bluuebunny/crossref_metadata_2025_split huggingface dataset:
Erythrocyte Membrane Phospholipid Fatty Acid Concentrations and Risk of Colorectal Adenomas: A Case–Control Nested in the French E3N-EPIC Cohort Study
Authors: Cottet Vanessa , Collin Mélanie , Gross Anne-Sophie , Boutron-Ruault Marie-Christine , Morois Sophie , Clavel-Chapelon Françoise , Chajès Véronique 
Published: May 2013

Abstract
Background: Although dietary fatty acids may influence colorectal carcinogenesis, few studies have examined the association with adenoma risk. We assessed the association between biomarkers of dietary fatty acids or metabolism of fatty acids and the risk of colorectal adenomas in a nested case–control study from the French E3N-EPIC cohort.
Methods: Among 13,106 women without prevalent cancer who completed the diet history questionnaire and who provided blood samples, 328 cases of adenomatous polyp were identified during an average of 6.6-year follow-up and randomly matched to 619 polyp-free colonoscopy controls. Erythrocyte membrane phospholipid fatty acid concentrations were determined by gas chromatography. Adjusted ORs for risk of colorectal adenomas with increasing concentrations of fatty acids were calculated using conditional logistic regression, separately for advanced and nonadvanced adenomas.
Results: Associations were stronger with advanced than nonadvanced adenomas. High concentration of pentadecanoate plus heptadecanoate acids were inversely associated with the risk of advanced adenomas [highest vs. lowest tertile: ORT3vsT1 = 0.40 (95% confidence interval (CI) 0.20–0.79); Ptrend = 0.009]. Oleic acid was associated with an increased risk of advanced adenomas [ORT3vsT1 = 2.32 (1.16–4.64); Ptrend = 0.018]. Some polyunsaturated fatty acids were associated with the risk of advanced adenomas, either positively for di-homo-γ-linolenate [ORT3vsT1 = 2.07 (1.15–3.72); Ptrend = 0.013], or negatively for eicosapentaenoic and docosahexaenoic acids [ORT3vsT1 = 0.50 (0.27–0.93); Ptrend = 0.044 and ORT3vsT1 = 0.50 (0.26–0.96); Ptrend = 0.028, respectively].
Conclusion: A specific erythrocyte membrane phospholipid fatty acid profile, presumably reflecting both a complex dietary pattern and altered fatty acid metabolism, is associated with advanced colorectal adenoma risk.
Impact: Adenomas could be a target for primary prevention of colorectal cancer, using interventional strategy based on lipidomic profile of patients. Cancer Epidemiol Biomarkers Prev; 22(8); 1417–27. ©2013 AACR.
Gastric Reflux Is an Independent Risk Factor for Laryngopharyngeal Carcinoma
Authors: Langevin Scott M. , Michaud Dominique S. , Marsit Carmen J. , Nelson Heather H. , Birnbaum Ariel E. , Eliot Melissa , Christensen Brock C. , McClean Michael D. , Kelsey Karl T. 
Published: May 2013

AbstractBackground: Gastric reflux can reach into the upper airway, inducing cellular damage in the epithelial lining. This condition is believed to be a risk factor for development of laryngopharyngeal squamous cell carcinoma (LPSCC), although the literature is conflicting.Methods: To better clarify this relationship, we assessed the association of self-reported heartburn history and medication use among 631 patients with LPSCCs and 1234 control subjects (frequency-matched on age, gender, and town of residence) enrolled as part of a population-based case–control study of head and neck squamous cell carcinoma in the greater Boston area.Results: After adjusting for age, gender, race, smoking, alcohol consumption, HPV16 seropositivity, education, and body mass index, subjects reporting a history of frequent heartburn and who were neither a heavy smoker nor heavy drinker had a significantly elevated risk of LPSCCs [OR, 1.78; 95% confidence interval (CI), 1.00–3.16]. Among those with a history of heartburn, there was an inverse association between antacid use and LPSCCs relative to those never taking heartburn medication (OR, 0.59; 95% CI, 0.38–0.93) that remained consistent when analyzed by smoking/drinking status, HPV16 status, or by primary tumor site.Conclusions: Our data show that gastric reflux is an independent risk factor for squamous cancers of the pharynx and larynx. Further studies are needed to clarify the possible chemopreventive role of antacid use for patients with gastric reflux.Impact: Elucidation of additional risk factors for head and neck cancer can allow for risk stratification and inform surveillance of high-risk patients. Cancer Epidemiol Biomarkers Prev; 22(6); 1061–8. ©2013 AACR.
Genetic variation of platelet function and pharmacology: An update of current knowledge
Authors: Schaeffeler Elke , Schaeffeler Elke , Gawaz Meinrad , Schwab Matthias , Geisler Tobias 
Published: May 2013

SummaryPlatelets are critically involved in atherosclerosis and acute thrombosis. The platelet phenotype shows a wide variability documented by the inherited difference of platelet reactivity, platelet volume and count and function of platelet surface receptors. Several candidate genes have been put into focus and investigated for their functional and prognostic role in healthy individuals and patients with cardiovascular (CV) disease treated with antiplatelet agents. In addition to genetic variation, other clinical, disease-related and demographic factors are important so-called non-genetic factors. Due to the small effect sizes of single nucleotide polymorphisms (SNP) in candidate genes and due to the low allele frequencies of functional relevant candidate SNPs, the identification of genetic risk factors with high predictive values generally depends on the sample size of study cohorts. In the post-genome era new array and bioinformatic technologies facilitate high throughput genome-wide association studies (GWAS) for the identification of novel candidate genes in large cardiovascular cohorts. One of the crucial aspects of platelet genomic studies is the precise definition of a specific clinical phenotype (e.g. stent thrombosis) as this will impact importantly the findings of genomic studies like GWAS. Here, we provide an update on genetic variation of platelet receptors and drug metabolising enzymes under specific consideration of data derived by GWAS. The potential impact of this information and the role in personalised therapeutic concepts will be discussed.
Circulating Blood Endothelial Nitric Oxide Synthase Contributes to the Regulation of Systemic Blood Pressure and Nitrite Homeostasis
Authors: Wood Katherine C. , Cortese-Krott Miriam M. , Kovacic Jason C. , Noguchi Audrey , Liu Virginia B. , Wang Xunde , Raghavachari Nalini , Boehm Manfred , Kato Gregory J. , Kelm Malte , Gladwin Mark T. 
Published: May 2013

Objective—

Mice genetically deficient in endothelial nitric oxide synthase (eNOS
−/−
) are hypertensive with lower circulating nitrite levels, indicating the importance of constitutively produced nitric oxide (NO•) to blood pressure regulation and vascular homeostasis. Although the current paradigm holds that this bioactivity derives specifically from the expression of eNOS in endothelium, circulating blood cells also express eNOS protein. A functional red cell eNOS that modulates vascular NO• signaling has been proposed.

Approach and Results—

To test the hypothesis that blood cells contribute to mammalian blood pressure regulation via eNOS-dependent NO• generation, we cross-transplanted wild-type and eNOS
−/−
mice, producing chimeras competent or deficient for eNOS expression in circulating blood cells. Surprisingly, we observed a significant contribution of both endothelial and circulating blood cell eNOS to blood pressure and systemic nitrite levels, the latter being a major component of the circulating NO• reservoir. These effects were abolished by the NOS inhibitor L-NG-nitroarginine methyl ester and repristinated by the NOS substrate
l
-arginine and were independent of platelet or leukocyte depletion. Mouse erythrocytes were also found to carry an eNOS protein and convert
14
C-arginine into
14
C-citrulline in NOS-dependent fashion.

Conclusions—
These are the first studies to definitively establish a role for a blood-borne eNOS, using cross-transplant chimera models, that contributes to the regulation of blood pressure and nitrite homeostasis. This work provides evidence suggesting that erythrocyte eNOS may mediate this effect.
Risk Stratification and Transplant Benefit in Children Listed for Heart Transplant in the United States
Authors: Singh Tajinder P. , Almond Christopher S. , Piercey Gary , Gauvreau Kimberlee 
Published: May 2013

Background—
The sickest children among those listed for heart transplant (HT) are also at higher risk of post-transplant mortality. We hypothesized that transplant benefit, defined as percentage reduction in risk of 1-year mortality on receiving HT, increases with higher risk of wait-list mortality.

Methods and Results—

We analyzed all children aged <18 years listed for first HT in the United States between July 2004 and December 2010. We developed a model for 90-day wait-list mortality (or removal because of deterioration) and stratified listed children into deciles based on their risk of wait-list mortality. Listed children were followed up for 1 year to assess cumulative 1-year wait-list mortality among the 10 risk groups. We developed a model for 1-year post-transplant mortality to estimate the risk of post-transplant mortality for children in each risk group. Of 2979 listed children, 15% reached the wait-list end point within 90 days and 18% within 1 year. Of 2034 HT recipients, 6.8% died within 90 days and 10.8% within 1 year. The risk of 90-day wait-list mortality increased progressively from 2.4% to 51.6% from the first to the tenth risk decile. Transplant benefit increased progressively across the wait-list risk groups (
P
<0.001 for trend). However, transplant benefit for children in the top 5% of risk (7.4%) was lower than that for children in the 91st to 95th percentile of risk (10.3%).

Conclusions—
Sicker children on the wait-list benefit more from HT unless the post-transplant mortality is predicted to be very high. Whether consideration of transplant benefit in allocation policy can improve overall survival among listed children requires further analysis.
South Asians Have Elevated Postexercise Blood Pressure and Myocardial Oxygen Consumption Compared to Europeans Despite Equivalent Resting Pressure
Authors: Chaturvedi Nish , Bathula Rajaram , Shore Angela C. , Panerai Ronney , Potter John , Kooner Jaspal , Chambers John , Hughes Alun D. 
Published: May 2013

Background
Stroke mortality rate is higher in South Asians than in Europeans, despite equivalent or lower resting blood pressure (BP). Elevated recovery BP after exercise predicts stroke, independently of resting values. We hypothesized that South Asians would have adverse postexercise hemodynamics and sought explanations for this.

Methods and Results

A population‐based sample of 147 European and 145 South Asian middle‐aged men and women performed the Dundee 3‐minute step test. Cardiovascular risk factors were measured. BP, heart rate, and rate–pressure product, a measure of myocardial oxygen consumption, were compared. With 90% power and 5% significance, we could detect a difference of 0.38 of a standard deviation in any outcome measure. Resting systolic BP was similar in South Asians (144 mm Hg) and Europeans (142 mm Hg) (
P
=0.2), as was exercise BP (
P
=0.4). However, recovery systolic BP at 3 minutes after exercise was higher in South Asians by 4.3 mm Hg (95% confidence interval [CI], 0.2 to 8.3 mm Hg;
P
=0.04). This effect persisted when adjusted for exercise BP and work effort (5.4 mm Hg [95% CI, 2.2 to 8.7 mm Hg;
P
=0.001]). Adjustment for baroreflex insensitivity and greater aortic stiffness in South Asians contributes greatly to attenuating this ethnic difference (1.9 mm Hg [95% CI, −0.9 to 4.6 mm Hg;
P
=0.4]). Similarly, rate–pressure product recovery after exercise was impaired in South Asians by 735 mm Hg/min (95% CI, 137 to 1334 mm Hg/min;
P
=0.02); again, adjustment for baroreflex insensitivity and aortic stiffness attenuated this difference (261 mm Hg/min [95% CI, −39 to 561 mm Hg/min;
P
=0.3]).

Conclusion

Postexercise recovery of BP and rate–pressure product is impaired in South Asians compared to Europeans even though resting and exercise BP are similar. This is associated with the autonomic dysfunction and aortic stiffness in South Asians.

(
J Am Heart Assoc
. 2012;1:e000281 doi

:
10.1161/JAHA.111.000281
.)
Aldosterone Increases Early Atherosclerosis and Promotes Plaque Inflammation Through a Placental Growth Factor‐Dependent Mechanism
Authors: McGraw Adam P. , Bagley Jessamyn , Chen Wei‐Sheng , Galayda Carol , Nickerson Heather , Armani Andrea , Caprio Massimiliano , Carmeliet Peter , Jaffe Iris Z. 
Published: May 2013

Background
Aldosterone levels correlate with the incidence of myocardial infarction and mortality in cardiovascular patients. Aldosterone promotes atherosclerosis in animal models, but the mechanisms are poorly understood.

Methods and Results

Aldosterone was infused to achieve pathologically relevant levels that did not increase blood pressure in the atherosclerosis‐prone apolipoprotein E–knockout mouse (ApoE−/−). Aldosterone increased atherosclerosis in the aortic root 1.8±0.1‐fold after 4 weeks and in the aortic arch 3.7±0.2‐fold after 8 weeks, without significantly affecting plaque size in the abdominal aorta or traditional cardiac risk factors. Aldosterone treatment increased lipid content of plaques (2.1±0.2‐fold) and inflammatory cell content (2.2±0.3‐fold), induced early T‐cell (2.9±0.3‐fold) and monocyte (2.3±0.3‐fold) infiltration into atherosclerosis‐prone vascular regions, and enhanced systemic inflammation with increased spleen weight (1.52±0.06‐fold) and the circulating cytokine
RANTES
(regulated and normal T cell secreted; 1.6±0.1‐fold). To explore the mechanism, 7 genes were examined for aldosterone regulation in the ApoE−/− aorta. Further studies focused on the proinflammatory placental growth factor (Pl
GF
), which was released from aldosterone‐treated ApoE−/− vessels. Activation of the mineralocorticoid receptor by aldosterone in human coronary artery smooth muscle cells (
SMC
s) caused the release of factors that promote monocyte chemotaxis, which was inhibited by blocking monocyte Pl
GF
receptors. Furthermore, Pl
GF
‐deficient ApoE−/− mice were resistant to early aldosterone‐induced increases in plaque burden and inflammation.

Conclusions

Aldosterone increases early atherosclerosis in regions of turbulent blood flow and promotes an inflammatory plaque phenotype that is associated with rupture in humans. The mechanism may involve
SMC
release of soluble factors that recruit activated leukocytes to the vessel wall via Pl
GF
signaling. These findings identify a novel mechanism and potential treatment target for aldosterone‐induced ischemia in humans.
Elevated PCSK9 Levels in Untreated Patients With Heterozygous or Homozygous Familial Hypercholesterolemia and the Response to High‐Dose Statin Therapy
Authors: Raal Frederick , Panz Vanessa , Immelman Andrew , Pilcher Gillian 
Published: May 2013

Background

Proprotein convertase subtilisin kexin type 9 (
PCSK
9) is an enzyme that impairs low‐density lipoprotein cholesterol (
LDL
‐C) clearance from the plasma by promoting
LDL
receptor degradation. Patients with familial hypercholesterolemia (
FH
) have reduced or absent
LDL
receptors and should therefore have elevated
PCSK
9 levels.

Methods and Results

Fasting lipograms and
PCSK
9 levels were measured 51 homozygous
FH
(
HoFH
), 20 heterozygous
FH
(
HeFH
), and 20 normocholesterolemic control subjects. Levels were repeated following high‐dose statin therapy.
LDL
‐C levels were significantly higher in untreated
HoFH
(13.4±0.7 mmol/L) and
HeFH
patients (7.0±0.2 mmol/L) compared with controls (2.6±0.1 mmol/L) (
P
<0.01). Statin therapy decreased
LDL
‐C levels from 13.4±0.7 to 11.1±0.7 mmol/L in
HoFH
and from 7.0±0.2 to 3.6±0.2 mmol/L in
HeFH
patients (
P
<0.01).
PCSK
9 levels were higher in untreated
HoFH
(279±27 ng/mL) and
HeFH
(202±14 ng/mL) than in controls (132±10 ng/mL) (both
P
<0.01). High‐dose statin therapy increased
PCSK
9 levels from 279±27 to 338±50 ng/mL in
HoFH
, and significantly so in the
HeFH
patients from 202±14 to 278±20 ng/mL (
P
<0.01). Linear regression analysis showed a correlation between
PCSK
9 and
LDL
‐C (r=0.6769;
P
<0.0001); however, this was eliminated following statin therapy (r=0.2972;
P
=0.0625).

Conclusions

PCSK
9 levels are elevated in untreated
FH
patients, particularly in those with
HoFH
. High‐dose statin therapy further increases
PCSK
9 levels.
PCSK
9 inhibitors might be a beneficial therapy for
FH
patients, even in those with
HoFH
.
Joint Commission Primary Stroke Centers Utilize More rt‐PA in the Nationwide Inpatient Sample
Authors: Mullen Michael T. , Kasner Scott E. , Kallan Michael J. , Kleindorfer Dawn O. , Albright Karen C. , Carr Brendan G. 
Published: May 2013

Background

The Joint Commission began certifying primary stroke centers (
PSC
s) in December 2003 and provides a standardized definition of stroke center care. It is unknown if
PSC
s outperform noncertified hospitals. We hypothesized that
PSC
s would use more recombinant tissue plasminogen activator (rt‐
PA
) for ischemic stroke than would non‐
PSC
s.

Methods and Results

Data were obtained from the Nationwide Inpatient Sample from 2004 to 2009. The analysis was limited to states that publicly reported hospital identity. All patients ≥18 years with a primary diagnosis of acute ischemic stroke were included. Subjects were excluded if the treating hospital was not identified, if it was not possible to determine the temporal relationship between certification and admission, and/or if admitted as a transfer. Rt‐
PA
was defined by
ICD
9 procedure code 99.10. All eligibility criteria were met by 323 228 discharges from 26 states. There were 63 145 (19.5%) at certified
PSC
s. Intravenous rt‐
PA
was administered to 3.1% overall: 2.2% at non‐
PSC
s and 6.7% at
PSC
s. Between 2004 and 2009, rt‐
PA
administration increased from 1.4% to 3.3% at non‐
PSC
s and from 6.0% to 7.6% at
PSC
s. In a multivariable model incorporating year, age, sex, race, insurance, income, comorbidities,
DRG
‐based disease severity, and hospital characteristics, evaluation at a
PSC
was significantly associated with rt‐
PA
utilization (
OR
, 1.87; 95%
CI
, 1.61 to 2.16).

Conclusions

Subjects evaluated at
PSC
s were more likely to receive rt‐
PA
than those evaluated at non‐
PSC
s. This association was significant after adjustment for patient and hospital‐level variables. Systems of care are necessary to ensure stroke patients have rapid access to
PSC
s throughout the United States.
Hemoglobin A
1c
Is Associated With Increased Risk of Incident Coronary Heart Disease Among Apparently Healthy, Nondiabetic Men and Women
Authors: Pai Jennifer K. , Cahill Leah E. , Hu Frank B. , Rexrode Kathryn M. , Manson JoAnn E. , Rimm Eric B. 
Published: May 2013

Background

Hemoglobin A1c (HbA
1c
), a time‐integrated marker of glycemic control, predicts risk of coronary heart disease (
CHD
) among diabetics. Few studies have examined HbA
1c
and risk of
CHD
among women and men without clinically elevated levels or previously diagnosed diabetes.

Methods and Results

We conducted parallel nested case–control studies among women (
N
urses'
H
ealth
S
tudy) and men (
H
ealth
P
rofessionals
F
ollow‐up
S
tudy). During 14 and 10 years of follow‐up, 468 women and 454 men developed incident nonfatal myocardial infarction (
MI
) and fatal
CHD
. Controls were matched 2:1 based on age, smoking, and date of blood draw. For these analyses, participants with a history of diabetes or HbA
1c
levels ≥6.5% at baseline were excluded. Compared with HbA
1c
of 5.0% to <5.5%, those with an HbA
1c
of 6.0% to <6.5% had a multivariable‐adjusted relative risk (
RR
) of
CHD
of 1.90 (95%
CI
1.11 to 3.25) in women and 1.81 (95%
CI
1.09 to 3.03) in men. The pooled
RR
of
CHD
was 1.29 (95%
CI
1.11 to 1.50) for every 0.5%‐increment increase in HbA
1c
levels and 1.67 (95%
CI
1.23 to 2.25) for every 1%‐increment increase, with the risk plateauing around 5.0%. Furthermore, participants with HbA
1c
levels between 6.0% and <6.5% and
C
‐reactive protein levels >3.0 mg/L had a 2.5‐fold higher risk of
CHD
compared with participants in the lowest categories of both biomarkers.

Conclusions

Our findings suggest that HbA
1c
is associated with
CHD
risk among apparently healthy, nondiabetic women and men and may be an important early clinical marker of disease risk.
Prospective Observational Study of Implantable Cardioverter‐Defibrillators in Primary Prevention of Sudden Cardiac Death: Study Design and Cohort Description
Authors: Cheng Alan , Dalal Darshan , Butcher Barbara , Norgard Sanaz , Zhang Yiyi , Dickfeld Timm , Eldadah Zayd A. , Ellenbogen Kenneth A. , Guallar Eliseo , Tomaselli Gordon F. 
Published: May 2013

Background

Primary‐prevention implantable cardioverter‐defibrillators (
ICDs
) reduce total mortality in patients with severe left ventricular systolic function. However, only a minority of patients benefit from these devices. We designed the Prospective Observational Study of Implantable Cardioverter‐Defibrillators (
PROSE
‐
ICD
) to identify risk factors and enhance our understanding of the biological mechanisms that predispose to arrhythmic death in patients undergoing
ICD
implantation for primary prevention of sudden death.

Methods and Results

This is a multicenter prospective cohort study with a target enrollment of 1200 patients. The primary end point is
ICD
shocks for adjudicated ventricular tachyarrhythmias. The secondary end point is total mortality. All patients undergo a comprehensive evaluation including history and physical examination, signal‐averaged electrocardiograms, and blood sampling for genomic, proteomic, and metabolomic analyses. Patients are evaluated every 6 months and after every known
ICD
shock for additional electrocardiographic and blood sampling. As of December 2011, a total of 1177 patients have been enrolled with more nonwhite and female patients compared to previous randomized trials. A total of 143 patients have reached the primary end point, whereas a total of 260 patients died over an average follow‐up of 59 months. The
PROSE
‐
ICD
study represents a real‐world cohort of individuals with systolic heart failure receiving primary‐prevention
ICDs
.

Conclusions

Extensive electrophysiological and structural phenotyping as well as the availability of serial
DNA
and serum samples will be important resources for evaluating novel metrics for risk stratification and identifying patients at risk for arrhythmic sudden death.

Clinical Trial Registration

URL
:
http://clinicaltrials.gov/
Unique Identifier:
NCT
00733590.