bluuebunny/crossref_metadata_2025 huggingface dataset:
Reactivation of the Epicardium at the Origin of Myocardial Fibro-Fatty Infiltration During the Atrial Cardiomyopathy
Authors: Suffee Nadine , Moore-Morris Thomas , Jagla Bernd , Mougenot Nathalie , Dilanian Gilles , Berthet Myriam , Proukhnitzky Julie , Le Prince Pascal , Tregouet David A. , Pucéat Michel , Hatem Stéphane N.
Published: March 2020

Rationale:

Fibro-fatty infiltration of subepicardial layers of the atrial wall has been shown to contribute to the substrate of atrial fibrillation.

Objective:

Here, we examined if the epicardium that contains multipotent cells is involved in this remodeling process.

Methods and Results:

One hundred nine human surgical right atrial specimens were evaluated. There was a relatively greater extent of epicardial thickening and dense fibro-fatty infiltrates in atrial tissue sections from patients aged over 70 years who had mitral valve disease or atrial fibrillation when compared with patients aged less than 70 years with ischemic cardiomyopathy as indicated using logistic regression adjusted for age and gender. Cells coexpressing markers of epicardial progenitors and fibroblasts were detected in fibro-fatty infiltrates. Such epicardial remodeling was reproduced in an experimental model of atrial cardiomyopathy in rat and in Wilms tumor 1 (WT1)
CreERT2/+
;ROSA-tdT
+/−
mice. In the latter, genetic lineage tracing demonstrated the epicardial origin of fibroblasts within fibro-fatty infiltrates. A subpopulation of human adult epicardial-derived cells expressing PDGFR (platelet-derived growth factor receptor)-α were isolated and differentiated into myofibroblasts in the presence of Ang II (angiotensin II). Furthermore, single-cell RNA-sequencing analysis identified several clusters of adult epicardial-derived cells and revealed their specification from adipogenic to fibrogenic cells in the rat model of atrial cardiomyopathy.

Conclusions:

Epicardium is reactivated during the formation of the atrial cardiomyopathy. Subsets of adult epicardial-derived cells, preprogrammed towards a specific cell fate, contribute to fibro-fatty infiltration of subepicardium of diseased atria. Our study reveals the biological basis for chronic atrial myocardial remodeling that paves the way of atrial fibrillation.
Hyperglycemia Acutely Increases Cytosolic Reactive Oxygen Species via
O
-linked GlcNAcylation and CaMKII Activation in Mouse Ventricular Myocytes
Authors: Lu Shan , Liao Zhandi , Lu Xiyuan , Katschinski Dörthe M. , Mercola Mark , Chen Ju , Heller Brown Joan , Molkentin Jeffery D. , Bossuyt Julie , Bers Donald M.
Published: March 2020

Rationale:

Diabetes mellitus is a complex, multisystem disease, affecting large populations worldwide. Chronic CaMKII (Ca
2+
/calmodulin-dependent kinase II) activation may occur in diabetes mellitus and be arrhythmogenic. Diabetic hyperglycemia was shown to activate CaMKII by (1)
O
-linked attachment of N-acetylglucosamine (
O
-GlcNAc) at S280 leading to arrhythmia and (2) a reactive oxygen species (ROS)–mediated oxidation of CaMKII that can increase postinfarction mortality.

Objective:

To test whether high extracellular glucose (Hi-Glu) promotes ventricular myocyte ROS generation and the role played by CaMKII.

Methods and Results:

We tested how extracellular Hi-Glu influences ROS production in adult ventricular myocytes, using DCF (2′,7′-dichlorodihydrofluorescein diacetate) and genetically targeted Grx-roGFP2 redox sensors. Hi-Glu (30 mmol/L) significantly increased the rate of ROS generation—an effect prevented in myocytes pretreated with CaMKII inhibitor KN-93 or from either global or cardiac-specific CaMKIIδ KO (knockout) mice. CaMKII KO or inhibition also prevented Hi-Glu–induced sarcoplasmic reticulum Ca
2+
release events (Ca
2+
sparks). Thus, CaMKII activation is required for Hi-Glu–induced ROS generation and sarcoplasmic reticulum Ca
2+
leak in cardiomyocytes. To test the involvement of
O
-GlcNAc–CaMKII pathway, we inhibited GlcNAcylation removal by Thiamet G (ThmG), which mimicked the Hi-Glu–induced ROS production. Conversely, inhibition of GlcNAcylation (OSMI-1 [(αR)-α-[[(1,2-dihydro-2-oxo-6-quinolinyl)sulfonyl]amino]-N-(2-furanylmethyl)-2-methoxy-N-(2-thienylmethyl)-benzeneacetamide]) prevented ROS induction in response to either Hi-Glu or ThmG. Moreover, in a CRSPR-based knock-in mouse in which the functional GlcNAcylation site on CaMKIIδ was ablated (S280A), neither Hi-Glu nor ThmG induced myocyte ROS generation. So CaMKIIδ-S280 is required for the Hi-Glu–induced (and GlcNAc dependent) ROS production. To identify the ROS source(s), we used different inhibitors of NOX (NADPH oxidase) 2 (Gp91ds-tat peptide), NOX4 (GKT137831), mitochondrial ROS (MitoTempo), and NOS (NO synthase) pathway inhibitors (L-NAME, L-NIO, and L-NPA). Only NOX2 inhibition or KO prevented Hi-Glu/ThmG–induced ROS generation.

Conclusions:

Diabetic hyperglycemia induces acute cardiac myocyte ROS production by NOX2 that requires
O
-GlcNAcylation of CaMKIIδ at S280. This novel ROS induction may exacerbate pathological consequences of diabetic hyperglycemia.
Single-Cell Reconstruction of Progression Trajectory Reveals Intervention Principles in Pathological Cardiac Hypertrophy
Authors: Ren Zongna , Yu Peng , Li Dandan , Li Zheng , Liao Yingnan , Wang Yin , Zhou Bingying , Wang Li
Published: March 2020

Background:

Pressure overload–induced pathological cardiac hypertrophy is a common predecessor of heart failure, the latter of which remains a major cardiovascular disease with increasing incidence and mortality worldwide. Current therapeutics typically involve partially relieving the heart’s workload after the onset of heart failure. Thus, more pathogenesis-, stage-, and cell type–specific treatment strategies require refined dissection of the entire progression at the cellular and molecular levels.

Methods:

By analyzing the transcriptomes of 11,492 single cells and identifying major cell types, including both cardiomyocytes and noncardiomyocytes, on the basis of their molecular signatures, at different stages during the progression of pressure overload–induced cardiac hypertrophy in a mouse model, we characterized the spatiotemporal interplay among cell types, and tested potential pharmacological treatment strategies to retard its progression in vivo.

Results:

We illustrated the dynamics of all major cardiac cell types, including cardiomyocytes, endothelial cells, fibroblasts, and macrophages, as well as those of their respective subtypes, during the progression of disease. Cellular crosstalk analysis revealed stagewise utilization of specific noncardiomyocytes during the deterioration of heart function. Specifically, macrophage activation and subtype switching, a key event at middle-stage of cardiac hypertrophy, was successfully targeted by Dapagliflozin, a sodium glucose cotransporter 2 inhibitor, in clinical trials for patients with heart failure, as well as TD139 and Arglabin, two anti-inflammatory agents new to cardiac diseases, to preserve cardiac function and attenuate fibrosis. Similar molecular patterns of hypertrophy were also observed in human patient samples of hypertrophic cardiomyopathy and heart failure.

Conclusions:

Together, our study not only illustrated dynamically changing cell type crosstalk during pathological cardiac hypertrophy but also shed light on strategies for cell type- and stage-specific intervention in cardiac diseases.
Deficiency of Prebiotic Fiber and Insufficient Signaling Through Gut Metabolite-Sensing Receptors Leads to Cardiovascular Disease
Authors: Kaye David M. , Shihata Waled A. , Jama Hamdi A. , Tsyganov Kirill , Ziemann Mark , Kiriazis Helen , Horlock Duncan , Vijay Amrita , Giam Beverly , Vinh Antony , Johnson Chad , Fiedler April , Donner Daniel , Snelson Matthew , Coughlan Melinda T. , Phillips Sarah , Du Xiao-Jun , El-Osta Assam , Drummond Grant , Lambert Gavin W. , Spector Tim D. , Valdes Ana M. , Mackay Charles R. , Marques Francine Z.
Published: March 2020

Background:

High blood pressure (BP) continues to be a major, poorly controlled but modifiable risk factor for cardiovascular death. Among key Western lifestyle factors, a diet poor in fiber is associated with prevalence of high BP. The impact of lack of prebiotic fiber and the associated mechanisms that lead to higher BP are unknown. Here we show that lack of prebiotic dietary fiber leads to the development of a hypertensinogenic gut microbiota, hypertension and its complications, and demonstrate a role for G-protein coupled-receptors (GPCRs) that sense gut metabolites.

Methods:

One hundred seventy-nine mice including C57BL/6J, gnotobiotic C57BL/6J, and knockout strains for GPR41, GPR43, GPR109A, and GPR43/109A were included. C57BL/6J mice were implanted with minipumps containing saline or a slow-pressor dose of angiotensin II (0.25 mg·kg
-1
·d
-1
). Mice were fed diets lacking prebiotic fiber with or without addition of gut metabolites called short-chain fatty acids ([SCFA)] produced during fermentation of prebiotic fiber in the large intestine), or high prebiotic fiber diets. Cardiac histology and function, BP, sodium and potassium excretion, gut microbiome, flow cytometry, catecholamines and methylation-wide changes were determined.

Results:

Lack of prebiotic fiber predisposed mice to hypertension in the presence of a mild hypertensive stimulus, with resultant pathological cardiac remodeling. Transfer of a hypertensinogenic microbiota to gnotobiotic mice recapitulated the prebiotic-deprived hypertensive phenotype, including cardiac manifestations. Reintroduction of SCFAs to fiber-depleted mice had protective effects on the development of hypertension, cardiac hypertrophy, and fibrosis. The cardioprotective effect of SCFAs were mediated via the cognate SCFA receptors GPR43/GPR109A, and modulated L-3,4-dihydroxyphenylalanine levels and the abundance of T regulatory cells regulated by DNA methylation.

Conclusions:

The detrimental effects of low fiber Westernized diets may underlie hypertension, through deficient SCFA production and GPR43/109A signaling. Maintaining a healthy, SCFA-producing microbiota is important for cardiovascular health.
Exploring the Possible Impact of Unbalanced Open-Label Drop-In of Glucose-Lowering Medications on EXSCEL Outcomes
Authors: Bethel M. Angelyn , Stevens Susanna R. , Buse John B. , Choi Jasmine , Gustavson Stephanie M. , Iqbal Nayyar , Lokhnygina Yuliya , Mentz Robert J. , Patel Rishi A. , Öhman Peter , Schernthaner Guntram , Lecube Albert , Hernandez Adrian F. , Holman Rury R.
Published: March 2020

Background:

EXSCEL (Exenatide Study of Cardiovascular Event Lowering) assessed the impact of once-weekly exenatide 2 mg versus placebo in patients with type 2 diabetes mellitus, while aiming for glycemic equipoise. Consequently, greater drop-in of open-label glucose-lowering medications occurred in the placebo group. Accordingly, we explored the potential effects of their unbalanced use on major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, and all-cause mortality (ACM), given that some of these agents are cardioprotective.

Methods:

Cox hazard models were performed by randomized treatment for drug classes where >5% open-label drop-in glucose-lowering medication occurred, and for glucagon-like peptide-1 receptor agonists (GLP-1 RAs; 3.0%) using three methodologies: drop-in visit right censoring, inverse probability for treatment weighting (IPTW), and applying drug class risk reductions.

Results:

Baseline glucose-lowering medications for the 14 752 EXSCEL participants (73.1% with previous cardiovascular disease) did not differ between treatment groups. During median 3.2 years follow-up, open-label drop-in occurred in 33.4% of participants, more frequently with placebo than exenatide (38.1% versus 28.8%), with metformin (6.1% versus 4.9%), sulfonylurea (8.7% versus 6.9%), dipeptidyl peptidase-4 inhibitors (10.6% versus 7.5%), SGLT-2i (10.3% versus 8.1%), GLP-1 RA (3.4% versus 2.4%), and insulin (13.8% versus 9.4%). The MACE effect size was not altered meaningfully by right censoring, but the favorable HR for exenatide became nominally significant in the sulfonylurea and any glucose-lowering medication groups, while the ACM HR and p-values were essentially unchanged. IPTW decreased the MACE HR from 0.91 (
P
=0.061) to 0.85 (
P
=0.008) and the ACM HR from 0.86 (
P
=0.016) to 0.81 (
P
=0.012). Application of literature-derived risk reductions showed no meaningful changes in MACE or ACM HRs or
P
values, although simulations of substantially greater use of drop-in cardioprotective glucose-lowering agents demonstrated blunting of signal detection.

Conclusions:

EXSCEL-observed HRs for MACE and ACM remained robust after right censoring or application of literature-derived risk reductions, but the exenatide versus placebo MACE effect size and statistical significance were increased by IPTW. Effects of open-label drop-in cardioprotective medications need to be considered carefully when designing, conducting, and analyzing cardiovascular outcome trials of glucose-lowering agents under the premise of glycemic equipoise.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01144338.
Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Advanced Chronic Kidney Disease
Authors: Stanifer John W. , Pokorney Sean D. , Chertow Glenn M. , Hohnloser Stefan H. , Wojdyla Daniel M. , Garonzik Samira , Byon Wonkyung , Hijazi Ziad , Lopes Renato D. , Alexander John H. , Wallentin Lars , Granger Christopher B.
Published: March 2020

Background:

Compared with the general population, patients with advanced chronic kidney disease have a >10-fold higher burden of atrial fibrillation. Limited data are available guiding the use of nonvitamin K antagonist oral anticoagulants in this population.

Methods:

We compared the safety of apixaban with warfarin in 269 patients with atrial fibrillation and advanced chronic kidney disease (defined as creatinine clearance [CrCl] 25 to 30 mL/min) enrolled in the ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation). Cox proportional models were used to estimate hazard ratios for major bleeding and major or clinically relevant nonmajor bleeding. We characterized the pharmacokinetic profile of apixaban by assessing differences in exposure using nonlinear mixed effects models.

Results:

Among patients with CrCl 25 to 30 mL/min, apixaban caused less major bleeding (hazard ratio, 0.34 [95% CI, 0.14–0.80]) and major or clinically relevant nonmajor bleeding (hazard ratio, 0.35 [95% CI, 0.17–0.72]) compared with warfarin. Patients with CrCl 25 to 30 mL/min randomized to apixaban demonstrated a trend toward lower rates of major bleeding when compared with those with CrCl >30 mL/min (
P
interaction=0.08) and major or clinically relevant nonmajor bleeding (
P
interaction=0.05). Median daily steady-state areas under the curve for apixaban 5 mg twice daily were 5512 ng/(mL·h) and 3406 ng/(mL·h) for patients with CrCl 25 to 30 mL/min or >30 mL/min, respectively. For apixaban 2.5 mg twice daily, the median exposure was 2780 ng/(mL·h) for patients with CrCl 25 to 30 mL/min. The area under the curve values for patients with CrCl 25 to 30 mL/min fell within the ranges demonstrated for patients with CrCl >30 mL/min.

Conclusions:

Among patients with atrial fibrillation and CrCl 25 to 30 mL/min, apixaban caused less bleeding than warfarin, with even greater reductions in bleeding than in patients with CrCl >30 mL/min. We observed substantial overlap in the range of exposure to apixaban 5 mg twice daily for patients with or without advanced chronic kidney disease, supporting conventional dosing in patients with CrCl 25 to 30 mL/min. Randomized, controlled studies evaluating the safety and efficacy of apixaban are urgently needed in patients with advanced chronic kidney disease, including those receiving dialysis.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00412984.
Comprehensive Evaluation of Rhythm Monitoring Strategies in Screening for Atrial Fibrillation
Authors: Diederichsen Søren Zöga , Haugan Ketil Jørgen , Kronborg Christian , Graff Claus , Højberg Søren , Køber Lars , Krieger Derk , Holst Anders Gaarsdal , Nielsen Jonas Bille , Brandes Axel , Svendsen Jesper Hastrup
Published: March 2020

Background:

Stroke is an increasing health problem worldwide. Atrial fibrillation (AF) is a major risk factor for stroke, and the attention given to AF screening is rising, as new monitoring technologies emerge. We aimed to evaluate the performance of a large panel of screening strategies and to assess population characteristics associated with diagnostic yield.

Methods:

Individuals with stroke risk factors but without AF were recruited from the general population to undergo screening with an implantable loop recorder. New-onset AF lasting ≥6 minutes was adjudicated by senior cardiologists. After continuous monitoring for >3 years, complete day-to-day heart rhythm data sets were reconstructed for every participant, including exact time of onset and termination of all AF episodes. Random sampling was applied to assess the sensitivity and negative predictive value of screening with various simulated screening strategies compared with the implantable loop recorder. The diagnostic yield across strategies and population subgroups was compared by use of nonparametric tests.

Results:

The rhythm data sets comprised 590 participants enduring a total of 659 758 days of continuous monitoring and 20 110 AF episodes. In these data, a single 10-second ECG yielded a sensitivity (and negative predictive value) of 1.5% (66%) for AF detection, increasing to 8.3% (67%) for twice-daily 30-second ECGs during 14 days and to 11% (68%), 13% (68%), 15% (69%), 21% (70%), and 34% (74%) for a single 24-hour, 48-hour, 72-hour, 7-day, or 30-day continuous monitoring, respectively. AF detection further improved when subsequent screenings were performed or when the same monitoring duration was spread over several periods compared with a single period (eg, three 24-hour monitorings versus one 72-hour monitoring;
P
<0.0001 for all comparisons). The sensitivity was consistently higher among participants with age ≥75 years, male sex, CHADS
2
score >2, or NT-proBNP (N-terminal pro-B-type natriuretic peptide) ≥40 pmol/L and among participants with underlying ≥24-hour AF episodes compared with shorter AF (
P
<0.0001 for all screening strategies).

Conclusions:

In screening for AF among participants with stroke risk factors, the diagnostic yield increased with duration, dispersion, and number of screenings, although all strategies had low yield compared with the implantable loop recorder. The sensitivity was higher among participants who were older, were male, or had higher NT-proBNP.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier:
NCT02036450
.
Primary Aldosteronism Decreases Insulin Secretion and Increases Insulin Clearance in Humans
Authors: Adler Gail K. , Murray Gillian R. , Turcu Adina F. , Nian Hui , Yu Chang , Solorzano Carmen C. , Manning Robert , Peng Dungeng , Luther James M.
Published: March 2020

Primary aldosteronism is a frequent cause of resistant hypertension and is associated with an increased risk of developing diabetes mellitus. Aldosterone impairs insulin secretion in isolated islets, and insulin secretion is increased in aldosterone synthase–deficient mice. We hypothesized that treatment for primary aldosteronism increases insulin secretion and insulin sensitivity in humans. We conducted a prospective cohort study in patients with primary aldosteronism, with assessment of glucose metabolism before and 3 to 12 months after treatment. Participants underwent treatment for primary aldosteronism with adrenalectomy or a mineralocorticoid receptor antagonist at the discretion of their treating physician. We assessed insulin secretion and insulin sensitivity by hyperglycemic and hyperinsulinemic-euglycemic clamps, respectively, on 2 study days after a 5-day standardized diet. After treatment, the C-peptide and insulin response during the hyperglycemic clamp increased compared with pretreatment (ΔC-peptide at 90–120 minutes +530.5±384.1 pmol/L,
P
=0.004; Δinsulin 90–120 minutes +183.0±122.6,
P
=0.004). During hyperinsulinemic-euglycemic clamps, insulin sensitivity decreased after treatment (insulin sensitivity index 30.7±6.2 versus 18.5±4.7 nmol·kg
−1
·min
−1
·pmol
−1
·L;
P
=0.02). Insulin clearance decreased after treatment (872.8±207.6 versus 632.3±178.6 mL/min;
P
=0.03), and disposition index was unchanged. We conclude that the insulin response to glucose increases and insulin clearance decreases after treatment for primary aldosteronism, and these effects were not due to alterations in creatinine clearance or plasma cortisol. These studies may provide further insight into the mechanism of increased diabetes mellitus risk in primary aldosteronism.
Blood Pressure Control and Dementia Risk in Midlife Patients With Atrial Fibrillation
Authors: Kim Daehoon , Yang Pil-Sung , Jang Eunsun , Tae Yu Hee , Kim Tae-Hoon , Uhm Jae-Sun , Kim Jong-Youn , Sung Jung-Hoon , Pak Hui-Nam , Lee Moon-Hyoung , Lip Gregory Y.H. , Joung Boyoung
Published: March 2020

Atrial fibrillation (AF) is associated with increased risk of cognitive impairment and dementia, even with no overt stroke. Hypertension has been a potentially modifiable risk factor for dementia, especially in midlife (<70 years) individuals. We aimed to investigate the associations of blood pressure (BP) and hypertension burden with dementia risk among midlife AF patients. From the Korean National Health Insurance Service database, we enrolled 171 228 incident AF patients aged 50 to 69 years with no prior dementia from 2005 to 2016. During a mean of 6.6 years of follow-up, 9909 patients received a first-time diagnosis of dementia. U-shaped relationships were noted between systolic or diastolic BP and dementia risk: A 10 mm Hg increase or decrease in systolic BP starting from 120 mm Hg was associated with 4.4% (95% CI, 2.7%–6.0%) and 4.6% (95% CI, 0.1%–8.2%) higher dementia risk, respectively. An increase or decrease in diastolic BP starting from 80 mm Hg also increased dementia risk. In subtype analyses, Alzheimer disease increases with BP decrease whereas vascular dementia increases according to BP increase. When BP changes over time were accounted for in time-updated models, BP of 120 to 129/80 to 84 mm Hg was associated with the lowest dementia risk. Increasing hypertension burden (the proportion of days with increased BP during follow-up) was associated with higher dementia risk (hazard ratio, 1.10 per 10% increase [95% CI, 1.08–1.12]). Among midlife AF patients, there were a U-shaped association of BP and a log-linear association of hypertension burden with dementia risk. Minimizing the burden of hypertension in AF patients might help to prevent dementia.
Increased Aortic Characteristic Impedance Explains Relations Between Urinary Na
+
/K
+
and Pulse or Systolic Blood Pressure
Authors: Mmopi Keneilwe N. , Norton Gavin R. , Bello Hamza , Libhaber Carlos , Masiu Mohlabani , Da Silva Fernandes Daniel , Sareli Pinhas , Peterson Vernice , Woodiwiss Angela J.
Published: March 2020

Alterations in sodium (Na
+
) relative to potassium (K
+
) intake increase systolic blood pressure, effects in-part attributed to enhanced pulsatile loads (pulse pressure) beyond steady-state pressures (mean arterial pressure). Whether this effect is through reversible changes (increases in blood volume and hence aortic flow [Q] or wave reflection [Pb]), or potentially irreversible structural changes in the proximal aorta, is unknown. In 581 black South Africans, we determined 24-hour urinary Na
+
and K
+
excretion and aortic function from central aortic pressure (radial pulse wave analysis [SphygmoCor software]), velocity, and diameter measurements. Proximal aortic function was assessed from characteristic impedance (Zc). Beyond mean arterial pressure and additional confounders, urinary Na
+
/K
+
was independently associated with Zc (
P
<0.005) but not peak aortic Q (
P
=0.30) or alternative aspects of Q or ejection volume. Although age was strongly associated with proximal aortic diameter, no independent relations between urinary Na
+
/K
+
and aortic diameter were noted (
P
=0.17). Relations between urinary Na
+
/K
+
and Zc translated into independent relations with early systolic compression wave pressures (QxZc [P
QxZc
]) and aortic forward wave pressures but not Pb. Moreover, neither reflected wave magnitude (
P
=0.92) nor aortic pulse wave velocity were independently associated with urinary Na
+
/K
+
. In product of coefficient mediation analysis, the independent relations between urinary Na
+
/K
+
and peak aortic or brachial pulse pressure or systolic blood pressure were accounted for by Zc and P
QxZc
. In conclusion, abnormalities in Na
+
/K
+
intake determine pulse pressure or systolic blood pressure beyond mean arterial pressure mainly through potentially irreversible impacts on proximal aortic impedance rather than readily modifiable increases in aortic flow (blood volume) or wave reflection.
Effects of Chronic Nicotine Inhalation on Systemic and Pulmonary Blood Pressure and Right Ventricular Remodeling in Mice
Authors: Oakes Joshua M. , Xu Jiaxi , Morris Tamara M. , Fried Nicholas D. , Pearson Charlotte S. , Lobell Thomas D. , Gilpin Nicholas W. , Lazartigues Eric , Gardner Jason D. , Yue Xinping
Published: March 2020

Cigarette smoking is the single most important risk factor for the development of cardiovascular and pulmonary diseases; however, the role of nicotine in the pathogenesis of these diseases is incompletely understood. The purpose of this study was to examine the effects of chronic nicotine inhalation on the development of cardiovascular and pulmonary disease with a focus on blood pressure and cardiac remodeling. Male C57BL6/J mice were exposed to air (control) or nicotine vapor (daily, 12 hour on/12 hour off) for 8 weeks. Systemic blood pressure was recorded weekly by radio-telemetry, and cardiac remodeling was monitored by echocardiography. At the end of the 8 weeks, mice were subjected to right heart catheterization to measure right ventricular systolic pressure. Nicotine-exposed mice exhibited elevated systemic blood pressure from weeks 1 to 3, which then returned to baseline from weeks 4 to 8, indicating development of tolerance to nicotine. At 8 weeks, significantly increased right ventricular systolic pressure was detected in nicotine-exposed mice compared with the air controls. Echocardiography showed that 8-week nicotine inhalation resulted in right ventricular (RV) hypertrophy with increased RV free wall thickness and a trend of increase in RV internal diameter. In contrast, there were no significant structural or functional changes in the left ventricle following nicotine exposure. Mechanistically, we observed increased expression of angiotensin-converting enzyme and enhanced activation of mitogen-activated protein kinase pathways in the RV but not in the left ventricle. We conclude that chronic nicotine inhalation alters both systemic and pulmonary blood pressure with the latter accompanied by RV remodeling, possibly leading to progressive and persistent pulmonary hypertension.
Statins and Risk of Intracerebral Hemorrhage in Individuals With a History of Stroke
Authors: Ribe Anette Riisgaard , Vestergaard Claus Høstrup , Vestergaard Mogens , Pedersen Henrik Schou , Prior Anders , Lietzen Lone Winther , Brynningsen Peter Krogh , Fenger-Grøn Morten
Published: March 2020

Background and Purpose—

It has been suggested that statins increase the risk of intracerebral hemorrhage in individuals with a history of stroke, which has led to a precautionary principle of avoiding statins in patients with prior intracerebral hemorrhage. However, such prescribing reticence may be unfounded and potentially harmful when considering the well-established benefits of statins. This study is so far the largest to explore the statin-associated risk of intracerebral hemorrhage in individuals with prior stroke.

Methods—

We conducted a population-based, propensity score–matched cohort study using information from Danish national registers. We included all individuals initiating statin treatment after a first-time stroke diagnosis (intracerebral hemorrhage, N=2728 or ischemic stroke, N=52 964) during 2002 to 2016. For up to 10 years of follow-up, they were compared with a 1:5 propensity score–matched group of statin nonusers with the same type of first-time stroke. The difference between groups was measured by adjusted hazard ratios for intracerebral hemorrhage calculated by type of first-time stroke as a function of time since statin initiation.

Results—

Within the study period, 118 new intracerebral hemorrhages occurred among statin users with prior intracerebral hemorrhage and 319 new intracerebral hemorrhages in users with prior ischemic stroke. The risk of intracerebral hemorrhage was similar for statin users and nonusers when evaluated among those with prior intracerebral hemorrhage, and it was reduced by half in those with prior ischemic stroke. These findings were consistent over time since statin initiation and could not be explained by concomitant initiation of other medications, by dilution of treatment effect (due to changes in exposure status over time), or by healthy initiator bias.

Conclusions—

This large study found no evidence that statins increase the risk of intracerebral hemorrhage in individuals with prior stroke; perhaps the risk is even lower in the subgroup of individuals with prior ischemic stroke.
Migraine With Aura as Early Disease Marker in Hereditary Dutch-Type Cerebral Amyloid Angiopathy
Authors: Koemans Emma A. , Voigt Sabine , Rasing Ingeborg , van Etten Ellis S. , van Zwet Erik W. , van Walderveen Marianne A.A. , Wermer Marieke J.H. , Terwindt Gisela M.
Published: March 2020

Background and Purpose—

To determine whether migraine, which has often been described as an inaugural manifestation in monogenic cerebrovascular syndromes, is associated with cerebral amyloid pathology, we assessed migraine and its correlation with magnetic resonance imaging markers in Hereditary Dutch-Type Cerebral Amyloid Angiopathy (D-CAA or Hereditary Cerebral Hemorrhage With Amyloidosis-Dutch type).

Methods—

All D-CAA mutation carriers who visited our clinic between 2012 and 2018 were included. Migraine was diagnosed by an interview and classified according to the
International Classification of Headache Disorders
. Magnetic resonance imaging scans were scored for intracerebral hemorrhage (ICH) location(s) and presence of cortical superficial siderosis. Kaplan Meier survival analysis was used for age of ICH onset in carriers with and without migraine. Correlation with ICH location(s) and cortical superficial siderosis were calculated with Poisson regression analysis adjusted for confounders.

Results—

We included 86 D-CAA mutation carriers (57% women, mean age 57 years), 48 (56%) suffered from migraine, all with aura. Prevalence was higher than expected compared with the general population (women,
P
<0.05; men,
P
<0.001). Migraine was the inaugural symptom in 77% and an isolated symptom in 35% of the carriers. Carriers with and without migraine did not differ for age of first ICH, cortical superficial siderosis prevalence, or occipital ICH. Time between migraine onset and first ICH was 8.5 years. Aura attacks lasting ≥60 minutes signaled acute ICH in 55%.

Conclusions—

Migraine with aura is an important, often inaugural, symptom in D-CAA. Aura attacks lasting ≥60 minutes may signal acute ICH in D-CAA. Migraine with aura may be regarded as an early marker of disease in hereditary CAA preceding the occurrence of symptomatic ICH by several years.
Early Recanalization in Patients With Cerebral Venous Thrombosis Treated With Anticoagulation
Authors: Aguiar de Sousa Diana , Lucas Neto Lia , Arauz Antonio , Sousa Ana Luísa , Gabriel Denis , Correia Manuel , Gil-Gouveia Raquel , Penas Sara , Carvalho Dias Mariana , Correia Manuel A. , Carvalho Marta , Canhão Patrícia , Ferro José M.
Published: March 2020

Background and Purpose—

The hypothesis that venous recanalization prevents progression of venous infarction is not established in patients with cerebral venous thrombosis (CVT). Evidence is also scarce on the association between residual symptoms, particularly headache, and the recanalization grade. We aimed to assess, in patients with CVT treated with standard anticoagulation, (1) the rate of early venous recanalization, (2) whether lack of early recanalization was predictor of parenchymal brain lesion progression, and (3) the prevalence and features of persistent headache according to the recanalization grade achieved.

Methods—

PRIORITy-CVT (Pathophysiology of Venous Infarction – Prediction of Infarction and Recanalization in CVT) was a multicenter, prospective, cohort study including patients with newly diagnosed CVT. Standardized magnetic resonance imaging was performed at inclusion (≤24 hours of therapeutic anticoagulation), days 8 and 90. Potential imaging predictors of recanalization were predefined and analyzed at each anatomical segment. Primary outcomes were rate of early recanalization and brain lesion progression at day 8. Secondary outcomes were headache (days 8 and 90) and functional outcome (modified Rankin Scale at days 8 and 90).

Results—

Sixty eight patients with CVT were included, of whom 30 (44%) had parenchymal lesions. At the early follow-up (n=63; 8±2 days), 68% (n=43) of patients had partial recanalization and 6% (n=4) full recanalization. Early recanalization was associated both with early regression (
P
=0.03) and lower risk of enlargement of nonhemorrhagic lesions (
P
=0.02). Lesions showing diffusion restriction (n=12) were fully reversible in 66% of cases, particularly in patients showing early venous recanalization. Evidence of new or enlarged hemorrhagic lesions, headache at days 8 and 90, and unfavorable functional outcome at days 8 and 90 were not significantly different in patients achieving recanalization.

Conclusions—

Venous recanalization started within the first 8 days of therapeutic anticoagulation in most patients with CVT and was associated with early regression of nonhemorrhagic lesions, including venous infarction. There was an association between persistent venous occlusion at day 8 and enlargement of nonhemorrhagic lesions.
FROM PROTECTIONISM TO TRADE WARS: THEIR EFFECTS OBSERVED THROUGH FINANCIAL MARKETS
Authors: YILMAZ Derya
Published: March 2020

Even the outcomes of free trade are well known and accepted widely in economic literature, protectionism has never totally lost its ground. Today, the protectionist trade policies of the US are transformed into a trade war. The costs accrued by the outcomes of a trade war would be extensive. These costs have been materialized via 2018 tariff hikes to a certain extent but the remaining impacts–in case of an escalated trade war- could be excessive. The trade war would also lead to certain consequences via financial markets. The present study aimed to analyze how protectionism evolved into a trade war and its ample effects that would be observed through financial markets. The study demonstrated that global uncertainty would scale up as a result of trade conflicts between nations. The rising global uncertainty would have remarkable consequences for both developed and developing countries via financial markets.
The Stochastic Delta Rule: Faster and More Accurate Deep Learning Through Adaptive Weight Noise
Authors: Frazier-Logue Noah , Hanson Stephen José
Published: March 2020

Multilayer neural networks have led to remarkable performance on many kinds of benchmark tasks in text, speech, and image processing. Nonlinear parameter estimation in hierarchical models is known to be subject to overfitting and misspecification. One approach to these estimation and related problems (e.g., saddle points, colinearity, feature discovery) is called Dropout. The Dropout algorithm removes hidden units according to a binomial random variable with probability p prior to each update, creating random “shocks” to the network that are averaged over updates (thus creating weight sharing). In this letter, we reestablish an older parameter search method and show that Dropout is a special case of this more general model, stochastic delta rule (SDR), published originally in 1990. Unlike Dropout, SDR redefines each weight in the network as a random variable with mean μwij and standard deviation σwij. Each weight random variable is sampled on each forward activation, consequently creating an exponential number of potential networks with shared weights (accumulated in the mean values). Both parameters are updated according to prediction error, thus resulting in weight noise injections that reflect a local history of prediction error and local model averaging. SDR therefore implements a more sensitive local gradient-dependent simulated annealing per weight converging in the limit to a Bayes optimal network. We run tests on standard benchmarks (CIFAR and ImageNet) using a modified version of DenseNet and show that SDR outperforms standard Dropout in top-5 validation error by approximately 13% with DenseNet-BC 121 on ImageNet and find various validation error improvements in smaller networks. We also show that SDR reaches the same accuracy that Dropout attains in 100 epochs in as few as 40 epochs, as well as improvements in training error by as much as 80%.
‘Bolder’ together — response to human social cues in groups of free-ranging dogs
Authors: Bhattacharjee Debottam , Sau Shubhra , Bhadra Anindita
Published: March 2020

In urban environments, humans are a part of an interaction network of several species, impacting them directly or indirectly. The positive, negative and neutral components of such impact can be assessed by studying human-animal interactions in various habitats. While studies have shown animals’ reactions to specific human social cues, information is lacking on how animals respond to such cues in the presence and absence of conspecifics. We investigated the behavioural responses of free-ranging dogs (Canis lupus familiaris) towards various human social cues (neutral, friendly, low- and high-impact threatening) when presented to groups. We used previously published data on dogs’ reactions to identical cues when presented solitarily, and compared them with the group-level responses. Our results strengthen the idea of situation-relevant responsiveness in free-ranging dogs. Dogs in groups exhibited higher approach and less avoidance towards the unfamiliar human experimenter, especially towards the threatening cues, compared to dogs tested alone.
The Unity Status of Continental States’ Outlying Archipelagos
Authors: Su Jinyuan
Published: March 2020

This article argues that the United Nations Convention on the Law of the Sea (LOSC) does not exhaust rules of baseline regimes; those for continental States’ outlying archipelagos were set aside for development outside the Convention by negotiating States during the Third United Nations Conference on the Law of the Sea. Today, most of the continental States possessing outlying archipelagos have applied the unity theory to such archipelagos, many by enclosing them with straight baselines, which has been protested by very few States. The application of straight baselines to big- island-dominating outlying archipelagos may be justifiable under the second limb of Article 7(1) of the LOSC or a customary rule that it reflects, thus causing a fragmentation of outlying archipelagos; however, this alternative justification remains hypothetical and, even if established, would not detract from the generality of State practice applying unity theory to outlying archipelagos without such geographical configuration.
Inherited National Questions: The Soviet Legacy in Russia’s International Law Doctrine on Self-determination
Authors: Lundstedt Tero
Published: March 2020

All 15 former Soviet Republics share a unique federal history with a particular understanding of the right to self-determination. Moreover, seven of them were federalised during the Soviet era, amounting to a major challenge to their territorial integrity after independence. While these states confronted their minorities in different ways, the Russian solution to its inherited national question has been the most comprehensive. This has made Russian understanding on self-determination essentially different from the mainstream of the international community, which in turn explains Russian persistent objections over the Kosovo independence (2008) and partly clarifies the events in Georgia (2008) and Crimea (2014). This article analyses how the former Soviet Republics coped with the transformation from the ethnofederal state to independence. The focus will be on Russia as the most affected of them and on the persistent Soviet legacy in its interpretations of self-determination and, consequently, its policies towards its post-Soviet neighbours.
Incorporation of the UN Convention on the Rights of the Child in National Law
Authors: Hoffman Simon , Stern Rebecca Thorburn
Published: March 2020

Incorporation is amongst the legislative measures of implementation of the UN Convention on the Rights of the Child (crc) recommended by the Committee on the Rights of the Child. This article will discuss incorporation of the crc in national law. It will show how incorporation is understood in different contexts, and highlight possible tensions between child rights and international law discourse and analysis. It begins by reviewing literature on incorporation of human rights treaties before discussing how incorporation is conceptualised in the context of the crc. The focus then shifts to a review of studies that provide insights into how incorporation and legal integration of the crc impact on how children’s rights are treated in national legal systems. While primarily a commentary on the available literature, the authors reflect on the significance of incorporation and how this is understood for academic and legal analysis, and what the evidence tells us about its contribution to the realisation of children’s rights.
Children’s Economic and Social Rights and Child Poverty: The State of Play
Authors: Nolan Aoife , Pells Kirrily
Published: March 2020

This article focuses on both economic and social rights (esr) and child poverty. In doing so, it identifies and considers key developments and gaps in child rights scholarship (crs) in these areas. The authors’ treatment of these issues together is logical (albeit certainly not inevitable) given the strong connection between esr and poverty. Both are areas which have been under-explored in crs: esr have been historically under-theorised and marginalised in child rights research, whereas child poverty is an area that has received extensive academic attention but only a limited amount of this has been from a child rights perspective.

The article begins by outlining the state of the existing theoretical child rights literature on esr, before going on to consider the growing body of crs focused on specific esr-thematic areas. The authors make clear the historic dominance of law in terms of child esr scholarship while flagging the increasing esr-focused/framed work emerging from other disciplines, arguing that this is evidence of an ever-wider and more multidisciplinary engagement with esr. Moving on to the topic of child poverty, the authors note that, with some notable exceptions, there has been a failure on the part of child rights scholars to engage with child poverty, a fact that is at least partially attributable to disciplinary disconnects: while crs (and esr scholarship in particular) has come to be dominated by lawyers to a large degree, much academic work on child poverty originates in economics, development studies and social policy. There is, however, some recognition by child poverty scholars (and more so by practitioners) that child poverty is a “child rights” issue, albeit that there is an ongoing failure on the part of child poverty scholarship to really come to terms with the complexities of child rights in terms of the implications of such for the definition and measurement of child poverty. The authors conclude by flagging future avenues for academic engagements with child esr and child poverty, considering both the ways in which existing scholarship may be enriched as well as the potential dangers that new directions may pose in terms of child esr specifically.
Judaism, Ethics, and Time: On Levinas’s Re-Interpretation of Rosenzweig’s Concept of the Kingdom of God
Authors: Aidler Alexandra
Published: March 2020

Since Emmanuel Levinas declared in Totality and Infinity (1961) that Franz Rosenzweig’s The Star of Redemption is “too often present” in his own work “to be cited,” an uninterrupted affinity between the two authors has been assumed. Nevertheless, throughout his æuvre, Levinas frequently underlines the philosophical differences marking his and Rosenzweig’s thought. In this article, I endeavor to demonstrate that the concept of redemption and salvation are wholly incompatible in Rosenzweig’s and Levinas’s philosophies. Whereas Rosenzweig pleads for a Jewish redemptive model that turns towards Judaism’s past, Levinas seeks to mobilize Judaism’s salvific potential in the name of a common human future. It is this conjunction between salvation and futurity that allows Levinas to establish a notion of the Kingdom of God that can redeem humanity from its own catastrophe after the Shoah.
The Austro-Hungarian Beginnings of the Research on the ‘European Genizah’
Authors: Turán Tamás
Published: March 2020

Research on Hebrew manuscript fragments retrieved from bookbindings started in the second half of the 19th century, some earlier forays into this field notwithstanding. Austria-Hungary played an important role in this field of research for its first hundred years – a fact that deserves attention. This pioneering research in Austria-Hungary was made possible by a recognition and appreciation of the importance of minor source materials (‘small finds’) by local scholars, and was characterized by a historical – rather than a literary-historical – interest in this source material. This article explores the particular historical and cultural factors which contributed to this regional development.
Pit and pit aperture dimensions in plantation-grown Douglas fir as affected by local growth conditions and height in stem
Authors: Christof Andreas , Ræbild Anders , Thygesen Lisbeth G.
Published: March 2020

This study assessed whether allometric scaling applied to pit sizes in stems of Douglas fir. Pit and pit aperture diameters were measured in xylem from stems of four plantation-grown Douglas fir (Pseudotsuga menziesii) trees from each of two different sites in Denmark. One site had fertile soil, the other had poor soil fertility. Three different heights were accessed for each tree, and 40 pits were measured per height. Results showed that pit diameter varied between 17 and 24 μm and decreased significantly with increasing height above ground. Representing the position in the tree as a power function of distance from the top of the tree (L0.2) rather than the height above ground improved the model fit for pit diameter as expressed by the R2 value. However, the pit diameter relationship was found to be significantly affected by site, suggesting that anatomic dimensions relate not only to tree size but also to growth conditions. This would imply that even though pit size supposedly has a strong biophysical determination, some xylem plasticity may still be induced by environmental factors.