bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting Cx40 (Connexin40) Expression or Function Reduces Angiogenesis in the Developing Mouse Retina
Authors: Haefliger Jacques-Antoine , Allagnat Florent , Hamard Lauriane , Le Gal Loïc , Meda Paolo , Nardelli-Haefliger Denise , Génot Elisabeth , Alonso Florian 
Published: October 2017

Objective—
Cx40 (Connexin40) forms intercellular channels that coordinate the electric conduction in the heart and the vasomotor tone in large vessels. The protein was shown to regulate tumoral angiogenesis; however, whether Cx40 also contributes to physiological angiogenesis is still unknown.

Approach and Results—
Here, we show that Cx40 contributes to physiological angiogenesis. Genetic deletion of Cx40 leads to a reduction in vascular growth and capillary density in the neovascularization model of the mouse neonatal retina. At the angiogenic front, vessel sprouting is reduced, and the mural cells recruited along the sprouts display an altered phenotype. These alterations can be attributed to disturbed endothelial cell functions as selective reexpression of Cx40 in these cells restores normal angiogenesis. In vitro, targeting Cx40 in microvascular endothelial cells, by silencing its expression or by blocking gap junction channels, decreases their proliferation. Moreover, loss of Cx40 in these cells also increases their release of PDGF (platelet-derived growth factor) and promotes the chemoattraction of mural cells. In vivo, an intravitreal injection of a Cx40 inhibitory peptide, phenocopies the loss of Cx40 in the retinal vasculature of wild-type mice.

Conclusions—
Collectively, our data show that endothelial Cx40 contributes to the early stages of physiological angiogenesis in the developing retina, by regulating vessel growth and maturation. Cx40 thus represents a novel therapeutic target for treating pathological ocular angiogenesis.
Endogenous Cholesterol Excretion Is Negatively Associated With Carotid Intima–Media Thickness in Humans
Authors: Lin Xiaobo , Racette Susan B. , Ma Lina , Wallendorf Michael , Dávila-Román Victor G. , Ostlund Richard E. 
Published: October 2017

Objective—
Epidemiological studies strongly suggest that lipid factors independent of low-density lipoprotein cholesterol contribute significantly to cardiovascular disease risk. Because circulating lipoproteins comprise only a small fraction of total body cholesterol, the mobilization and excretion of cholesterol from plasma and tissue pools may be an important determinant of cardiovascular disease risk. Our hypothesis is that fecal excretion of endogenous cholesterol is protective against atherosclerosis.

Approach and Results—

Cholesterol metabolism and carotid intima–media thickness were quantitated in 86 nondiabetic adults. Plasma cholesterol was labeled by intravenous infusion of cholesterol-d
7
solubilized in a lipid emulsion and dietary cholesterol by cholesterol-d
5
and the nonabsorbable stool marker sitostanol-d
4
. Plasma and stool samples were collected while subjects consumed a cholesterol- and phytosterol-controlled metabolic kitchen diet and were analyzed by mass spectrometry. Carotid intima–media thickness was negatively correlated with fecal excretion of endogenous cholesterol (
r
=−0.426;
P
<0.0001), total cholesterol (
r
=−0.472;
P
≤0.0001), and daily percent excretion of cholesterol from the rapidly mixing cholesterol pool (
r
=−0.343;
P
=0.0012) and was positively correlated with percent cholesterol absorption (
r
=+0.279;
P
=0.0092). In a linear regression model controlling for age, sex, systolic blood pressure, hemoglobin A1c, low-density lipoprotein, high-density lipoprotein cholesterol, and statin drug use, fecal excretion of endogenous cholesterol remained significant (
P
=0.0008).

Conclusions—
Excretion of endogenous cholesterol is strongly, independently, and negatively associated with carotid intima–media thickness. The reverse cholesterol transport pathway comprising the intestine and the rapidly mixing plasma, and tissue cholesterol pool could be an unrecognized determinant of cardiovascular disease risk not reflected in circulating lipoproteins. Further work is needed to relate measures of reverse cholesterol transport to atherosclerotic disease.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01603758.
Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption
Authors: Sané Alain Théophile , Seidman Ernest , Peretti Noel , Kleme Marie Laure , Delvin Edgard , Deslandres Colette , Garofalo Carole , Spahis Schohraya , Levy Emile 
Published: October 2017

Background—
Understanding the specific mechanisms of rare autosomal disorders has greatly expanded insights into the complex processes regulating intestinal fat transport. Sar1B GTPase is one of the critical proteins governing chylomicron secretion by the small intestine, and its mutations lead to chylomicron retention disease, despite the presence of Sar1A paralog.

Objective—
The central aim of this work is to examine the cause–effect relationship between Sar1B expression and chylomicron output and to determine whether Sar1B is obligatory for normal high-density lipoprotein biogenesis.

Approach and Results—

The
SAR1B
gene was totally silenced in Caco-2/15 cells using the zinc finger nuclease technique.
SAR1B
deletion resulted in significantly decreased secretion of triglycerides (≈40%), apolipoprotein B-48 (≈57%), and chylomicron (≈34.5%). The absence of expected chylomicron production collapse may be because of the compensatory
SAR1A
elevation observed in our experiments. Therefore, a double knockout of
SAR1A
and
SAR1B
was engineered in Caco-2/15 cells, which led to almost complete inhibition of triglycerides, apolipoprotein B-48, and chylomicron output. Further experiments with labeled cholesterol revealed the downregulation of high-density lipoprotein biogenesis in cells deficient in SAR1B or with the double knockout of the 2 SAR1 paralogs. Similarly, there was a fall in the movement of labeled cholesterol from cells to basolateral medium containing apolipoprotein A-I, thereby limiting newly synthesized high-density lipoprotein in genetically modified cells. The decreased cholesterol efflux was associated with impaired expression of ABCA1 (ATP-binding cassette subfamily A member 1).

Conclusions—

These findings demonstrate that the deletion of the 2
SAR1
isoforms is required to fully eliminate the secretion of chylomicron in vitro. They also underscore the limited high-density lipoprotein production by the intestinal cells in response to
SAR1
knockout.
Multimodality Intracoronary Imaging With Near-Infrared Spectroscopy and Intravascular Ultrasound in Asymptomatic Individuals With High Calcium Scores
Authors: Madder Ryan D. , VanOosterhout Stacie , Klungle David , Mulder Abbey , Elmore Matthew , Decker Jeffrey M. , Langholz David , Boyden Thomas F. , Parker Jessica , Muller James E. 
Published: October 2017

Background—
This study sought to determine the frequency of large lipid-rich plaques (LRP) in the coronary arteries of individuals with high coronary artery calcium scores (CACS) and to determine whether the CACS correlates with coronary lipid burden.

Methods and Results—

Combined near-infrared spectroscopy and intravascular ultrasound was performed in 57 vessels in 20 asymptomatic individuals (90% on statins) with no prior history of coronary artery disease who had a screening CACS ≥300 Agatston units. Among 268 10-mm coronary segments, near-infrared spectroscopy images were analyzed for LRP, defined as a bright yellow block on the near-infrared spectroscopy block chemogram. Lipid burden was assessed as the lipid core burden index (LCBI), and large LRP were defined as a maximum LCBI in 4 mm ≥400. Vessel plaque volume was measured by quantitative intravascular ultrasound. Vessel-level CACS significantly correlated with plaque volume by intravascular ultrasound (
r
=0.69;
P
<0.0001) but not with LCBI by near-infrared spectroscopy (
r
=0.24;
P
=0.07). Despite a high CACS, no LRP was detected in 8 (40.0%) subjects. Large LRP having a maximum LCBI in 4 mm ≥400 were infrequent, found in only 5 (25.0%) of 20 subjects and in only 5 (1.9%) of 268 10-mm coronary segments analyzed.

Conclusions—
Among individuals with a CACS ≥300 Agatston units mostly on statins, CACS correlated with total plaque volume but not LCBI. This observation may have implications on coronary risk among individuals with a high CACS considering that it is coronary LRP, rather than calcification, that underlies the majority of acute coronary events.
Validating Utility of Dual Antiplatelet Therapy Score in a Large Pooled Cohort From 3 Japanese Percutaneous Coronary Intervention Studies
Authors: Yoshikawa Yusuke , Shiomi Hiroki , Watanabe Hirotoshi , Natsuaki Masahiro , Kondo Hirokazu , Tamura Toshihiro , Nakagawa Yoshihisa , Morimoto Takeshi , Kimura Takeshi 
Published: October 2017

Background:
The dual antiplatelet therapy (DAPT) score was developed to estimate ischemic and bleeding risks from the DAPT study. However, few studies validated its utility externally. We sought to validate the utility of the DAPT score in the Japanese population.

Methods:
In a pooled cohort of 3 studies conducted in Japan (the CREDO-Kyoto [Coronary Revascularization Demonstrating Outcome Study in Kyoto] Registry Cohort-2, RESET [Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial], and NEXT [NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial]), we compared risks for ischemic and bleeding events from 13 to 36 months after percutaneous coronary intervention among patients with a DAPT score ≥2 (high DS) and a DAPT score <2 (low DS).

Results:

Among 12 223 patients receiving drug-eluting stents who were free from ischemic or bleeding events at 13 months after percutaneous coronary intervention, 3944 patients had high DS and 8279 had low DS. The cumulative incidence of primary ischemic end point (myocardial infarction/stent thrombosis) was significantly higher in high DS than in low DS (1.5% versus 0.9%,
P
=0.002), whereas the cumulative incidence of primary bleeding end point (GUSTO moderate/severe) tended to be lower in high DS than in low DS (2.1% versus 2.7%,
P
=0.07). The cumulative incidences of cardiac death, myocardial infarction, and stent thrombosis were also significantly higher in high DS than in low DS (2.0% versus 1.4%,
P
=0.03; 1.5% versus 0.8%,
P
=0.002; 0.7% versus 0.3%,
P
<0.001, respectively), whereas the cumulative incidences of noncardiac death and GUSTO severe bleeding were significantly lower in high DS than in low DS (2.4% versus 3.9%,
P
<0.001; 1.0% versus 1.6%,
P
=0.03, respectively).

Conclusions:
In the current population, the DAPT score successfully stratified ischemic and bleeding risks, although the ischemic event rate was remarkably low even in high DS. Further studies would be warranted to evaluate the utility of prolonged DAPT guided by the DAPT score.
Increase in Endovascular Therapy in Get With The Guidelines-Stroke After the Publication of Pivotal Trials
Authors: Smith Eric E. , Saver Jeffrey L. , Cox Margueritte , Liang Li , Matsouaka Roland , Xian Ying , Bhatt Deepak L. , Fonarow Gregg C. , Schwamm Lee H. 
Published: October 2017

Background:
Beginning in December 2014, a series of pivotal trials showed that endovascular thrombectomy (EVT) was highly effective, prompting calls to reorganize stroke systems of care. However, there are few data on how these trials influenced the frequency of EVT in clinical practice. We used data from the Get With The Guidelines-Stroke program to determine how the frequency of EVT changed in US practice.

Methods:
We analyzed prospectively collected data from a cohort of 2 437 975 patients with ischemic stroke admitted to 2222 participating hospitals between April 2003 and the third quarter of 2016. Weighted linear regression with 2 linear splines and a knot at January 2015 was used to compare the slope of the change in EVT use before and after the pivotal trials were published. Potentially eligible patients were defined as last known well to arrival time ≤4.5 hours and National Institutes of Health Stroke Scale score ≥6.

Results:
The frequency of EVT use was slowly increasing before January 2015 but then sharply accelerated thereafter. In the third quarter 2016, EVT was provided to 3.3% of all patients with ischemic stroke at all hospitals, representing 15.1% of all patients who were potentially eligible for EVT based on stroke duration and severity. At EVT-capable hospitals, 7.5% of all patients with ischemic stroke were treated in the third quarter of 2016, including 27.3% of the potentially eligible patients. From 2013 to 2016, case volumes nearly doubled at EVT-capable hospitals. Mean case volume per EVT-capable hospital was 37.6 per year in the last 4 quarters. EVT case volumes increased in nearly all US states from 2014 to the last 4 quarters, but with persistent geographic variation unexplained by differences in potential patient eligibility.

Conclusions:
EVT use is increasing rapidly; however, there are still opportunities to treat more patients. Reorganizing stroke systems to route patients to adequately resourced EVT-capable hospitals might increase treatment of eligible patients, improve outcomes, and reduce disparities.
Cohort Study of ECG Left Ventricular Hypertrophy Trajectories: Ethnic Disparities, Associations With Cardiovascular Outcomes, and Clinical Utility
Authors: Iribarren Carlos , Round Alfred D. , Lu Meng , Okin Peter M. , McNulty Edward J. 
Published: October 2017

Background

ECG left ventricular hypertrophy (
LVH
) is a well‐known predictor of cardiovascular disease. However, no prior study has characterized patterns of presence/absence of
ECG LVH
(“
ECG LVH
trajectories”) across the adult lifespan in both sexes and across ethnicities. We examined: (1) correlates of
ECG LVH
trajectories; (2) the association of
ECG LVH
trajectories with incident coronary heart disease, transient ischemic attack, ischemic stroke, hemorrhagic stroke, and heart failure; and (3) reclassification of cardiovascular disease risk using
ECG LVH
trajectories.

Methods and Results

We performed a cohort study among 75 412 men and 107 954 women in the Northern California Kaiser Permanente Medical Care Program who had available longitudinal exposures of
ECG LVH
and covariates, followed for a median of 4.8 (range <1–9.3) years.
ECG LVH
was measured by Cornell voltage‐duration product. Adverse trajectories of
ECG LVH
(persistent, new development, or variable pattern) were more common among blacks and Native American men and were independently related to incident cardiovascular disease with hazard ratios ranging from 1.2 for
ECG LVH
variable pattern and transient ischemic attack in women to 2.8 for persistent
ECG LVH
and heart failure in men.
ECG LVH
trajectories reclassified 4% and 7% of men and women with intermediate coronary heart disease risk, respectively.

Conclusions

ECG LVH
trajectories were significant indicators of coronary heart disease, stroke, and heart failure risk, independently of level and change in cardiovascular disease risk factors, and may have clinical utility.
Sodium and Fluid Excretion With Torsemide in Healthy Subjects is Limited by the Short Duration of Diuretic Action
Authors: Shah Salim , Pitt Bertram , Brater D. Craig , Feig Peter U. , Shen Wen , Khwaja Fatima S. , Wilcox Christopher S. 
Published: October 2017

Background
Loop diuretics are highly natriuretic but their short duration of action permits postdiuretic sodium retention, which limits salt loss unless dietary salt is severely restricted. We tested the hypothesis that a more prolonged duration of action would enhance salt loss.

Methods and Results

Ten healthy participants were crossed over between 20 mg of oral immediate‐release or extended‐release (
ER
) torsemide while consuming a fixed diet with 300 mmol·d
−1
of Na
+
. Compared with immediate‐release, plasma torsemide after
ER
was 59% lower at 1 to 3 hours but 97% higher at 8 to 10 hours as a result of a >3‐fold prolongation of time to maximal plasma concentrations. The relationship of natriuresis to log torsemide excretion showed marked hysteresis, but participants spent twice as long with effective concentrations of torsemide after
ER
, thereby enhancing diuretic efficiency. Compared with immediate‐release,
ER
torsemide did not reduce creatinine clearance and increased fluid (1634±385 versus 728±445 mL,
P
<0.02) and Na
+
output (98±15 versus 42±17 mmol,
P
<0.05) despite an 18% reduction in exposure. Neither formulation increased K
+
excretion.

Conclusions

Torsemide
ER
prolongs urine drug levels, thereby increasing the time spent with effective drug concentrations, reduces postdiuretic Na
+
retention, and moderates a fall in glomerular filtration rate. It caused significant Na
+
loss even during very high salt intake. Thus, a short duration of action limits salt loss with loop diuretics. These conclusions warrant testing in subjects with edema and heart failure.
Prediction Score for Anticoagulation Control Quality Among Older Adults
Authors: Lin Kueiyu Joshua , Singer Daniel E. , Glynn Robert J. , Blackley Suzanne , Zhou Li , Liu Jun , Dube Gina , Oertel Lynn B. , Schneeweiss Sebastian 
Published: October 2017

Background

Time in the therapeutic range (
TTR
) is associated with the effectiveness and safety of vitamin K antagonist (
VKA
) therapy. To optimize prescribing of
VKA
, we aimed to develop and validate a prediction model for
TTR
in older adults taking
VKA
for nonvalvular atrial fibrillation and venous thromboembolism.

Methods and Results

The study cohort comprised patients aged ≥65 years who were taking
VKA
for atrial fibrillation or venous thromboembolism and who were identified in the 2
US
electronic health record databases linked with Medicare claims data from 2007 through 2014. With the predictors identified from a systematic review and clinical knowledge, we built a prediction model for
TTR
, using one electronic health record system as the training set and the other as the validation set. We compared the performance of the new models to that of a published prediction score for
TTR
,
SAM
e‐
TT
2
R
2
. Based on 1663 patients in the training set and 1181 in the validation set, our optimized score included 42 variables and the simplified model included 7 variables, abbreviated as
PROSPER
(Pneumonia, Renal dysfunction, Oozing blood [prior bleeding], Staying in hospital ≥7 days, Pain medication use, no Enhanced [structured] anticoagulation services, Rx for antibiotics). The
PROSPER
score outperformed
SAM
e‐
TT
2
R
2
when predicting both
TTR
≥70% (area under the receiver operating characteristic curve 0.67 versus 0.55) and the thromboembolic and bleeding outcomes (area under the receiver operating characteristic curve 0.62 versus 0.52).

Conclusions

Our geriatric
TTR
score can be used as a clinical decision aid to select appropriate candidates to receive
VKA
therapy and as a research tool to address confounding and treatment effect heterogeneity by anticoagulation quality.
Inhibiting Histone Deacetylase 2 (HDAC2) Promotes Functional Recovery From Stroke
Authors: Tang Ying , Lin Yu‐Hui , Ni Huan‐Yu , Dong Jian , Yuan Hong‐Jin , Zhang Yu , Liang Hai‐Ying , Yao Meng‐Cheng , Zhou Qi‐Gang , Wu Hai‐Yin , Chang Lei , Luo Chun‐Xia , Zhu Dong‐Ya 
Published: October 2017

Background
Stroke is a leading cause of long‐term disability worldwide. However, current therapies that promote functional recovery from stroke are limited to physical rehabilitation. No pharmacological therapy is available. Thus, understanding the role of histone deacetylase 2 (HDAC2) in the pathophysiological process of stroke‐induced functional loss may provide a novel strategy for stroke recovery.

Methods and Results

Focal stroke was induced by photothrombosis. LV‐HDAC2‐shRNA‐GFP, LV‐GFP, Ad‐HDAC2‐Flag, or Ad‐inactive‐HDAC2‐Flag was microinjected into the peri‐infarct area immediately after stroke. HDAC inhibitors were microinjected into the peri‐infarct area 4 to 10 days after stroke. Grid‐walking task and cylinder task were conducted to assess motor function. Golgi‐Cox staining, chromatin immunoprecipitation, and electrophysiology were used to reveal the mechanisms underlying stroke recovery. Knockdown or knockout of HDAC2 promoted stroke recovery, whereas overexpression of HDAC2 worsened stroke‐induced functional impairment. More importantly, trichostatin A, a pan‐HDAC inhibitor, promoted functional recovery from stroke in WT mice when used in the delayed phase, but it was ineffective in
Hdac2
conditional knockout (
Hdac2
CKO) mice. Treatment with suberoylanilide hydroxamic acid, a selective HDAC1 and HDAC2 inhibitor, in the delayed phase of stroke produced sustained functional recovery in mice via epigenetically enhancing neuroplasticity of surviving neurons in the peri‐infarct zone.

Conclusions
Our novel findings provide evidence that HDAC2 is a crucial target for functional recovery from stroke. As there are clinically available HDAC inhibitors, our findings could be directly translated into clinical research of stroke.
Self-awareness four years after severe traumatic brain injury: discordance between the patient’s and relative’s complaints. Results from the PariS-TBI study
Authors: Chesnel Camille , Jourdan Claire , Bayen Eleonore , Ghout Idir , Darnoux Emmanuelle , Azerad Sylvie , Charanton James , Aegerter Philippe , Pradat-Diehl Pascale , Ruet Alexis , Azouvi Philippe , Vallat-Azouvi Claire 
Published: October 2017

Objective: To evaluate the patient’s awareness of his or her difficulties in the chronic phase of severe traumatic brain injury (TBI) and to determine the factors related to poor awareness. Design/Setting/Subjects: This study was part of a larger prospective inception cohort study of patients with severe TBI in the Parisian region (PariS-TBI study). Intervention/Main measures: Evaluation was carried out at four years and included the Brain Injury Complaint Questionnaire (BICoQ) completed by the patient and his or her relative as well as the evaluation of impairments, disability and quality of life. Results: A total of 90 patient-relative pairs were included. Lack of awareness was measured using the unawareness index that corresponded to the number of discordant results between the patient and relative in the direction of under evaluation of difficulties by the patient. The only significant relationship found with lack of awareness was the subjective burden perceived by the relative (Zarit Burden Inventory) ( r = 0.5; P < 0.00001). There was no significant relationship between lack of awareness and injury severity, pre-injury socio-demographic data, cognitive impairments, mood disorders, functional independence (Barthel index), global disability (Glasgow Outcome Scale), return to work at four years or quality of life (Quality Of Life after Brain Injury scale (QOLIBRI)). Conclusion: Lack of awareness four years post severe TBI was not related to the severity of the initial trauma, sociodemographic data, the severity of impairments, limitations of activity and participation, or the patient’s quality of life. However, poor awareness did significantly influence the weight of the burden perceived by the relative.