bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic evaluation of an oral tablet form of low-molecular-weight heparin and deoxycholic acid conjugate as a novel oral anticoagulant
Authors: Park Jin Woo , Jeon Ok Cheol , Kim Sang Kyoon , Al-Hilal Taslim , Lim Kyung-Min , Moon Hyun Tae , Kim Choong Yong , Byun Youngro 
Published: March 2011

SummaryThis study was designed to develop a solid oral dosage form of deoxycholic acid (DOCA)-conjugated low-molecular-weight heparin (LMWH) and to evaluate its oral absorption, distribution, and metabolic stability for the prospect of providing an orally bioavailable LMWH. The LMWH derivative (LHD) was synthesised and then formulated with solubilisers and other pharmaceutical excipients to form a solid tablet. Its absorption and distribution after oral administration were evaluated in mice, rats, and monkeys. The in vitro metabolic stability of LHD was examined by liver microsome assays. More than 80% of LHD was released from the tablet within 60 minutes, guaranteeing rapid tablet disintegration after oral administration. Oral bioavailability of LHD in mice, rats and monkeys were 16.1 ± 3.0, 15.6 ± 6.1, and 15.8 ± 2.5%, respectively. After the oral administration of 131I-tyramine-LHD, most of the absorbed drug remained in the blood circulation and was eliminated mainly through the kidneys. LHD was hardly metabolised by the liver microsomes and showed a stable metabolic pattern similar to that of LMWH. In a rat thrombosis model, 10 mg/kg of orally administered LHD reduced thrombus formation by 60.8%, which was comparable to the antithrombotic effect of the subcutaneously injected LMWH (100 IU/ kg). Solid tablets of LHD exhibited high oral absorption and statistically significant therapeutic effects in preventing venous thromboembolism. Accordingly, LHD tablets are expected to satisfy the unmet medical need for an oral heparin-based anticoagulant as an alternative to injectable heparin and oral warfarin.
Activation of Aryl Hydrocarbon Receptor Induces Vascular Inflammation and Promotes Atherosclerosis in Apolipoprotein E−/− Mice
Authors: Wu Dalei , Nishimura Noriko , Kuo Victoria , Fiehn Oliver , Shahbaz Sevini , Van Winkle Laura , Matsumura Fumio , Vogel Christoph Franz Adam 
Published: March 2011

Objective—

Exposure to dioxins has been shown to contribute to the development of inflammatory diseases, such as atherosclerosis. Macrophage-mediated inflammation is a critical event in the initiation of atherosclerosis. Previously, we showed that treatment of macrophages with 2,3,7,8-tetrachlorodibenzo-
p
-dioxin (TCDD) leads to aryl hydrocarbon receptor (AhR)–dependent activation of inflammatory mediators and the formation of cholesterol-laden foam cells. However, the mechanisms responsible for the formation of atherosclerotic lesions mediated through AhR have not been identified.

Methods and Results—
An in vitro macrophage and an apolipoprotein E (ApoE)−/− mouse model were used to determine whether chemokines and their receptors are responsible for the AhR-mediated atherogenesis. Exposure of ApoE−/− mice to TCDD caused a time-dependent progression of atherosclerosis, which was associated with induction of inflammatory genes, including interleukin-8, as well as F4/80 and matrix metalloproteinase-12. A high-fat diet enhanced the TCDD-mediated inflammatory response and aggravated the formation of complex atheromas. Treatment with a CXCR2 inhibitor and an AhR antagonist reduced the TCDD-induced progression of early atherosclerotic lesions in ApoE−/− mice.

Conclusion—
The results suggest that CXCR2 mediates the atherogenic activity of environmental pollutants, such as dioxins, and contributes to the development of atherosclerosis through the induction of a vascular inflammatory response by activating the AhR-signaling pathway.
Peroxisome Proliferator-Activated Receptor-α Activation Promotes Macrophage Reverse Cholesterol Transport Through a Liver X Receptor–Dependent Pathway
Authors: Nakaya Kazuhiro , Tohyama Junichiro , Naik Snehal U. , Tanigawa Hiroyuki , MacPhee Colin , Billheimer Jeffrey T. , Rader Daniel J. 
Published: March 2011

Objective—
Peroxisome proliferator-activated receptor-α (PPARα) activation has been shown in vitro to increase macrophage cholesterol efflux, the initial step in reverse cholesterol transport (RCT). However, it remains unclear whether PPARα activation promotes macrophage RCT in vivo.

Methods and Results—
We demonstrated that a specific potent PPARα agonist GW7647 inhibited atherosclerosis and promoted macrophage RCT in hypercholesterolemic mice expressing the human apolipoprotein A-I (apoA-I) gene. We compared the effect of GW7647 on RCT in human apoA-I transgenic (hA-ITg) mice with wild-type mice and showed that the PPARα agonist promoted RCT in hA-ITg mice to a much greater extent than in wild-type mice, indicating that human apoA-I expression is important for PPARα-induced RCT. We further investigated the dependence of the macrophage PPARα–liver X receptor (LXR) pathway on the promotion of RCT by GW7647. Primary murine macrophages lacking PPARα or LXR abolished the ability of GW7647 to promote RCT in hA-ITg mice. In concert, the PPARα agonist promoted cholesterol efflux and ATP binding cassette transporter A1/G1 expression in primary macrophages, and this was also by the PPARα-LXR pathway.

Conclusion—
Our observations demonstrate that a potent PPARα agonist promotes macrophage RCT in vivo in a manner that is enhanced by human apoA-I expression and dependent on both macrophage PPARα and LXR expression.
A Novel Lead Configuration for Optimal Spatio-Temporal Detection of Intracardiac Repolarization Alternans
Authors: Weiss Eric H. , Merchant Faisal M. , d'Avila Andre , Foley Lori , Reddy Vivek Y. , Singh Jagmeet P. , Mela Theofanie , Ruskin Jeremy N. , Armoundas Antonis A. 
Published: March 2011

Background—
Electric alternans is a pattern of variation in the shape of ECG waveform that occurs every other beat. In humans, alternation in ventricular repolarization, known as repolarization alternans (RA), has been associated with increased vulnerability to ventricular tachycardia/fibrillation and sudden cardiac death.

Methods and Results—
This study investigates the spatio-temporal variability of intracardiac RA and its relationship to body surface RA in an acute myocardial ischemia model in swine. We developed a real-time multichannel repolarization signal acquisition, display, and analysis system to record ECG signals from catheters in the right ventricle, coronary sinus, left ventricle, and epicardial surface before and after circumflex coronary artery balloon occlusion. We found that RA is detectable within 4 minutes after the onset ischemia and is most prominently seen during the first half of the repolarization interval. Ischemia-induced RA was detectable on unipolar and bipolar leads (both in near- and far-field configurations) and on body surface leads. Far-field bipolar intracardiac leads were more sensitive for RA detection than body surface leads, with the probability of body surface RA detection increasing as the number of intracardiac leads detecting RA increased, approaching 100% when at least three intracardiac leads detected RA. We developed a novel, clinically applicable intracardiac lead system based on a triangular arrangement of leads spanning the right ventricular and coronary sinus catheters, which provided the highest sensitivity for intracardiac RA detection when compared with any other far-field bipolar sensing configurations.

Conclusions—
In conclusion, intracardiac alternans, a complex spatio-temporal phenomenon associated with arrhythmia susceptibility and sudden cardiac death, can be reliably detected through a novel triangular right ventricular–coronary sinus lead configuration.
Serotonin Transporter Gene Polymorphism in Chinese Patients With Poststroke Depression
Authors: Fang Jing , Yan Weihong , Jiang Guo-Xin , Li Wei , Cheng Qi 
Published: March 2011

Background and Purpose—
We sought to compare the distribution of the serotonin transporter gene SLC6A4 polymorphism between depressed and nondepressed poststroke patients.

Methods—
Patients with cerebral stroke admitted to hospital during a 1-year period were enrolled in a 1:1 case-control study. All cases and controls were genotyped for polymorphism of the serotonin transporter-linked promoter region and the single-nucleotide polymorphism rs25531.

Results—

Among 367 patients with cerebral stroke, 57 (15.5%) were diagnosed with poststroke depression at 1 month after stroke. In the patients with poststroke depression, 7 genotypes of the serotonin transporter gene SLC6A4 were detected, and the frequency of
S/S
homozygotes was significantly higher (
P
=0.049) than that in controls.

Conclusions—

S/S
homozygosity may be positively associated with the occurrence of poststroke depression in Chinese patients.
A Consensus on Stroke
Authors: Fisher Rebecca J. , Gaynor Catherine , Kerr Micky , Langhorne Peter , Anderson Craig , Bautz-Holter Erik , Indredavik Bent , Mayo Nancy E. , Power Michael , Rodgers Helen , Rønning Ole Morten , Widén Holmqvist Lotta , Wolfe Charles D.A. , Walker Marion F. 
Published: March 2011

Background and Purpose—
Research evidence supporting Early Supported Discharge (ESD) services has been summarized in a Cochrane Systematic Review. Trials have shown that ESD can reduce long-term dependency and admission to institutional care and reduce the length of hospital stay. No adverse impact on the mood or well-being of patients or carers has been reported. With the implementation of many national and international stroke initiatives, we felt it timely to reach consensus about ESD among trialists who contributed to the review.

Methods—
We used a modified Delphi approach with 10 ESD trialists. An agreed list of statements about ESD was generated from the Cochrane review and three rounds of consultation completed. ESD trialists rated statements regarding team composition, model of team work, intervention, and success.

Results—
Consensus of opinion (>75% agreement) was obtained on 47 of the 56 statements. Multidisciplinary, specialist stroke ESD teams should plan and co-ordinate both discharge from hospital and provide rehabilitation in the community. Specific eligibility criteria (safety, practicality, medical stability, and disability) need to be followed to ensure this service is provided for mild to moderate stroke patients who can benefit from ESD. Length of stay in hospital, patient and carer outcome measures and cost, need to be routinely audited.

Conclusions—
We have created a consensus document that can be used by commissioners and service providers in implementing ESD services. Our aim is to promote the use of recommendations derived from research findings to facilitate successful implementation of stroke services nationally and internationally.
Are Stroke Biomarkers Seeing Brain Vessels in Patients With Ischemic Stroke?
Authors: Kim Suk Jae , Choe Yeon Hyeon , Bang Oh Young ,   for the CHAOS-BIOMARKER Collaborators
Published: March 2011

Background and Purpose—
The significance of asymptomatic coronary artery atherosclerosis burden (CAB) in the interpretation of stroke biomarker results is unknown. We investigated biomarker values to determine if they are related to cerebral atherosclerosis with consideration of CAB.

Methods—
We prospectively recruited patients with noncardioembolic ischemic cerebrovascular disease who had no history of coronary artery disease. Patient-based vascular assessment was conducted using MRA for the cerebral arteries and cardiac CT angiography for the coronary arteries. Biomarkers including the C-reactive protein and homocysteine were measured.

Results—
A total of 178 patients were included in the study. The extracranial carotid stenosis was associated with the highest quartile of C-reactive protein (OR, 2.24; 95% CI, 1.04–4.55), whereas age was the only predictor of the highest quartile of homocysteine (OR, 1.06; 95% CI, 1.02–1.11). However, with consideration of CAB, CAB (≥2 segments with ≥50% stenosis) remained the only independent predictor for the highest quartile of C-reactive protein (OR, 8.69; 95% CI, 2.41–31.30) and homocysteine (OR, 11.44; 95% CI, 2.61–50.11).

Conclusions—
Our data emphasize the importance of CAB in biomarker studies of patients with ischemic stroke.
Arriba: effects of an educational intervention on prescribing behaviour in prevention of CVD in general practice
Authors: Keller Heidemarie , Krones Tanja , Becker Annette , Hirsch Oliver , Sönnichsen Andreas C , Popert Uwe , Kaufmann-Kolle Petra , Rochon Justine , Wegscheider Karl , Baum Erika , Donner-Banzhoff Norbert 
Published: March 2011

Background: Evidence on the effectiveness of educational interventions on prescribing behaviour modification in prevention of cardiovascular disease is still insufficient. We evaluated the effects of a brief educational intervention on prescription of hydroxymethylglutaryl-CoA reductase inhibitors (statins), inhibitors of platelet aggregation (IPA), and antihypertensive agents (AH). Design: Cluster randomised controlled trial with continuous medical education (CME) groups of general practitioners (GPs). Methods: Prescription of statins, IPA, and AH were verified prior to study start (BL), immediately after index consultation (IC), and at follow-up after 6 months (FU). Prescription in patients at high risk (>15% risk of a cardiovascular event in 10 years, based on the Framingham equation) and no prescription in low-risk patients (≤ 15%) were considered appropriate. Results: An intervention effect on prescribing could only be found for IPA. Generally, changes in prescription over time were all directed towards higher prescription rates and persisted to FU, independent of risk status and group allocation. Conclusions: The active implementation of a brief evidence-based educational intervention on global risk in CVD did not lead directly to risk-adjusted changes in prescription. Investigations on an extended time scale would capture whether decision support of this kind would improve prescribing risk-adjusted sustainably.
The use of pure and impure placebo interventions in primary care - a qualitative approach
Authors: Fent Rahel , Rosemann Thomas , Fässler Margrit , Senn Oliver , Huber Carola A 
Published: March 2011

Abstract

Background
Placebos play an important role in clinical trials and several surveys have shown that they are also common in daily practice. Previous research focused primarily on the frequency of placebo use in outpatient care. Our aim was to explore physicians' views on the use of placebos in daily practice, whereby distinction was made between pure placebos (substances with no pharmacological effect, e.g. sugar pills) and impure placebos (substances with pharmacological effect but not on the condition being treated, e.g. antibiotics in viral infections or vitamins).

Methods
We performed semi-structured interviews with a sample of twelve primary care physicians (PCPs). The interview addressed individual definitions of a placebo, attitudes towards placebos and the participants' reasons for prescribing them. The interviews were transcribed and analysed using qualitative content analysis.

Results
The definition of a placebo given by the majority of the PCPs in our study was one which actually only describes pure placebos. This definition, combined with the fact that most impure placebos were not regarded as placebos at all, means that most of the participating PCPs were not aware of the extent to which placebos are used in daily practice. The PCPs stated that they use placebos (both pure and impure) mainly in the case of non-severe diseases for which there was often no satisfactory somatic explanation. According to the PCPs, cases like this are often treated by complementary and alternative therapies and these, too, are associated with placebo effects. However, all PCPs felt that the ethical aspects of such treatment were unclear and they were unsure as to how to communicate the use of placebos to their patients. Most of them would appreciate ethical guidelines on how to deal with this issue.

Conclusions
Many PCPs seem to be unaware that some of the drugs they prescribe are classified as impure placebos. Perceptions of effectiveness and doubts about the legal and ethical aspects of the use of placebos by PCPs may discourage their application. Dissemination of guidelines and consensus papers may be one approach, but it has to be acknowledged that the topic itself is in conflict with the PCPs' perception of themselves as professional and reliable physicians.
Mortality and morbidity among people living close to incinerators: a cohort study based on dispersion modeling for exposure assessment
Authors: Ranzi Andrea , Fano Valeria , Erspamer Laura , Lauriola Paolo , Perucci Carlo A , Forastiere Francesco 
Published: March 2011

Abstract

Background
Several studies have been conducted on the possible health effects for people living close to incinerators and well-conducted reviews are available. Nevertheless, several uncertainties limit the overall interpretation of the findings. We evaluated the health effects of emissions from two incinerators in a pilot cohort study.

Methods
The study area was defined as the 3.5 km radius around two incinerators located near Forlì (Italy). People who were residents in 1/1/1990, or subsequently became residents up to 31/12/2003, were enrolled in a longitudinal study (31,347 individuals). All the addresses were geocoded. Follow-up continued until 31/12/2003 by linking the mortality register, cancer registry and hospital admissions databases. Atmospheric Dispersion Model System (ADMS) software was used for exposure assessment; modelled concentration maps of heavy metals (annual average) were considered the indicators of exposure to atmospheric pollution from the incinerators, while concentration maps of nitrogen dioxide (NO2) were considered for exposure to other pollution sources. Age and area-based socioeconomic status adjusted rate ratios and 95% Confidence Intervals were estimated with Poisson regression, using the lowest exposure category to heavy metals as reference.

Results
The mortality and morbidity experience of the whole cohort did not differ from the regional population. In the internal analysis, no association between pollution exposure from the incinerators and all-cause and cause-specific mortality outcomes was observed in men, with the exception of colon cancer. Exposure to the incinerators was associated with cancer mortality among women, in particular for all cancer sites (RR for the highest exposure level = 1.47, 95% CI: 1.09, 1.99), stomach, colon, liver and breast cancer. No clear trend was detected for cancer incidence. No association was found for hospitalizations related to major diseases. NO2 levels, as a proxy from other pollution sources (traffic in particular), did not exert an important confounding role.

Conclusions
No increased risk of mortality and morbidity was found in the entire area. The internal analysis of the cohort based on dispersion modeling found excesses of mortality for some cancer types in the highest exposure categories, especially in women. The interpretation of the findings is limited given the pilot nature of the study.
Inhibition of Oesophageal Squamous Cell Carcinoma Progression by in vivo Targeting of Hyaluronan Synthesis
Authors: Twarock Sören , Freudenberger Till , Poscher Eva , Dai Guang , Jannasch Katharina , Dullin Christian , Alves Frauke , Prenzel Klaus , Knoefel Wolfram T , Stoecklein Nikolas H , Savani Rashmin C , Homey Bernhard , Fischer Jens W 
Published: March 2011

Abstract

Background
Oesophageal cancer is a highly aggressive tumour entity with at present poor prognosis. Therefore, novel treatment options are urgently needed. Hyaluronan (HA) is a polysaccharide present in the matrix of human oesophageal squamous cell carcinoma (ESCC). Importantly, in vitro ESCC cells critically depend on HA synthesis to maintain the proliferative phenotype. The aim of the present study is (1) to study HA-synthase (HAS) expression and regulation in human ESCC, and (2) to translate the in vitro results into a mouse xenograft model of human ESCC to study the effects of systemic versus tumour targeted HAS inhibition on proliferation and distribution of tumour-bound and stromal hyaluronan.

Methods
mRNA expression was investigated in human ESCC biopsies by semiquantitative real-time RT PCR. Furthermore, human ESCC were xenografted into NMRI nu/nu mice. The effects on tumour progression and morphology of 4-methylumbelliferone (4-MU), an inhibitor of HA-synthesis, and of lentiviral knock down of HA-synthase 3 (HAS3), the main HAS isoform in the human ESCC tissues and the human ESCC cell line used in this study, were determined. Tumour progression was monitored by calliper measurements and by flat-panel detector volume computed tomography (fpVCT). HA content, cellular composition and proliferation (Ki67) were determined histologically.

Results
mRNA of HAS isoform 3 (HAS3) was upregulated in human ESCC biopsies and HAS3 mRNA was positively correlated to expression of the epidermal growth factor (EGF) receptor. EGF was also proven to be a strong inductor of HAS3 mRNA expression in vitro. During the course of seven weeks, 4-MU inhibited progression of xenograft tumours. Interestingly, remodelling of the tumour into a more differentiated phenotype and inhibition of cell proliferation were observed. Lentiviral knockdown of HAS3 in human ESCC cells prior to xenografting mimicked all effects of 4-MU treatment suggesting that hyaluronan produced by ESCC is accountable for major changes in tumour environment in vivo.

Conclusions
Systemic inhibition of HA-synthesis and knockdown of tumour cell HAS3 cause decreased ESCC progression accompanied by tumour stroma remodelling and may therefore be used in novel approaches to ESCC therapy.
Association of GWAS-Based Candidate Genes with HDL-Cholesterol Levels before and after Bariatric Surgery in the Swedish Obese Subjects Study
Authors: Sarzynski Mark A. , Jacobson Peter , Rankinen Tuomo , Carlsson Björn , Sjöström Lars , Carlsson Lena M. S. , Bouchard Claude 
Published: March 2011

Context and Objective:
The magnitude of weight loss-induced high-density lipoprotein cholesterol (HDL-C) changes may depend on genetic factors. We examined the associations of eight candidate genes, identified by genome-wide association studies, with HDL-C at baseline and 10 yr after bariatric surgery in the Swedish Obese Subjects study.

Methods:
Single-nucleotide polymorphisms (SNP) (n = 60) in the following gene loci were genotyped: ABCA1, APOA5, CETP, GALNT2, LIPC, LIPG, LPL, and MMAB/MVK. Cross-sectional associations were tested before (n = 1771) and 2 yr (n = 1583) and 10 yr (n = 1196) after surgery. Changes in HDL-C were tested between baseline and yr 2 (n = 1518) and yr 2 and 10 (n = 1149). A multiple testing corrected threshold of P = 0.00125 was used for statistical significance.

Results:
In adjusted multivariate models, CETP SNP rs3764261 explained from 3.2–4.2% (P &lt; 10−14) of the variation in HDL-C at all three time points, whereas CETP SNP rs9939224 contributed an additional 0.6 and 0.9% at baseline and yr 2, respectively. LIPC SNP rs1077834 showed consistent associations across all time points (R2 = 0.4–1.1%; 3.8 × 10−6 &lt; P &lt; 3 × 10−3), whereas LPL SNP rs6993414 contributed approximately 0.5% (5 × 10−4 &lt; P &lt; 0.0012) at yr 2 and 10. In aggregate, four SNP in three genes explained 4.2, 6.8, and 5.6% of the HDL-C variance at baseline, yr 2, and yr 10, respectively. None of the SNP was significantly associated with weight loss-related changes in HDL-C.

Conclusions:
SNP in the CETP, LIPC, and LPL loci contribute significantly to plasma HDL-C levels in obese individuals, and the associations persist even after considerable weight loss due to bariatric surgery. However, they are not associated with surgery-induced changes in HDL-C levels.