bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of Genetic Diversity and Antibiotic Options for Clinical Listeria monocytogenes Infections in China
Authors: Yu Wei , Huang Yicheng , Ying Chaoqun , Zhou Yanzi , Zhang Li , Zhang Jiajie , Chen Yingsha , Qiu Yunqing
Published: April 2021

Background

The aim of this study was to investigate the mechanism of Listeria monocytogenes (Lm) pathogenicity and resistance. In addition, the effect of existing treatment options against Lm were systematically evaluated.

Methods

Six Lm isolates were collected and antimicrobial susceptibility testing of 15 antibiotics were done. Subsequently, whole genome sequencing and bioinformatics analysis were performed. Biofilm formation was evaluated by crystal violet staining. Furthermore, the effect of meropenem, linezolid, penicillin, vancomycin, and trimethoprim/sulfamethoxazole were determined using the time-kill assay.

Results

Four sequence types (STs) were identified (ST1, ST3, ST87, ST451). Multivirulence-locus sequence typing results classified ST87 isolates into cluster. All isolates were resistant to fosfomycin and daptomycin with fosX and mprF. In addition, a total of 80 virulence genes were detected and 72 genes were found in all 6 isolates. Seven genes associated with hemolysin were found in 26530 and 115423. However, due to lack of one genomic island including virulence genes related to flagellar synthesis, isolate 115423 produced less biofilm than 5 other isolates. Although all isolates were susceptible to vancomycin, the in vitro time-kill assay showed that vancomycin monotherapy resulted in less than 2 log10 cerebrospinal fluid (CFU)/mL compared with the initial count. Trimethoprim/sulfamethoxazole at serum or CFU concentrations had bactericidal effect against tested Lm strains at 24 hours.

Conclusions

ST87 clone was a typical prevalent ST in clinical Lm isolates in China. Trimethoprim/sulfamethoxazole might be greater potential therapeutic option against Lm infections.
Major components of the KARRIKIN INSENSITIVE2-dependent signaling pathway are conserved in the liverwortMarchantia polymorpha
Authors: Mizuno Yohei , Komatsu Aino , Shimazaki Shota , Naramoto Satoshi , Inoue Keisuke , Xie Xiaonan , Ishizaki Kimitsune , Kohchi Takayuki , Kyozuka Junko
Published: April 2021

KARRIKIN INSENSITIVE2 (KAI2) was first identified as a receptor of karrikins, smoke-derived germination stimulants. KAI2 is also considered a receptor of an unidentified endogenous molecule called the KAI2 ligand. Upon KAI2 activation, signals are transmitted through the degradation of D53/SMXL proteins via MAX2-dependent ubiquitination. Although components in the KAI2-dependent signaling pathway, namely MpKAI2A and MpKAI2B, MpMAX2, and MpSMXL, exist in the genome of the liverwort Marchantia polymorpha, their functions remain unknown. Here, we show that early thallus growth is retarded and gemma dormancy in the dark is suppressed in Mpkai2a and Mpmax2 loss-of-function mutants. These defects are counteracted in Mpkai2a Mpsmxl and Mpmax2 Mpsmxl double mutants indicating that MpKAI2A, MpMAX2, and MpSMXL act in the same genetic pathway. Introduction of MpSMXLd53, in which a domain required for degradation is mutated, into wild-type plants mimicks Mpkai2a and Mpmax2 plants. In addition, the detection of citrine fluorescence in Nicotiana benthamiana cells transiently expressing a SMXL-Citrine fusion protein requires treatment with MG132, a proteasome inhibitor. These findings imply that MpSMXL is subjected to degradation, and that the degradation of MpSMXL is crucial for MpKAI2A-dependent signaling in M. polymorpha. Therefore, we claim that the basic mechanisms in the KAI2-dependent signaling pathway are conserved in M. polymorpha.
The Efficacy, Adverse Events, and Withdrawal Rates of the Pharmacological Management of Chronic Spinal Cord Injury Pain: A Systematic Review and Meta-Analysis
Authors: Canavan Clare , Inoue Takayoshi , McMahon Sinead , Doody Catherine , Blake Catherine , Fullen Brona M
Published: April 2021

Objective

To establish the efficacy of medications, incidence of adverse events (AEs), and withdrawal rates associated with the pharmacological management of chronic spinal cord injury pain.

Methodology

PubMed, MEDLINE, Embase, CINAHL, Web of Science, CENTRAL, and PsycINFO were searched (November 2017) and updated (January 2020). Two independent review authors screened and identified papers for inclusion.

Results

Twenty-one studies met inclusion requirements for efficacy analysis and 17 for AE and withdrawal rate analysis; no additional papers were included from the updated 2020 search. Treatments were divided into six categories: anticonvulsants (n = 6), antidepressants (n = 3), analgesics (n = 8), anti-spasticity medications (n = 2), cannabinoids (n = 1), and other (n = 2). Trials of anticonvulsants, antidepressants, and cannabinoids included long-term follow-up trials (2 weeks to 4 months), and trials of analgesics and anti-spasticity medications, among others, were short-term trials (0–2 days). Effectiveness for neuropathic pain was found for pregabalin (3/3 studies) and lidocaine (2/3 studies). Studies using ketamine also reported effectiveness (2/2), but the quality of these papers was rated as poor. The most frequently reported AEs included dizziness, dry mouth, nausea, and constipation. Pregabalin was associated with a higher risk of somnolence (risk ratio [RR] 3.15, 95% confidence interval [CI]: 2.00–4.98) and dizziness (RR 2.9, 95% CI: 1.58–5.30). Ketamine was associated with a higher risk of reduced vision (RR 9.00, 95% CI: 0.05–146.11), dizziness (RR 8.33, 95% CI: 1.73–40.10), and somnolence (RR 7.00, 95% CI: 1.73–40.1). Withdrawal rates ranged from 18.4% for antidepressants to 0–30% for anticonvulsants, 0–10% for anti-spasticity medications, 0–48% for analgesics, 28.6% for cannabinoids, and 0–22.2% for other medications.

Conclusion

Pregabalin was found to be effective for neuropathic pain vs placebo. Cannabinoids were ineffective for neuropathic pain. AEs are a common cause for withdrawal. The nature of AEs was poorly reported, and AE reporting should be improved in future randomized controlled trials.
Private Information, Securities Lending, and Asset Prices
Authors: Nezafat Mahdi , Schroder Mark
Published: April 2021

We study the role of private information in the equity lending market in a rational expectations model with endogenous loan fees. When all investors are privately informed, an increase in information precision reduces the fee by increasing trade aggressiveness and decreasing demand dispersion. However, when some investors are uninformed, the information asymmetry tends to increase the fee, and, thus, the overall effect of an increase in precision is ambiguous. We show that the fee can be incrementally informative given the stock price and that fee opaqueness tends to increase the fee but has an ambiguous effect on the stock price.
SODIUM ACETATE ATTENUATES MYOCARDIAL TRIGLYCERIDE ACCUMULATION IN COMBINED ORAL CONTRACEPTIVE-TREATED RATS BY SUPPRESSING ADENOSINE DEAMINASE/XANTHINE OXIDASE-DEPENDENT PATHWAY
Authors: Omolekulo Tolulope , Olatunji Lawrence Aderemi
Published: April 2021

Objective:

Myocardial triglyceride accumulation characterizes many cardiovascular disorders. Cardiovascular disorders are the leading cause of mortality and morbidity worldwide. Continuous usage of Combined Oral Contraceptive (COC) has been associated with disrupted lipid metabolism, however, the exact mechanism is not clear. Adenosine Deaminase (ADA) and Xanthine Oxidase (XO) are reportedly involved in cardiometabolic derangement, particularly lipid dysmetabolism. We, therefore hypothesized that increased ADA and XO activities and elevated uric acid level are involved in COC-induced myocardial triglyceride accumulation. This study also aimed at investigating the ameliorative effects of sodium acetate on COC-induced myocardial lipid accumulation in female Wistar rats.

Design and method:

Female Wistar rats received vehicle per ostium (p.o.) and COC (1.0 microgram of ethinylestradiol plus 5.0 microgram of levonorgestrel; p.o.) with or without sodium acetate (ACE; 200 miligram/kilogram; p.o.) for 8 weeks (n = 6/group). Insulin resistance was estimated by homeostatic model of assessment whereas glucose tolerance was determined by oral glucose tolerance test. Other biochemical variables were evaluated using standard methods. Data were analysed using one-way analysis of variance followed by Bonferroni's post hoc test. Significant differences were accepted at p < 0.05.

Results:

Treatment with COC led to increased 1-h postload glucose response, plasma insulin, triglyceride-glucose index, insulin resistance and impaired glucose tolerance. COC treatment also resulted in increased plasma and cardiac free fatty acid, triglyceride, triglyceride/high density lipoprotein-cholesterol ratio, malondialdehyde, uric acid, ADA and XO activities. On the other hand, COC led to reduction in nitric oxide level. However, sodium acetate significantly ameliorated the alterations induced by COC treatment, but XO activity remains elevated during COC treatment.

Conclusions:

Therefore, sodium acetate would impact positively on myocardial lipid accumulation-related cardiovascular disorders, at least in part, by suppression of adenosine deaminase/xanthine oxidase/uric acid-dependent pathway.
PREDICTIVE POWER OF 24-HOUR AMBULATORY PULSE PRESSURE AND ITS COMPONENTS FOR MORTALITY AND CARDIOVASCULAR OUTCOMES IN 11,848 PARTICIPANTS RECRUITED FROM 13 POPULATIONS
Authors: Gavish Benjamin , Bursztyn Michael , Yang Wen Yi , Thijs Lutgrade , Zhang Zhen-Yu , Boggia José , Hansen Tine W. , Asayama Kei , Ohkubo Takayoshi , Kikuya Masahiro , Imai Yutaka , Stolarz-Skrzypek Katarzyna , Li Yan , Wang Ji -Guang , Casiglia Edoardo , Malyutina Sofia , Staessen Jan
Published: April 2021

Objective:

The role of pulse pressure ’widening’ at older age, as a cardiovascular risk factor is still controversial. 24-hour ambulatory pulse pressure (PP) was previously expressed as a sum of two components: ’elastic’ PP (elPP) and 'stiffening’ PP (stPP) associated, respectively, with arterial stiffness at diastole and the change in stiffness during systole. We investigated the association of PP, elPP and stPP (’PP variables’) with mortality and composite cardiovascular (CV) events in different age classes.

Design and method:

Longitudinal population-based cohort study of adults from Europe, Asia, and South America with baseline observations, including 24-hour ambulatory BP. Age classes were age < 50, 50–60, 60–70, and > 70 year. Co-primary endpoints were total mortality and composite CV events. Hazard ratios (HRs) per 1-SD increase in the PP variables were calculated from multivariable adjusted Cox regression models.

Results:

The 11,848 participants from 13 cohorts (age 53 ± 16, 50% males) were followed up for 13.4 ± 6.9 years. A total of 2946 participants died (18.1 per 1000 person-years) and 2093 experienced a fatal or non-fatal cardiovascular event (12.9 per 1000 person-years). PP components were uncorrelated (r = -0.07), and the ratio stPP/elPP was 0.143. PP and elPP showed a curvilinear relationship with age reaching a nadir around middle-age, whereas stPP steadily increased from age 30 years onwards. In persons ?50 years of age, but not in those < 50 years, both PP and elPP were associated with increased risk for the primary endpoints. For total mortality and cardiovascular events hazard ratios for PP decreased from 50–60 years old participants to those aged > 70 years (P < 0.02); from 1.29[95%CI: 1.13–1.46] to 1.11[1.05–1.15], and from 1.40[1.24–1.58] to 1.16[1.10–1.23], respectively, and for elPP for cardiovascular events; from 1.29[1.14–1.45] to 1.16[1.09–1.23]. On the other hand, stPP was associated with increased risk for the primary endpoints in subjects 50 to 60 years of age but not in the older age groups.

Conclusions:

The age-related increase in PP variables is not reflected in a corresponding PP-associated increase in cardiovascular risk. Results support the view that normal ageing weakens the association of PP variables with CV risk.
SUBSTANTIAL CHANGES IN CARDIOVASCULAR HEALTH OCCUR FROM ADOLESCENCE TO EMERGING ADULTHOOD
Authors: Park Chloe , Taylor Hannah , Rapala Alicja , Williams Suzanne , Jones Siana , Howe Laura , Chaturvedi Nish , Hughes Alun
Published: April 2021

Objective:

17–24 years is a distinct period of lifestyle change. However little is known regarding changes in cardiovascular (CV) health during this time. We explored changes in Left ventricle (LV) structure and function, arterial stiffness, compliance and resistance in a large population-based birth cohort and investigated associations with body composition, haemodynamics and lifestyle choices.

Design and method:

724 participants had repeated echocardiography, blood pressure (BP) and body composition (using DEXA) measures aged 17y and 24y. Change in key outcomes and exposures from 17–24y were derived. Principal Component Analysis (PCA) was applied to reduce intercorrelated exposures into groups of independent factors. Principal Component (PC) 1: contained factors relating to change in blood pressure, PC2: change in body size (body mass index, fat mass and lean mass), and PC3: lifestyle (smoking and alcohol)). Linear regression assessed associations between PCs and change in CV outcomes.

Results:

From 17–24y systolic BP, pulse pressure and alcohol use decreased. All other exposures increased (Table). Indexed LV mass (LVMI) and systolic function (cardiac output (CO), Tissue Doppler peak S) increased, while diastolic function declined (Mitral E:e’). Pulse wave velocity (PWV) and compliance (TAC) increased, peripheral resistance (TPR) decreased. In age and sex adjusted regression analysis PC2 had the strongest association with all LV changes. Vascular changes (PWV,TPR) were most strongly associated with PC1. While PC3 showed the weakest associations. All associations remained after further adjustment for socioeconomic status, birth weight and education

Conclusions:

Substantial CV changes occur from adolescence to emerging adulthood. Changes in body size and composition have a considerable effect on LV structure and function, while changes in vascular health are associated with changing haemodynamics. These results imply that despite being relatively early in the life-course, this is an important time to control CV risk factors to improve future CV health.
A NEW GENETIC RISK SCORE FOR BLOOD PRESSURE STRONGLY ASSOCIATES WITH THE INCIDENCE OF HYPERTENSION AND CARDIOVASCULAR ENDPOINTS IN TWO SWEDISH COHORTS
Authors: Giontella Alice , Sjögren Marketa , Lotta Luca , Overton John , Baras Aris , Center Regeneron Genetics , Cristiano Fava , Melander Olle
Published: April 2021

Objective:

The clinical value of the polygenetic component of blood pressure is commonly questioned. We constructed a new BP-GRS, including the most recently published variants genome wide significantly associated with either systolic or diastolic blood pressure (SBP, DBP), to investigate its association to the incidence of hypertension and cardiovascular endpoints in two urban-based cohorts: the Malmö Diet and Cancer (MDC, n = 29295) and Malmö Preventive Project (MPP, n = 9367).

Design and method:

The genotyping was performed with the Illumina GWAS chip (GSA array v1) and a weighted BP-GRS858 based on 858 SNPs was calculated, normalized, and divided into deciles. Logistic regression and survival Cox Regression models were used to test the associations of the new BP-GRS858 with outcomes.

Results:

At baseline, we found a difference of 11.2 mmHg (SBP) and 6 mmHg (DBP) between the top and the bottom deciles of BP-GRS858. In MPP, the top vs bottom decile of BP-GRS858 was associated with a doubled risk of incident hypertension (OR, 95%CI: 2.2, 1.7–2.8, p-value: 2.0E-10). In MDC, when comparing the top and bottom deciles of BP-GRS858, significant association was found between the age and sex adjusted BP-GRS858 and the incidence of total cardiovascular events (HR, 95%CI: 1.5; 1.3–1.7; p-value: 1.5E-12), stroke (HR, 95%CI: 1.6, 1.4–1.8; p-value: 2.1E-9), coronary artery disease (HR, 95%CI: 1.5, 1.4–1.8; p-value:1.3E-11), heart failure (HR, 95%CI: 1.5, 1.3–1.8, p-value: 2.5E-5), atrial fibrillation (HR, 95%CI: 1.2–1.1,1.4; p-value: 0.001) and total mortality (HR, 95%CI: 1.1, 1.0–1.2; p-value: 0.009). Most of these associations remained significant after adjusting for traditional risk factors, including hypertension.

Conclusions:

Our findings confirm that adding novel genetic variants into a polygenic BP-GRS, despite very low effect sizes of individual variants, increases its predictive performance. GRS858 contributes with clinically meaningful predictive information regarding future hypertension and CVD risk. Given that the exposure to high polygenetic risk starts at birth, we suggest that the BP-GRS858 might be useful to identify children or adolescents who would benefit from early hypertension screening and treatment.
AFFERENT PEPTIDERGIC NERVE FIBERS – IMPORTANCE FOR THE SALT METABOLISM BEYOND THE KIDNEYS?
Authors: Ditting Tilmann , Rodionova Kristina , Reeh Peter , Schmieder Roland , Schiffer Mario , Amann Kerstin , Ott Christianroland , Veelken Roland
Published: April 2021

Objective:

Sodium can be accumulated without commensurate water retention in the skin (non-osmotic sodium storage). Macrophages play a pivotal role in this context and their depletion can induce salt-sensitive hypertension. On the other hand renal afferent peptidergic nerves are involved. Since the skin is also densely innervated by afferent peptidergic nerves we hypothesized that high salt diet might enhance the release of neuropeptides from these nerve fibers.

Design and method:

In a cross-over design, two groups of rats (n = 6, each) were fed either low salt diet (LS; 0.2%) with free access to tab water for 14 days or high salt diet (HS; 8%) with free access to 0.9% saline as drinking water. After 14 days a skin sample (3x3 mm) of the groin area was excised, and the diet was switched for another 14 days. Then a contralateral skin sample was taken. Tissue analyzed in an organ-bath and calcitonin gene related peptide (CGRP) content in the supernatant was measured with ELISA.

Results:

After two baseline measurements within 5 min, the tissue was superfused with hypertonic saline (4.5%) for 5 min, and three further samples of the supernatant were taken every 5 min. Baseline CGRP release was similar with both diets (LS 11.9 ± 1.5 vs HS 13.6 ± 1.5ng/g skin). Maximum release was higher with HS diet (LS 17.5 ± 1.8 vs HS 29.8 ± 1.3ng/g skin; P < 0.05). After diet switch the results were similar: baseline LS 9.4 ± 1.2 vs HS 10.1 ± 3 however, in rats previously on HS diet release tended to be higher with LS diet, nevertheless with HS diet the release was higher again (LS 19.7 ± 2.1 vs HS 29.3 ± 1.7; P < 0.05).

Conclusions:

High sodium diet sensitized neuropeptide release from peptidergic sensory nerves in the skin. Hence peptidergic afferent nerves might be an integrated body-wide system involved in sodium handling in very different target areas like skin and kidney. Putative peptidergic mechanisms (vasoregulation, chemotaxis) remain to be determined in this respect.
INTROGRESSION OF A BROWN NORWAY CHROMOSOME 2 FRAGMENT INTO DAHL SALT-SENSITIVE RATS EXERTS ANTI- AND PRO-INFLAMMATORY EFFECTS UNDER A NORMAL AND HIGH-SALT DIET, RESPECTIVELY
Authors: Berillo Olga , Ouerd Sofiane , Rehman Asia , Richer Chantal , Sinnett Daniel , Kwitek Anne E. , Paradis Pierre , Schiffrin Ernesto L.
Published: April 2021

Objective:

Chromosome 2 (Chr2) introgression from normotensive Brown Norway (BN) rats into hypertensive Dahl salt-sensitive (SS) background (SB2) reduced blood pressure (BP) and vascular inflammation under normal-salt diet (NSD). We hypothesized that BN Chr2 contains anti-inflammatory genes that could reduce BP elevation and vascular inflammation in rats fed NSD and high-salt diet (HSD).

Design and method:

Four- to 6-week-old male SS and congenic rats containing the BN Chr2 distal (SB2a) and middle segment (SB2b) were fed NSD or HSD (4% NaCl) for 8 weeks. BP was determined by telemetry, reactive oxygen species generation using dihydroethidium staining, and vascular cell adhesion molecule 1 and monocyte chemoattractant protein-1 expression and monocyte/macrophage infiltration by immunofluorescence in aorta or perivascular fat. RNA was extracted from aorta and used for small and total RNA-sequencing. Differentially expressed genes (DEGs) were identified with fold change > 1.3 and fold discovery rate < 0.05 and some of them were validated with reverse transcription-quantitative PCR (RT-qPCR).

Results:

SS Systolic BP was 145 ± 2 mm Hg under NSD and 168 ± 1 mm Hg under HSD, which was lower in SB2a and SB2b SBP (125 ± 3 and 127 ± 6, P < 0.05) under NSD but similar under HSD. Examination of inflammation markers revealed that SB2a presented less and more inflammation under NSD and HSD, respectively, compared to SS. DEGs were identified in SB2a vs. SS uniquely under NSD (27) and HSD (608) and under both diet (7), and in SB2b vs. SS uniquely under NSD (133) and HSD (9) and under both diet (12). DEGs encoded within BN Chr2a were identified uniquely under NSD (2) and HSD (8), and in both diets (3). RNA-sequencing and RT-qPCR validation identified two DEGs encoded within BN Chr2 distal segment that could play a role in the vascular inflammation. These were down-regulated glutamyl aminopeptidase (Enpep) that was anti-inflammatory under NSD and up-regulated heparan sulfate 2-O-sulfotransferase 1 (Hs2st1) that was pro-inflammatory under HSD.

Conclusions:

Two DEGs encoded within introgressed BN Chr2 distal segment were identified: Enpep associated with decreased vascular inflammation under NSD, and Hs2st1, associated with elevated vascular inflammation under HSD.
THE STUDY ON THE CARDIAC AND VASCULAR CHARACTERISTICS AND THEIR RELATIONSHIPS TO THE COGNITIVE FUNCTION IN PERIMENOPAUSAL WOMEN WITH HYPERTENSION
Authors: Shi Hongxia , Yu Jing
Published: April 2021

Objective:

To explore the relationship and characteristics of cardiac, vascular and cognitive function in perimenopausal women with hypertension.

Design and method:

Female patients with hypertension aged 45–60 years old in Lanzhou University Second Hospital were selected as the case group (N = 355). And 355 age-matched healthy perimenopausal women were selected as control group. All subjects were surveyed by questionnaire for general characteristics. The blood pressure, heart rate, body mass index (BMI), waist-hip ratio and serum lipid including total cholesterol (TC), triglyceride (TG) and LDL cholesterol (LDL-C) were measured at the same time. Echocardiography was used to measure cardiac structure and function. The cardio-ankle vascular index (CAVI) and ankle-arm index (ABI) were detected also. The cognitive functions of all subjects were evaluated by mini-mental state examination (MMSE). All data were analyzed by SPSS20.0 software.

Results:

1) The influence factors of perimenopausal hypertensive women were less education and faster heart rate. 2) Compared with healthy group, there were significant difference on the left atrial diameter (LAd) [(33.11 ± 3.37) vs (28.91 ± 2.45)mm], and left ventricular posterior wall thickness (LVPWT) [(11.23 ± 1.22) vs (9.02 ± 0.86)mm] in perimenopausal hypertensive women (P < 0.05). 3) Hypertensive female also showed the significant differences in E/e’ [(8.08 ± 1.34) vs (7.46 ± 1.18)], interval e’ [(8.11 ± 1.70) vs (9.00 ± 1.75)cm/s] and lateral e’ [(10.46 ± 2.43) vs (11.42 ± 2.80)cm/s] (P < 0.05). 4) CAVI was higher in hypertension group than that of control group (P < 0.05). 5) More mild cognitive impairment patients were found in hypertension group than that of the control group(p < 0.05). 6) The main influencing factors of cognitive function among perimenopausal women with hypertension were age, menopause and the vascular dysfunction(p < 0.05).

Conclusions:

Family history of hypertension, high salt intake, alcohol abuse, poor education, heart rate and menopause may be the affect factors of hypertension among perimenopausal women. The influencing factors of cognitive function probably are age, arteriosclerosis and menopause, and also may promote the cognitive dysfunction among perimenopausal women with hypertension.
SATURATED FATTY ACIDS IN ERYTHROCYTE MEMBRANES IN ADOLESCENTS WITH TYPE 1 DIABETES MELLITUS
Authors: Marcon Denise , Tagetti Agela , Giontella Alice , Monamì Giada , Branz Lorella , Bortolotti Stefano , Piona Claudia , Morandi Anita , Trento Laura , Minuz Pietro , Maffeis Claudio , Fava Cristiano
Published: April 2021

Objective:

Type 1 diabetes mellitus (T1DM) is associated with early development of atherosclerosis. The aim of this study was to assess the association between saturated fatty acids (SFAs) contained in erythrocyte membranes and some indices of vascular damage in a sample of adolescents with T1DM.

Design and method:

Participants in regular follow-up at the Paediatric Diabetology Unit of Verona were sent for evaluation at the Vascular Laboratory of the General Medicine & Hypertension Unit Central blood pressure (BP), Pulse Wave Velocity (PWV) and Pulse Wave Analysis (PWA) were measured by the SphygmoCor Xcel, carotid Intima Media Thickness (cIMT) and carotid distensibility (DC) by ultrasound and elaborated with a dedicated hardware. Blood samples were evaluated for erythrocyte membrane SFA, expressed as a percentage of total Fatty Acids (FAs).

Results:

Hundred and forty-seven adolescents (78 males and 69 females, mean age 17,25 ± 1,93 years) were studied. Fifteen patients were classified as hypertensive (10,2%) according to current European Guidelines. Thirteen patients had central systolic BP (cSBP) (8,8%), 60 cIMT (40,8%), 49 (33,3%) DC and 1 PWV (0,7%) above the 95th percentile for sex and age/height. We observed a correlation between total SFAs and cSB and z-cSBP (r = 0,260 and 0,269 respectively, p < 0,05), not confirmed when each SFA was analysed separately. Furthermore, a positive correlation between total SFAs and either PWV or z-PWV was detectable (r = 0,241 and 0,251 respectively, p < 0,05). The latter association remained significant even after adjustment for age, sex, Body Mass Index (BMI), duration of diabetes, HbA1c, total cholesterol, triglycerides-HDL ratio. Total SFAs were also associated with BMI (r = 0,191, p < 0,05).

Conclusions:

Erythrocyte membrane FAs are associated with vascular (cSBP and PWV) and anthropometric parameters in patients with T1DM. The amount of SFAs in membranes does not depend only on diet, as they are also neo-synthetized from glucidic precursors. Thus, it can be speculated that a bad glycemic control could translate into a higher substrate amount to produce the different SFAs. Further studies are needed to better understand the mechanisms and the regulations of these pathways
THE IMPORTANCE OF B2 CELLS IN THE HYPERTENSION AND PATHOPHYSIOLOGY OF PLACENTAL ISCHEMIA DURING PREGNANCY
Authors: Lamarca Babbette , Herrock Owen , Fitzgerald Sarah , Lemonb James , Deer Evangelin , Ibrahim Tarik , Campbell Nathan , Amaral Lorena
Published: April 2021

Objective:

Preeclampsia (PE), is characterized by placental ischemia, inflammation, hypertension and IUGR. Antibodies activating the angiotensin II type I receptor (AT1-AA) activate cytolytic Natural Killer cells (NK) and cause clinical features of PE. The Reduced uterine perfusion pressure (RUPP) pregnant rat model of PE has elevated AT1-AA, NK cells and blood pressure. B cell depletion or AT1-AA epitope binding protein (‘n7AAc’) improved hypertension and AT1-AA activity and NK cells in RUPP rats. One unanswered question is the importance of B2 cells vs B1 cells in the production of the AT1-AA and thus the pathology of PE.

Design and method:

To test this hypothesis, splenic B Cells and B2 cells were isolated from RUPP rats on Gestation Day (GD) 19 and transferred into NP rats on GD12. Blood pressure (MAP) and cNKs were measured by flow cytometry on GD19. To test the role of AT1-AA in the hypertension, ‘n7AAc’ was administered to a group of recipient rats on GD14.

Results:

MAP increased in NP+RUPP B cells to 117 ± 1 mmHg, n = 10, and to 111 mmHg ± 3, n = 8, in NP+RUPP B2 cells, compared to NP rats, n = 10 (p < 0.001). ‘n7AAc’ attenuated hypertension in response to total RUPP B cells (99 mmHg ± 6, n = 5)(p < 0.01) and in response to RUPP B2 s (100 mmHg ± 5, p = 0.08). Circulating and placental cNKs were elevated with total RUPP B cells and RUPP B2 cells compared to NP. Circulating cNKs were elevated in NP+RUPPBcells (6 ± 2.5, n = 5)(p < 0.01) and in NP+RUPP B2 cells (8 ± 3.33, n = 4)(p < 0.01) compared to NP (0.67 ± 0.33, n = 10). Placental cNKs were elevated in NP+RUPPBcells (2.32 ± 0.73, n = 6)(p < 0.01) and in NP+RUPP B2 cells (1.33 ± 0.24, n = 3)(p < 0.01) compared to NP (0.2250 ± 0.133, n = 10).

Conclusions:

We conclude that RUPP total B Cells and RUPP B2 cells cause hypertension and NK cell activation via secretion of the AT1-AA during pregnancy. However, our studies do not rule out the importance of B1 cells in hypertension and AT1-AA production during PE or RUPP. Future studies from our laboratory will further examine B1 cells in the pathology of PE.
LOW DOSE SPIRONOLACTONE PROTECTS EXPERIMENTALLY-INDUCED POLYCYSTIC OVARIAN SYNDROME FROM INSULIN-RESISTANT METABOLIC DISTURBANCES
Authors: Adeyanju Oluwaseun , Falodun Timothy
Published: April 2021

Objective:

Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder in women of reproductive age and hyperandrogenism is a prominent feature of PCOS resulting in infertility and increased risk of developing metabolic disorders including insulin resistance (IR), abdominal adiposity, glucose intolerance and cardiovascular diseases. Spironolactone (SPL), a non-selective mineralocorticoid receptor (MR) antagonist, has been in wide clinical use for several decades. In this study, we investigated the effects of SPL on IR and metabolic disturbances in letrozole-induced PCOS rats.

Design and method:

Eighteen adults female Wistar rats were randomly divided into 3 groups and treated with vehicle, letrozole (LET; 1 mg/kg) and LET + SPL (SPL; 0.25 mg/kg), p.o. once daily for 21 consecutive days.

Results:

Results showed that LET treatment induced PCOS characterized by elevated plasma testosterone and luteinizing hormone (LH) accompanied with increased body weight and visceral adiposity, IR, glucose intolerance, dyslipidemia and altered histomorphological ovaries. Treatment with SPL however attenuated the elevated testosterone in LET-induced PCOS model accompanied with a reversal in all the observed alterations.

Conclusions:

Taken together, analysis of the physical, biochemical and histological evidences shows that the protective effect of this very low dose spironolactone may be through its anti-androgenic mechanism. In conclusion, this study shows for first time, the protective effect of spironolactone at this dose against insulin resistance and metabolic disturbances induced by experimental PCOS. The protective mechanisms appears to be through suppression of elevated circulating testosterone. Therefore, SPL alone at this very low dose might be very effective as against its combination with other known anti-androgenic drugs in the treatment of characteristic features of PCOS.
SODIUM INTAKE, LIFE EXPECTANCY AND ALL-CAUSE MORTALITY
Authors: Messerli Franz , Hoftetter Louis , Syrogiannouli Lamprini , Rexhaj Emrush , Siontis George , Seiler Christian , Bangalore Sripal
Published: April 2021

Objective:

Since dietary sodium intake has been identified as a risk factor for cardiovascular disease and premature death, a high dietary sodium intake can be expected to curtail life span. We tested this hypothesis by analyzing the relationship between sodium intake and life expectancy as well as survival in 181 countries worldwide.

Design and method:

We correlated age-standardized estimates of country specific average sodium consumption with healthy life expectancy at birth and at age of 60 years, and all-cause mortality for the year of 2010, after adjusting for potential confounders such as gross domestic product per capita and body mass index. We considered global health estimates as provided by World Health Organization.

Results:

Among the 181 countries included in this analysis, we found a positive correlation between sodium intake and healthy life expectancy at birth (R2 = 0.661, p < 0.001), as well as healthy life expectancy at age 60 (R2 = 0.600, p = 0.048). Conversely, all-cause mortality correlated inversely with sodium intake (R2 = 0.597, p < 0.001), Figure 1. In a sensitivity analysis restricted to 46 countries in the highest income class, sodium intake continued to correlate positively with healthy life expectancy at birth (R2 = 0.533, p < 0.001) and inversely with all-cause mortality (R2 = 0.497, p < 0.001).

Figure 1: Relation of sodium intake (grams/day) for the year of 2010 and healthy life expectancy at birth (in years) and age-standardized death rates (ASDR) for all-cause mortality in 181 countries worldwide. Schematic pattern of change in life expectancy and all-cause mortality with sodium intake in 181 countries worldwide. Note that proposed upper limits by some organizations such as AHA, WHO and ESC are associated with rather low life expectancy and high mortality.

Conclusions:

Our observation of sodium intake correlating positively with life expectancy and inversely with all-cause mortality worldwide and in high income countries argues against dietary sodium intake being a culprit of curtailing life span or a risk factor for premature death. These data are observational and should not be used as a base for nutritional interventions.
INTERACTION BETWEEN TRPM7 AND EPIDERMAL GROWTH FACTOR RECEPTOR MEDIATES VASCULAR SMOOTH MUSCLE CELL ACTIVATION AND PROLIFERATION
Authors: Zou Zhiguo , Rios Francisco , Neves Karla B. , Alves-Lopes Rheure , Ling Jiayue , Baillie George , Camargo Livia L. , Gudermann Thomas , Chubanov Vladimir , Montezano Augusto C. , Touyz Rhian M.
Published: April 2021

Objective:

Epidermal growth factor (EGF) binds to EGF receptor (EGFR) and stimulates multiple vascular signaling pathways. Transient receptor potential melastatin 7 (TRPM7) is a bifunctional protein (channel+enzyme, termed chanzyme) playing an important role in vascular homeostasis. Previous studies in renal cells demonstrated interactions between EGFR and TRPM6, a homologue of TRPM7. Here we questioned the importance of TRPM7 in EGF-mediated effects on vascular smooth muscle cell (VSMC) function.

Design and method:

Primary cultured VSMCs were isolated from humans and rodent models. Rat VSMCs (rVSMCs) and human VSMCs (hVSMCs) were stimulated with EGF (50ng/ml) in the absence/presence of gefitinib (1 μM), PP2 (10 μM), 2APB (30 μM) and NS8593 (40 μM), inhibitors of EGFR, c-Src kinase and TRPM7 respectively. Aorta were isolated from wild type (WT), TRPM7 kinase-deficient (TRPM7+/-kinase), and TRPM7 kinase-dead (TRPM7R/R) mice. Protein expression was investigated by immunoblotting. Intracellular Ca2+ and Mg2+ were assessed using fluorescence microscopy and flow cytometry respectively. EGFR-TRPM7 interaction was explored by proximity ligation assay (PLA) and immunoprecipitation. VSMC migration and proliferation were assessed by wound-healing assay and CFSE proliferation studies.

Results:

In hVSMC and rVSMC, EGF increased TRPM7 expression (47%) and phosphorylation (21%), p < 0.05 vs control; effects abolished by gefitinib and PP2. EGF-induced Mg2+ and Ca2+ influx was attenuated by gefitinib (4% and 8% respectively), NS8593 (5% for Mg2+) and 2-APB (6% and 13% respectively). EGF enhanced ERK1/2 phosphorylation (3-fold) in rVSMCs 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, primarily in the cell membrane. VSMCs from TRPM7+/-kinase showed reduced EGFR expression (73%), phospho-c-Src (22%), and phospho-ERK1/2 (90%). Aortas from TRPM7R/R exhibited reduced phospho-EGFR (63%) and phospho-ERK1/2 (36%). Vessels from TRPM7+/-kinase showed reduced wall thickness.

Conclusions:

Our findings demonstrate important cross talk between EGFR and TRPM7. EGF/EGFR is both upstream and downstream of TRPM7. This interaction, which involves c-Src, regulates VSMC migration and proliferation. We identify a novel EGFR:TRPM7 pathway that may play an important role in vascular function and remodeling.
RETURN OF NERVE FUNCTION FOLLOWING RENAL DENERVATION IN THE PRESENCE OF ANGIOTENSIN-CONVERTING ENZYME INHIBITION IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Walton Sarah , Parkington Helena , Kwok Edmund , Denton Kate
Published: April 2021

Objective:

Regrowth of renal nerves and functional restoration occurs following renal denervation (RDN). There is little information regarding the impact of concomitant anti-hypertensive therapies on the extent of reinnervation following RDN. Angiotensin-II has previously been shown to promote renal vessel innervation. We hypothesised that angiotensin-converting enzyme inhibition (ACEi) prolongs the antihypertensive effects of RDN by delaying renal nerve regrowth. The aim of this study was to examine the effect of ACEi treatment on the return of nerve function at 12-weeks post-RDN in spontaneously hypertensive rats (SHR).

Design and method:

Male SHRs (∼12 weeks of age, n > 7/group) were implanted with a radiotelemetry probe to record mean arterial pressure (MAP). Rats were infused with enalapril (1 mg/kg/day s.c.) or vehicle for two weeks. Rats then underwent sham or surgical RDN procedures and ACEi/vehicle infusion continued for an additional 12 weeks following RDN. Vascular contraction to perivascular nerve stimulation in renal lobar arteries was assessed using wire myography to determine the extent of renal nerve function return.

Results:

ACEi and RDN independently caused an immediate and sustained reduction in MAP (ACEi: -12 ± 3 mmHg, RDN: -19 ± 4 mmHg, both P < 0.05) across the 12-week period compared to untreated counterparts. However, the blood pressure-lowering effect of RDN was not enhanced by concomitant ACEi. Heart mass was ∼16% less in ACEi-RDN rats compared to untreated counterparts. Return of neurovascular function was observed in RDN-treated rats, but levels were only partially restored to that of untreated rats (P < 0.001). ACEi alone attenuated the response to perivascular nerve stimulation (P < 0.05) but the effects of ACEi in combination with RDN were not additive.

Conclusions:

Here we show partial functional reinnervation is evident 12 weeks following RDN in the SHR. This may account for the sustained reduction in MAP following RDN. ACEi infusion alone attenuated neurovascular function, but ACEi combined with RDN did not affect the return of renal neurovascular function. These findings suggest that RDN and ACEi effectively lower blood pressure in the long term and may confer cardioprotective benefits despite the return of nerve function. However, ACE inhibition does not provide additive benefits to delaying renal reinnervation.
VISIT-TO-VISIT GLOMERULAR FILTRATION RATE VARIABILITY AS A PREDICTOR FOR CARDIOVASCULAR AND RENAL OUTCOMES IN ESSENTIAL HYPERTENSION: DATA FROM A GREEK 8-YEAR-FOLLOW-UP STUDY
Authors: Laina A. , Tsioufis K. , Dimitriadis K. , Kasiakogias A. , Liatakis I. , Koutra E. , Leontsinis I. , Konstantinidis D. , Kouremeti M. , Dri E. , Iliakis P. , Vogiatzakis N. , Thomopoulos K. , Tousoulis D.
Published: April 2021

Objective:

Renal dysfunction is related with adverse prognosis in hypertension, however scarce data exist on the predictive value of kidney function variability on cardiovascular and renal outcomes in this setting. This study aims to assess the prognostic role of visit-to-visit glomerural filtration rate (GFR) variability on the incidence of coronary artery disease (CAD), stroke and end-stage renal disease in hypertensive patients.

Design and method:

We followed 2380 essential hypertensives (mean age 58.9 years, 1240 males, office blood pressure 144/91mmHg) free of cardiovascular disease for a mean period of 8 years. All subjects had at least one annual visit and blood sampling was performed in all visits for GFR estimation. We calculated standard deviation (SD) of mean GFR from visits 6months onward in patients with >or = 5 visits during follow-up. CAD was defined as the history of myocardial infarction or significant coronary artery stenosis revealed by angiography or coronary revascularization procedure, while stroke was defined as rapid onset of a new neurological deficit persisting at least 24 hours unless death supervened confirmed by imaging findings. End-stage renal disease was defined as GFR<15 mL/min/1.73 m2 or the need for long-term dialysis or transplantation.

Results:

The incidence of CAD, stroke and end-stage renal disease over the follow-up period were 2.8% (n = 68), 1.09% (n = 26) and 0.6% (n = 14). Hypertensives who developed CAD (n = 2312) had at baseline higher left ventricular mass index (115.7 ± 24.6 vs 103.7 ± 27.3 g/m2, p < 0.0001) compared to those who did not, whereas there was no difference with respect to baseline GFR (78 ± 19.6 vs 79.3 ± 18.6 mL/min/1.73 m2 (p = 0.573). In multivariate Cox regression models visit-to-visit glomerular filtration rate predicted end-stage renal disease (hazard ratio = 1.758, p = 0.01) but not CAD and stroke (p = NS for both). Baseline left ventricular mass index independently predicted CAD (hazard ratio = 1.042, p = 0.015) and stroke (hazard ratio = 1.035, p = 0.002).

Conclusions:

In essential hypertensive patients GFR variability predicts future development of end-stage renal disease but exhibits no independent prognostic value for CAD and stroke. These results suggest that fluctuations of renal function are related with damage at the kidneys and not at the cardiac and cerebrovascular level.
INCREASED CARDIOVASCULAR DEATH RATES IN A COVID-19 LOW PREVALENCE AREA
Authors: Del Pinto Rita , Desideri Giovambattista , Mammarella Leondino , Abballe Stefano , Dell’Anna Sofia , Cicogna Sabrina , Grassi Davide , Sacco Simona , Ferri Claudio
Published: April 2021

Objective:

Preliminary data indicate a reduction in hospitalizations for acute coronary syndromes during the Covid19 outbreak in Northern Italy. We investigated whether the albeit marginal Covid19 burden in the province of L Aquila, in Central Italy, had an impact on cardiovascular hospitalizations and outcomes.

Design and method:

We retrospectively analyzed de-identified data from all patients admitted to the five hospitals located in the province of L Aquila for all-cause and cardiovascular hospitalizations, cardiovascular acute phase treatments (coronary angioplasty, systemic fibrinolysis, endovascular procedures), and in-hospital cardiovascular deaths in the time window from January 1 to March 31, in the years 2020 (study period) and 2019 (control period). Unadjusted incidence rate ratios (IRR) comparing study/control period for the number of admissions/procedures were calculated through Poisson regression. Case fatality rate (%) for cardiovascular diseases in the examined periods was assessed.

Results:

5908 patients were hospitalized in the first quarter of 2020 (52.9% women, mean age 59.2 ± 24.9 years, 64.9 mean daily admissions). In the same period in 2019, 6852 patients were hospitalized (51.8% women, mean age 60.1 ± 24.6 years; 76.1 mean daily admissions). Significantly less all-cause and cardiovascular hospitalizations occurred in the study period than in the control period (IRR 0.85, 95%CI 0.82–0.88; IRR 0.73, 95%CI 0.67–0.80, respectively). The mean daily number of cardiovascular procedures was also lower (IRR: 0.74, p = 0.009). Importantly, a disproportionate decrease in the number of procedures was observed in relation to cardiovascular hospitalizations in the study period (13.8% versus 19.3%, p = 0.001). More intra-hospital cardiovascular deaths occurred in March 2020 (11.9%) compared with March 2019 (6.1%) (p = 0.048).

Conclusions:

Changes in healthcare seeking behaviors and an increased burden of cardiovascular-related deaths occurred in a Covid19 low prevalence Italian area. Besides unmeasured factors, including forced lifestyle changes, late hospital presentations and consequent greater disease severity might have affected eligibility and outcome of cardiovascular procedures. This evidence advances recent concerns regarding the impact of the pandemic on cardiovascular diseases and related deaths.
EVIDENCE OF A BLOOD PRESSURE REDUCTION DURING THE COVID-19 ASSOCIATED LOCKDOWN: A PLAUSIBLE EXPLANATION FOR THE OBSERVED DECLINES IN ACUTE CARDIOVASCULAR DISEASES?
Authors: Girerd Nicolas , Meune Christophe , Duarte Kevin , Vercamer Vincent , Lopez-Sublet Marilucy , Mourad Jean-Jacques
Published: April 2021

Objective:

The Covid-19 pandemic has been associated with a marked reduction in the incidence of cardiovascular diseases. The main objective of the study was to quantify the changes in blood pressure (BP) and heart rate (HR) prior to and after initiation of the lockdown.

Design and method:

A big data analysis of BP and HR measurements recorded during the lockdown period versus measurements during the Covid-19 period prior to confinement as well as versus measurements recorded in 2019. All participants were from the Paris urban area. Subjects used a Withings connected home blood pressure monitor and had at least one measurement prior to and during the lockdown and in 2019.

Results:

A total of 297,089 BP recordings were available from 2273 participants (age 56.3 ± 12.8 years, 81.1% male). Recording frequency was similar before and during the lockdown. BP gradually decreased during the first 4 weeks of confinement, reaching a decrease of 3 mmHg (-2.4 to -3.9) in systolic BP (SBP) and 1.5 mmHg (-1.4 to -2.2) in diastolic BP (DBP) from week 4 to week 7 (all p < 0.001). Age and sex-adjusted comparisons yielded similar results. Participants with higher SBP and DBP had a greater decrease in SBP and DBP during the lockdown (p < 0.0001 each); age and gender had no significant effect. No significant variation in HR was detected during the studied periods.

Conclusions:

Our study demonstrates a progressive decrease in SBP and DBP during the lockdown that may partly explain the concomitant reported reduction in the incidence of acute cardiovascular diseases.