had typical ATN initiation codons, and were terminated by typical TAN stop codons except for COII and ND5. Almost all tRNAs could be folded into the  typical cloverleaf secondary structure except for tRNASer(AGN). All the type specimens are deposited in the Guangxi Normal University.
Coating Polyelectrolyte Multilayers Loaded with Quercetin on Titanium Surfaces by Layer-By-Layer Assembly Technique to Improve Surface Osteogenesis Under Osteoporotic Condition
Authors: Wang Bingzhang , Chen Liang , Xie Jun , Tang Jiahao , Hong Chenxuan , Fang Kanhao , Jin Chen , Huang Chengbin , Xu Tianhao , Yang Lei
Published: August 2021

Titanium (Ti) and its alloy implants are widely used in the field of orthopedics, and osteoporosis is an important reason for implantation failure. This study aimed to establish a quercetin (QTN) controlled release system on the surface of titanium implants and to study its effects
on osteogenesis and osseointegration on the surface of implants. Polyethylenimine (PEI) was first immobilized on a titanium substrate as the base layer, and then, hyaluronic acid/chitosan-quercetin (HA/CS-QTN) multilayer films were assembled on the PEI layer by a self-assembly technique. Fourier
transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM) and contact angle measurements were used to characterize and analyze the samples. The release characteristics of QTN were studied by release assays. The osteogenic ability of the samples was evaluated by experiments
on an osteoporosis rat model and MC3T3-E1 cells. The FTIR, SEM, and contact angle measurements all showed that the PEI substrate layer and HA/CS-QTN multilayer film were successfully immobilized on the titanium matrix. The drug release test showed the successful establishment of a QTN controlled
release system. The in vitro results showed that osteoblasts exhibited higher adhesion, proliferation and differentiation ability on the coated titanium matrix than on the pure titanium surface. In addition, the in vivo results showed that the HA/CS-QTN coating significantly
increased the new bone mass around the implant. By depositing a PEI matrix layer and HA/CS-QTN multilayer films on titanium implants, a controlled release system of QTN was established, which improved implant surface osseointegration under osteoporotic conditions. This study proposes a new
implant therapy strategy for patients with osteoporosis.
The Effect of Wnt Family Member 5a Gene Silencing on the Proliferation of Achondroplasia Using a DNAzymes-CoOOH Nanocomposite
Authors: Xie Hairui , Zhou Lili , Chen Zhijiang , Zhao Hong
Published: August 2021

Achondroplasia is a kind of congenital dysplasia due to the defect of endochondral ossification. Achondroplasia is considered to be a protein folding disease leading to endoplasmic reticulum stress. Endoplasmic reticulum stress may lead to disease by affecting the function and survival
state of chondrocytes, but the specific mechanism requires further study. In this study, bioinformatics methods, online database mining, screening of differentially expressed genes for pathway enrichment, and interaction analysis were conducted to detect the Wnt family member 5a (Wnt5a) gene.
Additionally, we designed a novel DNAzymes-based nanocomposite that can simultaneously silence Wnt5a genes in chondrocytes. The nanocomposite was composed of amino-functionalized cobalt oxyhydroxide nanoflakes modified by DNAzymes that target the Wnt5a gene. Further, we conducted in vitro
experiments to verify that Wnt5a can mediate the mitogen-activated protein kinase signaling pathway through the endoplasmic reticulum stress pathway to affect the proliferation of chondrocytes.
Cu–Co Co-Doped Microporous Coating on Titanium with Osteogenic and Antibacterial Properties
Authors: Zhao Quan-Ming , Li Bo , Yu Fu-Xun , Li Yan-Kun , Wu Jie-Shi , Peng Zhi , He Jie , Han Quan-Sheng , Zhang Lei-Bing , Yi Lei , Xu Rui-Sheng , Jiao Yang
Published: August 2021

Titanium (Ti) and its alloys are widely used in bone surgery by virtue of their excellent mechanical properties and good biocompatibility; however, complications such as loosening and sinking have been reported post-implantation. Herein we deposited a copper–cobalt (Cu–Co)
co-doped titanium dioxide (TUO) coating on the surface of Ti implants by microarc oxidation. The osteogenic and antimicrobial properties of the coating were evaluated by in vitro experiments, and we also assessed β-catenin expression levels on different sample surfaces.
Our results revealed that the coating promoted the adhesion, proliferation, and differentiation of MG63 osteoblasts, and TUO coating promoted β-catenin expression; moreover, the proliferation of Staphylococcus aureus was inhibited. To summarize, we report that Cu–Co
co-doping can enhance the osteogenic and antibacterial activities of orthopedic Ti implants, leading to potentially improved clinical performance.
Moving Research into Practice: Can We Make Dissemination Stick?
Authors: Cook Bryan G. , Cook Lysandra , Landrum Timothy J.
Published: August 2021

Although researchers in special education have made significant advances in defining and identifying evidence-based practices, scholars often constitute an insular group that disseminates research findings primarily through outlets and venues targeting like-minded researchers using traditional approaches. Thus, despite tangible results in determining what works, using dissemination approaches that fail to resonate with or influence practitioners represents an important but often overlooked contributor to the ongoing research-to-practice gap in special education. The authors argue that empirical and theoretical literature outside of special education may offer insight into how ideas take hold, which may be especially relevant to the effective dissemination of evidence-based practices. Drawing on Heath and Heath's (2008) model, the authors describe 6 characteristics of messages that are likely to “stick”: (a) simple, (b) unexpected, (c) concrete, (d) credible, (e) emotional, and (f) stories. The authors consider each in terms of implications for dissemination of special education research findings, and urge special education researchers to consider researching, refining, and applying dissemination strategies that can make special education research matter on a broader scale.
How to Look at the Covid-19 Pandemic Through Climate Governance?
Authors: Nanda Samar
Published: August 2021

Climate change has been the ‘wicked problem’ the world has struggled to address so far. Further, the Covid-19 pandemic has deeply affected the soft underbelly of global governance by redrawing boundaries and fissures in the existing system. The pandemic is possibly the single biggest event in the post-Second World War period or in the last seventy years to shape and affect human emotion, response and survival instincts. The world has seen catastrophic changes and huge loss of life. There are multiple parallels and differences between the two of the most significant challenges faced by the humanity. Even though climate scientists were harping on the catastrophic impact of climate change for the last four decades, at the broader human consciousness level, the severity of the problem has never sunk into the common psyche. Covid-19 is a vivid example as to how a pathogen-led pandemic can torment and pervade the all-powerful and the highest evolved species on the earth, that is, the mankind. In this backdrop, climate governance and an ideal-type governance typology is being looked at to provide some key insights and possible answers for the future. The concern has been looked through at two levels: personal at the behavioural level and collective at the global-scale levels. Future prescriptions rooted in the current realities have been explored to find a way out of the crisis and the key learning points from the pandemic to face the future with more confidence and certainty.
Social Mobility and Tooth Loss: A Systematic Review and Meta-analysis
Authors: Celeste R.K. , Darin-Mattsson A. , Lennartsson C. , Listl S. , Peres M.A. , Fritzell J.
Published: August 2021

This study systematically reviews the evidence of the association between life course social mobility and tooth loss among middle-aged and older people. PubMed, Scopus, Embase, and Web of Science were systematically searched in addition to gray literature and contact with the authors. Data on tooth loss were collated for a 4-category social mobility variable (persistently high, upward or downward mobility, and persistently low) for studies with data on socioeconomic status (SES) before age 12 y and after age 30 y. Several study characteristics were extracted to investigate heterogeneity in a random effect meta-analysis. A total of 1,384 studies were identified and assessed for eligibility by reading titles and abstracts; 21 original articles were included, of which 18 provided sufficient data for a meta-analysis with 40 analytical data sets from 26 countries. In comparison with individuals with persistently high social mobility, the pooled odds ratios (ORs) for the other categories were as follows: upwardly mobile, OR = 1.73 (95% CI, 1.53 to 1.95); downwardly mobile, OR = 2.52 (95% CI, 2.19 to 2.90); and persistently low, OR = 3.96 (95% CI, 3.13 to 5.03). A high degree of heterogeneity was found( I2 > 78%), and subgroup analysis was performed with 17 study-level characteristics; however, none could explain heterogeneity consistently in these 3 social mobility categories. SES in childhood and adulthood is associated with tooth loss, but the high degree of heterogeneity prevented us from forming a robust conclusion on whether upwardly or downwardly mobile SES may be more detrimental. The large variability in effect size among the studies suggests that contextual factors may play an important role in explaining the difference in the effects of low SES in different life stages (PROSPERO CRD42018092427).
Privacy Worlds: Exploring Values and Design in the Development of the Tor Anonymity Network
Authors: Collier Ben , Stewart James
Published: August 2021

This paper explores, through empirical research, how values, engineering practices, and technological design decisions shape one another in the development of privacy technologies. We propose the concept of “privacy worlds” to explore the values and design practices of the engineers of one of the world’s most notable (and contentious) privacy technologies: the Tor network. By following Tor’s design and development we show a privacy world emerging—one centered on a construction of privacy understood through the topology of structural power in the Internet backbone. This central “cipher” discourse renders privacy as a problem that can be “solved” through engineering, allowing the translation and representation of different groups of imagined users, adversaries, and technical aspects of the Internet in the language of the system. It also stabilizes a “flattened,” neutralized conception of privacy, risking stripping it of its political and cultural depth. We argue for an enriched empirical focus on design practices in privacy technologies, both as sites where values and material power are shaped, and as a place where the various worlds that will go on to cluster around them—of users, maintainers, and others—are imagined and reconciled.