bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of the proapoptotic protein Bax is reduced in bronchial mucous cells of asthmatic subjects
Authors: Schwalm Kurt , Stevens Junko F. , Jiang Zeyu , Schuyler Mark R. , Schrader Ron , Randell Scott H. , Green Francis H. Y. , Tesfaigzi Yohannes
Published: April 2008

The present studies were designed to determine whether our findings in mice showing that the Bcl-2-associated protein X (Bax), which plays a role in the resolution of allergen-induced mucous cell metaplasia, can be applied to asthma in humans. Immunostaining of autopsy tissues from mild and severe asthmatic subjects showed a significant reduction in the percentage of Bax-positive mucous cells compared with those from nonasthmatic controls. To exclude the possibility that postmortem changes may have affected Bax expression, Bax mRNA levels in airway epithelial cells obtained from nonsmoking asthmatic subjects were compared with those from nonasthmatic controls. Because the number of cells obtained by bronchial brushings is limited, we developed a robust preamplification procedure of cDNA before quantitative real-time PCR to allow detection of 100 gene targets from limited sample size, even when it was prepared from partially degraded RNA. cDNA was prepared by reverse transcription from RNA isolated from bronchial epithelial cells obtained by bronchial brushings from well-characterized subjects without lung disease and from subjects with mild asthma. Quantitative analysis showed that Bax mRNA levels were significantly reduced in samples obtained from asthma patients compared with nonasthma controls. Furthermore, Bax mRNA levels were reduced when primary airway epithelial cells from 10 individuals were treated in culture with the T helper 2 cytokine IL-13. These studies show that Bax expression is reduced in airway epithelial cells of even mild asthmatic subjects and suggest that restoring Bax expression may provide a clinical approach for restoring the normal numbers of epithelial cells and reduced mucous hypersecretion in asthma.
MMP-12 induces IL-8/CXCL8 secretion through EGFR and ERK1/2 activation in epithelial cells
Authors: Quément Catherine Le , Guénon Isabelle , Gillon Jean-Yves , Lagente Vincent , Boichot Elisabeth
Published: April 2008

Macrophage metalloelastase (MMP-12) is described to be involved in pulmonary inflammatory response. To determine the mechanisms linking MMP-12 and inflammation, we examined the effect of recombinant human MMP-12 (rhMMP-12) catalytic domain on IL-8/CXCL8 production in cultured human airway epithelial (A549) cells. Stimulation with rhMMP-12 resulted in a concentration-dependent IL-8/CXCL8 synthesis 6 h later. Similar results were also observed in cultured BEAS-2B bronchial epithelial cells. In A549 cells, synthetic matrix metalloproteinase (MMP) inhibitors prevented rhMMP-12-induced IL-8/CXCL8 release. We further demonstrated that in A549 cells, rhMMP-12 induced transient, peaking at 5 min, activation of ERK1/2. Selective MEK inhibitors (U0126 and PD-98059) blocked both IL-8/CXCL8 release and ERK1/2 phosphorylation. IL-8/CXCL8 induction and ERK1/2 activation were preceded by EGF receptor (EGFR) tyrosine phosphorylation, within 2 min, and reduced by selective EGFR tyrosine kinase inhibitors (AG-1478 and PD168393) by a neutralizing EGFR antibody and by small interfering RNA oligonucleotides directed against EGFR, implicating EGFR activation. In addition, we observed an activation of c-Fos in A549 cells stimulated by rhMMP-12, dependent on ERK1/2. Using small interfering technique, we showed that c-Fos is involved in rhMMP-12-induced IL-8/CXCL8 production. From these results, we conclude that one mechanism, by which MMP-12 induces IL-8/CXCL8 release from the alveolar epithelium, is the EGFR/ERK1/2/activating protein-1 pathway.
GSK-3/β-catenin signaling axis in airway smooth muscle: role in mitogenic signaling
Authors: Nunes Raquel O. , Schmidt Martina , Dueck Gordon , Baarsma Hoeke , Halayko Andrew J. , Kerstjens Huib A. M. , Meurs Herman , Gosens Reinoud
Published: April 2008

β-Catenin plays a dual role in cellular signaling by stabilizing cadherin-mediated cell-cell contact and by regulating gene transcription associated with cell cycle progression. Nonetheless, its presence and function in airway smooth muscle have not been determined. We hypothesized a central role for β-catenin in mitogenic signaling in airway smooth muscle in response to growth factor stimulation. Immunocytochemical and biochemical analysis revealed that human airway smooth muscle cells indeed express abundant β-catenin, which was localized primarily to the plasma membrane in quiescent cells. Treatment of airway smooth muscle cells with PDGF or FBS induced sustained phosphorylation of glycogen synthase kinase-3 (GSK-3), a negative regulator in its unphosphorylated form that promotes β-catenin degradation. GSK-3 phosphorylation was also increased in airway smooth muscle cells with a proliferative phenotype compared with quiescent airway smooth muscle cells with a mature phenotype. Parallel with the increase in GSK-3 phosphorylation, growth factor treatment induced an increased expression and nuclear presence of β-catenin and activated promitogenic signaling in airway smooth muscle, including the phosphorylation of retinoblastoma protein, DNA synthesis ([3H]thymidine incorporation), and cell proliferation. Importantly, small interfering RNA knockdown of β-catenin strongly reduced retinoblastoma protein phosphorylation, [3H]thymidine incorporation, and cell proliferation induced by PDGF and FBS. Collectively, these data reveal the existence of a GSK-3/β-catenin signaling axis in airway smooth muscle that is regulated by growth factors and of central importance to mitogenic signaling.
Ion Transport and Energetics During Cell Death and Protection
Authors: Murphy Elizabeth , Steenbergen Charles
Published: April 2008

During ischemia, ATP and phosphocreatine (PCr) decline, whereas intracellular hydrogen ion, intracellular sodium (Na+), calcium (Ca2+), and magnesium (Mg2+) concentrations all rise. If the ischemia is relatively short and there is little irreversible injury (cell death), PCr, pH, Na+, Mg2+, and Ca2+all recovery quickly on reperfusion. ATP recovery can take up to 24 h because of loss of adenine base from the cell and the need for de novo synthesis. There are correlative data showing that a sustained rise in Ca2+during ischemia and/or lack of recovery during reperfusion is associated with irreversible cell injury. Interventions that reduce the rise in Ca2+during ischemia and reperfusion have been shown to reduce cell death. Therefore, a better understanding of the mechanisms responsible for the rise in Ca2+during ischemia and early reperfusion could have important therapeutic implications. This review will discuss mechanisms involved in alterations in ions and high energy phosphate metabolites in perfused or intact heart during ischemia and reperfusion.
Coffee Consumption and CYP1A2*1F Genotype Modify Age at Breast Cancer Diagnosis and Estrogen Receptor Status
Authors: Bågeman Erika , Ingvar Christian , Rose Carsten , Jernström Helena
Published: April 2008

CYP1A2 plays a key role in the metabolism of both estrogen and coffee. Women with higher coffee intake and the CYP1A2*1F A/A genotype have a ratio of high 2-hydroxyestrone (2-OHE1) to 16α-OHE1. 2-OHE1 is a weak estrogen and may even block the estrogen receptor (ER), whereas 16α-OHE1 is procarcinogenic. We hypothesized that moderate to high coffee consumption (≥2 cups per day) combined with the CYP1A2*1F A/A genotype would be associated with a later age at diagnosis and a greater proportion of ER-negative (ER−) tumors among patients with breast cancer. We genotyped 458 patients with breast cancer (age, 25-99 years) in Lund, Sweden, for CYP1A2*1F. Information on lifestyle factors and tumor characteristics were obtained from preoperative questionnaires and pathology reports. Among patients with CYP1A2*1F A/A (51.3%), moderate to high consumption was associated with a later age at diagnosis compared with low coffee consumption (59.8 versus 52.6 years, P = 0.0004). These patients were also more likely to have ER− tumors than patients with low consumption (14.7% versus 0%, P = 0.018). Coffee was not associated with ER status or age at diagnosis in patients with at least one C allele. Age at diagnosis was not associated with ER status in patients with CYP1A2*1F A/A, but younger patients (<50 years) with at least one C allele were more likely to have ER− tumors compared with older patients (odds ratio, 4.2; 95% confidence interval, 1.9-9.3; P = 0.0002). These findings raise the hypothesis that coffee slows the growth of ER-positive tumors in patients with CYP1A2*1F A/A and may have implications for breast cancer if confirmed. (Cancer Epidemiol Biomarkers Prev 2008;17(4):895–901)
Prediagnostic Use of Hormone Therapy and Mortality After Breast Cancer
Authors: Newcomb Polly A. , Egan Kathleen M. , Trentham-Dietz Amy , Titus-Ernstoff Linda , Baron John A. , Hampton John M. , Stampfer Meir J. , Willett Walter C.
Published: April 2008

Background: A few studies have observed reduced breast cancer mortality in women who used hormone therapy before diagnosis. Due to the high prevalence of past and current hormone use, it is important to investigate whether these preparations are related to breast cancer mortality.

Methods: To evaluate the influence of prediagnostic use of hormone therapy on breast cancer mortality, a prospective cohort of 12,269 women ages 50 years or more diagnosed with incident invasive breast cancer and residents of Wisconsin, Massachusetts, or New Hampshire were enrolled in three phases beginning in 1988. They were followed for death until December 31, 2005, using the National Death Index. Cumulative mortality and multivariable adjusted hazard rate ratios for breast cancer and other mortality causes were calculated for women according to any hormone therapy use, and for exclusive use of estrogen or estrogen-progestin (EP).

Results: During an average 10.3 years of follow-up, 1,690 deaths from breast cancer were documented. Cumulative mortality from breast cancer was lower among hormone therapy users, specifically current users at the time of diagnosis, and EP users, compared with nonusers. Adjusted survival varied by type and duration of hormone therapy before diagnosis. A reduced risk of death from breast cancer was associated with EP preparations (hazard rate ratio, 0.73; 0.59-0.91) and with ≥5 years of EP use (0.60; 0.43-0.84). No association was observed for women who were former or current users of E-alone preparations.

Conclusions: Although use of combined EP preparations increases breast cancer risk, in this study, use of these hormones before diagnosis was associated with reduced risk of death after a breast cancer diagnosis. The better survival among users, particularly of EP, persisted after adjustment of screening, stage, and measured confounders. (Cancer Epidemiol Biomarkers Prev 2008;17(4):864–71)
Association between Genetic Polymorphisms of Macrophage Scavenger Receptor 1 Gene and Risk of Prostate Cancer in the Health Professionals Follow-up Study
Authors: Chen Yen-Ching , Giovannucci Edward , Kraft Peter , Hunter David J.
Published: April 2008

Background: Macrophage scavenger receptor 1 (MSR1) is involved in chronic inflammation, which is a risk factor for prostate cancer. Association studies assessing the relationship between sequence variants of MSR1 and prostate cancer are inconsistent. We hypothesized that sequence variants of MSR1 were associated with prostate cancer risk.

Methods: In a nested case-control design within the Health Professionals Follow-up Study, we identified 700 participants with prostate cancer diagnosed after they had provided a blood specimen in 1993 and before January 2000. Controls were 700 age-matched men without prostate cancer who had had a prostate-specific antigen test after providing a blood specimen. We genotyped three common (>5%) single nucleotide polymorphisms (SNP) that have been reported previously to be associated with risk of prostate cancer.

Results: None of these MSR1 SNPs nor estimated haplotypes were associated with prostate cancer risk (P for the global test for haplotypes = 0.89). These MSR1 SNPs also did not appear to be associated with higher-grade or advanced-stage prostate cancer.

Conclusion: The association between these sequence variants of MSR1 and the risk of prostate cancer was null. Further study of aggressive prostate cancer may be warranted, as we had limited power to assess these. (Cancer Epidemiol Biomarkers Prev 2008;17(4):1001–3)
Genetic Polymorphisms Involved in Insulin-like Growth Factor (IGF) Pathway in Relation to Mammographic Breast Density and IGF Levels
Authors: Diorio Caroline , Brisson Jacques , Bérubé Sylvie , Pollak Michael
Published: April 2008

The insulin-like growth factor (IGF) pathway is believed to play a role in carcinogenesis of the mammary gland. Single nucleotide polymorphisms (SNPs) of IGF-I, IGF-binding protein-3 (IGFBP-3), IGF receptor 1, insulin receptor substrate 1, and phosphoinositide-3-kinase, catalytic, β polypeptide genes, which are members of the IGF pathway, have been associated with risk of common cancers, breast density, and/or IGF levels but results remain inconclusive. Thus, we evaluated the association of 11 targeted IGF pathway SNPs with circulating IGF levels and mammographic breast density. Among 741 white premenopausal women, blood samples were collected at time of screening mammography, and plasma IGF-I and IGFBP-3 levels were measured by ELISA. Percent and absolute breast density were estimated using a computer-assisted method. Multivariate linear models were used to examine the associations. Women carrying increasing number of copies of the rare allele of IGF-I rs1520220 and rs6220 SNPs had increased percent breast density (Ptrend = 0.04 and 0.06, respectively). Carriers of increasing number of copies of the rare allele of phosphoinositide-3-kinase, catalytic, β polypeptide rs361072 SNP had decreased percent (Ptrend = 0.04) and absolute (Ptrend = 0.02) breast density. An association of insulin receptor substrate 1 rs1801278 SNP with absolute density (Ptrend = 0.03) was also observed. All four IGFBP-3 SNPs (including rs2854744) were associated with IGF-I and IGFBP-3 levels. This study shows that several components of the IGF pathway are associated with breast density or IGF levels. Our findings provide additional support for the idea that several components of the IGF pathway may affect breast cancer risk and that this effect on breast cancer development may be mediated, at least in part, through its influence on the morphogenesis of breast tissue. (Cancer Epidemiol Biomarkers Prev 2008;17(4):880–8)
Impact of Estrogen Deprivation on Gene Expression Profiles of Normal Postmenopausal Breast Tissue In vivo
Authors: Kendall Anne , Anderson Helen , Dunbier Anita K. , Mackay Alan , Dexter Tim , Urruticoechea Ander , Harper-Wynne Catherine , Dowsett Mitch
Published: April 2008

Aromatase inhibitors play a key role in the clinical management of hormone receptor–positive breast cancer and have potential utility as chemopreventive agents. Further understanding of the molecular effects of estrogen and its deprivation in normal breast tissue may allow the development of biomarkers of risk of breast cancer and help to predict the value of chemoprevention with aromatase inhibitors. Core biopsies of normal breast tissue were taken before and after letrozole treatment from postmenopausal women in the LITMaS pilot prevention study. RNA was extracted from these samples and used for cDNA microarray analysis. Gene expression changes induced by letrozole treatment were much less extensive than observed in estrogen receptor–positive malignant tissue; however, overall, they correlated to a highly significant degree (ρ = 0.511; P < 10−20). As well as some classically estrogen-associated genes, many genes associated with extracellular matrix remodeling were affected by estrogen deprivation in the normal breast in vivo. These data indicate for the first time that gene expression of normal breast tissue remains dependent on endogenous estrogens after the menopause. The modest degree of gene change suggests that intermediate markers of chemoprevention may be difficult to identify. (Cancer Epidemiol Biomarkers Prev 2008;17(4):855–63)
Cancer High-Risk Subjects Identified by Serum Pepsinogen Tests: Outcomes after 10-Year Follow-up in Asymptomatic Middle-Aged Males
Authors: Yanaoka Kimihiko , Oka Masashi , Mukoubayashi Chizu , Yoshimura Noriko , Enomoto Shotaro , Iguchi Mikitaka , Magari Hirohito , Utsunomiya Hirotoshi , Tamai Hideyuki , Arii Kenji , Ohata Hiroshi , Fujishiro Mitsuhiro , Takeshita Tatsuya , Mohara Osamu , Ichinose Masao
Published: April 2008

Background: Gastric cancer screening using the pepsinogen filter test is receiving wide recognition in Japan owing to convenience, freedom from discomfort or risk, efficiency, and economy. Because the long-term outcomes of cancer development in extensive atrophic gastritis detected by pepsinogen test are unclear, test-positive and test-negative subjects were investigated in a longitudinal cohort study.

Methods: Subjects comprised 5,209 middle-aged men with measured serum pepsinogen levels who were followed for 10 years. Cancer development based on “atrophy-positive” and “atrophy-negative” criteria used for cancer screening was investigated.

Results: During the study, 63 cases of cancer developed in the cohort, representing an incidence rate of 125 per 100,000 person-years. Pepsinogen test screening using the most widely used atrophy-positive criterion (pepsinogen I, ≤70 ng/mL; pepsinogen I/II ratio, ≤3.0) displayed 58.7% sensitivity, 73.4% specificity, and 2.6% positive predictive value. Cancer incidence rate was 276 per 100,000 person-years for the atrophy-positive group and 70 per 100,000 person-years for the atrophy-negative group. Incidence rate was higher in groups fulfilling stricter positive criteria detecting more extensive atrophy, reaching 424 per 100,000 person-years. In addition, 9.2% of atrophy-negative subjects with pepsinogen I of >70 ng/mL and pepsinogen I/II ratio of ≤3.0 (reflecting putative inflammation-based high pepsinogen II level) are at high risk for cancer, particularly diffuse-type cancer, with a cancer incidence rate comparable with atrophy-positive subjects (216 per 100,000 person-years).

Conclusion: Atrophy-positive subjects by pepsinogen filter test, particularly those fulfilling stricter criteria, and atrophy-negative subjects with low pepsinogen I/II ratio reflecting putative extensive active inflammation constitute populations at high risk for gastric cancer, requiring thorough endoscopic examination. (Cancer Epidemiol Biomarkers Prev 2008;17(4):838–45)
The Common D302H Variant of CASP8 Is Associated with Risk of Glioma
Authors: Bethke Lara , Sullivan Kate , Webb Emily , Murray Anne , Schoemaker Minouk , Auvinen Anssi , Kiuru Anne , Salminen Tiina , Johansen Christoffer , Christensen Helle Collatz , Muir Kenneth , McKinney Patricia , Hepworth Sarah , Dimitropoulou Polyxeni , Lophatananon Artitaya , Feychting Maria , Lönn Stefan , Ahlbom Anders , Malmer Beatrice , Henriksson Roger , Swerdlow Anthony , Houlston Richard
Published: April 2008

Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and, hence, a defense against cancer. We tested the hypothesis that the CASP8 polymorphism D302H influences risk of glioma through analysis of five series of glioma case patients and controls (n = 1,005 and 1,011, respectively). Carrier status for the rare allele of D302H was associated with a 1.37-fold increased risk (95% confidence interval, 1.10-1.70; P = 0.004). The association of CASP8 D302H with glioma risk indicates the importance of inherited variation in the apoptosis pathway in susceptibility to this form of primary brain tumor. (Cancer Epidemiol Biomarkers Prev 2008;17(4):987–9)
Human Papillomavirus in Cervical Cancer Screening: Important Role as Biomarker
Authors: Boulet Gaëlle A.V. , Horvath Caroline A.J. , Berghmans Sarah , Bogers Johannes
Published: April 2008

Cervical cytology screening has reduced cervical cancer morbidity and mortality but shows important shortcomings in terms of sensitivity and specificity. Infection with distinct types of human papillomavirus (HPV) is the primary etiologic factor in cervical carcinogenesis. This causal relationship has been exploited for the development of molecular technologies for viral detection to overcome limitations linked to cytologic cervical screening. HPV testing has been suggested for primary screening, triage of equivocal Pap smears or low-grade lesions and follow-up after treatment for cervical intraepithelial neoplasia. Determination of HPV genotype, viral load, integration status and RNA expression could further improve the effectiveness of HPV-based screening and triage strategies. The prospect of prophylactic HPV vaccination stresses the importance of modification of the current cytology-based screening approach. (Cancer Epidemiol Biomarkers Prev 2008;17(4):810–7)
Single Nucleotide Polymorphisms in Obesity-Related Genes and the Risk of Esophageal Cancers
Authors: Doecke James D. , Zhao Zhen Zhen , Stark Mitchell S. , Green Adèle C. , Hayward Nicholas K. , Montgomery Grant W. , Webb Penelope M. , Whiteman David C. ,   and for the Australian Cancer Study
Published: April 2008

Rates of adenocarcinoma of the esophagus (EAC) and esophagogastric junction (EGJAC) have been rising rapidly in recent decades, in contrast to the declining rates of esophageal squamous cell carcinomas (ESCC). Obesity is a major risk factor for both EAC and EGJAC, but not ESCC, and there is speculation that obesity promotes adenocarcinoma development through endocrine and related pathways. We therefore compared the prevalence of 12 single nucleotide polymorphisms (SNPs) in nine candidate genes previously implicated in obesity pathways (LEP, LEPR, ADIPOQ, POMC, PPARα, PPARγ, RXRγ, GHRL, and INSIG2) in a large Australian case-control study comprising DNA samples from 260 EAC cases, 301 EGJAC cases, 213 ESCC cases, and 1,352 population controls. No SNPs were associated with EGJAC or ESCC. Although several SNPs seemed to be associated with EAC on crude analysis [ADIPOQ (rs1501299), LEP (5′-untranslated region), PPARγ (H447H), and GHRL (M72L)], effect sizes were modest and none of the associations was significant after correcting for multiple comparisons. Further, we found no consistent evidence that any of the genotypes were associated with risk of EAC or EGJAC within strata of body mass index (<25.0 kg/m2, 25.0-29.9 kg/m2, >30 kg/m2). In conclusion, our data suggest that these SNPs do not play a major role in esophageal carcinogenesis. (Cancer Epidemiol Biomarkers Prev 2008;17(4):1007–12)
New Data on the Intraindividual Variation of Cystatin C
Authors: Delanaye Pierre , Cavalier Etienne , Depas Gisèle , Chapelle Jean-Paul , Krzesinski Jean-Marie
Published: April 2008

Background: Cystatin C is a new interesting marker of glomerular filtration rate (GFR). However, data regarding its biological variance are scarce and conflicting. The ability of cystatin C to longitudinally follow renal function in patients therefore remains questionable. Methods: 12 healthy subjects (6 men and 6 women) were included in the final statistical analysis. Serum creatinine, plasma cystatin C and GFR were measured twice after a 1-week interval on the same day, at the same time, and under the same preanalytical and analytical conditions. GFR was measured with an iohexol method. Serum creatinine was measured with a compensated Jaffé and an enzymatic method. Plasma cystatin C was measured by a particle-enhanced immunonephelometric method. Analytical (CVA) and within-subject (CVI) variances were classically calculated. Results: CVA for creatinine (Jaffé and enzymatic methods) and cystatin C was 2.5, 0.97 and 1.29%, respectively. CVI was 5.8, 5 and 4.5% for the Jaffé creatinine, enzymatic creatinine and cystatin C determinations, respectively. Conclusion: Our study confirms that intraindividual variation of cystatin C and creatinine are similar. Therefore, from a biological point of view, cystatin C seems as accurate as creatinine for the longitudinal follow-up of renal function in daily clinical practice.
Comparison of Coronary Artery Stenting Outcomes in the Eras Before and After the Introduction of Drug-Eluting Stents
Authors: Hannan Edward L. , Racz Michael , Holmes David R. , Walford Gary , Sharma Samin , Katz Stanley , Jones Robert H. , King Spencer B.
Published: April 2008

Background—

Few studies have compared medium-term outcomes for drug-eluting stents (DES) and bare metal stents, and most are relatively small randomized controlled trials. Furthermore, since the introduction of DES, there has been increased use and duration of use of clopidogrel, statins, and other evidence-based therapies. The purpose of the present study was to compare outcomes for patients who underwent stenting in the eras before and after the introduction of DES.

Methods and Results—

New York state patients undergoing stenting in all nonfederal hospitals in the state were studied. Patients were excluded if they had a previous revascularization. Risk factors that were significant predictors of adverse outcomes were used to adjust adverse outcome rates. The study included 11 436 patients who received stents between October 1, 2002, and March 31, 2003, and 12 926 patients who underwent stenting between October 1, 2003, and March 31, 2004. Death rates, the combined end point of death and myocardial infarction (MI), nonfatal MI requiring readmission, target vessel revascularization, and target lesion revascularization were compared at 2 years. Patients in the DES era had significantly better risk-adjusted outcomes for death/MI (adjusted hazard ratio, 0.90; 95% confidence interval, 0.83 to 0.97), 9.9% versus 10.8%; nonfatal MI requiring readmission (adjusted hazard ratio, 0.86; 95% confidence interval, 0.76 to 0.97); target vessel revascularization (adjusted hazard ratio, 0.60; 95% confidence interval, 0.56 to 0.64), 11.2% versus 17.9%; and target lesion revascularization (hazard ratio, 0.55; 95% confidence interval, 0.51 to 0.59), 8.4% versus 14.7%.

Conclusions—

Patients in the DES era experienced lower rates of death/MI, nonfatal MI, target vessel revascularization, and target lesion revascularization, but there were no differences in the rates of death. These improvements are likely a result of increased use of clopidogrel, statins, and dual antiplatelet therapy, in addition to the introduction of DES.
Kidney Dysfunction and Sudden Cardiac Death Among Women With Coronary Heart Disease
Authors: Deo Rajat , Lin Feng , Vittinghoff Eric , Tseng Zian H. , Hulley Stephen B. , Shlipak Michael G.
Published: April 2008

We evaluated the association between kidney dysfunction and sudden cardiac death risk among ambulatory women with coronary heart disease. The Heart and Estrogen Replacement Study evaluated the effects of hormone treatment on cardiovascular events among 2763 postmenopausal women with coronary heart disease. Kidney dysfunction was categorized by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease equation. Multivariate proportional hazards models were used to adjust for cardiovascular risk factors, congestive heart failure, and myocardial infarction. At baseline, 37% (n=1027) had an eGFR of >60 mL/min, 54% (n=1503) had an eGFR of 40 to 60 mL/min, and 8% (n=230) had an eGFR of <40 mL/min. During the 6.8-year follow-up period, there were 136 adjudicated sudden cardiac deaths. The rate of sudden cardiac death was higher in those with lower kidney function (0.5% per year among those with an eGFR >60; 0.6% per year with an eGFR between 40 and 60; and 1.7% per year with an eGFR <40 mL/min;
P
for trend <0.001). After multivariate analysis with baseline risk factors, eGFR at 40 to 60 mL/min was not a significant predictor, but eGFR at <40 mL/min remained strongly associated with sudden cardiac death (hazard ratio: 3.2; 95% CI: 1.9 to 5.3); adjustment for incident congestive heart failure and myocardial infarction during follow-up diminished this association (hazard ratio: 2.3; 95% CI: 1.3 to 3.9), suggesting that congestive heart failure and myocardial infarction mediated only part of the association between kidney dysfunction and sudden cardiac death. Advanced kidney dysfunction is an independent predictor of sudden cardiac death among women with coronary heart disease.
Structure-Based Identification of Small-Molecule Angiotensin-Converting Enzyme 2 Activators as Novel Antihypertensive Agents
Authors: Hernández Prada José A. , Ferreira Anderson J. , Katovich Michael J. , Shenoy Vinayak , Qi Yanfei , Santos Robson A.S. , Castellano Ronald K. , Lampkins Andrew J. , Gubala Vladimir , Ostrov David A. , Raizada Mohan K.
Published: April 2008

Angiotensin-converting enzyme 2 (ACE2) is a key renin-angiotensin system enzyme involved in balancing the adverse effects of angiotensin II on the cardiovascular system, and its overexpression by gene transfer is beneficial in cardiovascular disease. Therefore, our objectives were 2-fold: to identify compounds that enhance ACE2 activity using a novel conformation-based rational drug discovery strategy and to evaluate whether such compounds reverse hypertension-induced pathophysiologies. We used a unique virtual screening approach. In vitro assays revealed 2 compounds (a xanthenone and resorcinolnaphthalein) that enhanced ACE2 activity in a dose-dependent manner. Acute in vivo administration of the xanthenone resulted in a dose-dependent transient and robust decrease in blood pressure (at 10 mg/kg, spontaneously hypertensive rats decreased 71±9 mm Hg and Wistar-Kyoto rats decreased 21±8 mm Hg;
P
<0.05). Chronic infusion of the xanthenone (120 μg/day) resulted in a modest decrease in the spontaneously hypertensive rat blood pressure (17 mm Hg; 2-way ANOVA;
P
<0.05), whereas it had no effect in Wistar-Kyoto rats. Strikingly, the decrease in blood pressure was also associated with improvements in cardiac function and reversal of myocardial, perivascular, and renal fibrosis in the spontaneously hypertensive rats. We conclude that structure-based screening can help identify compounds that activate ACE2, decrease blood pressure, and reverse tissue remodeling. Administration of ACE2 activators may be a valid strategy for antihypertensive therapy.
Children's Suffrage: A Critique of the Importance of Voters' Knowledge for the Well-Being of Democracy
Authors: Olsson Stefan
Published: April 2008

That children should not have the right to vote is something that most people think of as self-evident. It is so obvious that almost none of the prominent democratic theorists have given it any serious consideration. It is a non-issue. In this paper, I question this "self-evident" view. The main reason why children are excluded from the suffrage is that they lack political competence. By reviewing the research on political knowledge among voters, however, I show that the fear of the ignorant voter has been vastly exaggerated. If democracy works well with a large number of adult voters with little or no knowledge of politics, it should also work with children voting. The article also discusses the role of parents. The idea that children should have the right to vote very much depends on whether we accept that parents can act as their children's trustees or not. My argument is that this should not be a problem. Acting through representatives is already an accepted practice in the democratic system. Parents are already considered the children's legal representatives. There is no reason why they could not be thought of as their political representatives as well.
Frustrated, Resigned, Outspoken: Students' Engagement with School Rules and Some Implications for Participatory Citizenship
Authors: Raby Rebecca
Published: April 2008

School rules are frequently presented as fostering responsibility, respect and self-discipline, yet it is rare for them to discuss students' participation or rights. Drawing on data from nine focus groups with secondary students within a southern region of Ontario, Canada, this paper investigates students' reactions to school rules, particularly in terms of participation in their creation, appeal or challenge. While students often negotiated rules with their teachers, for the most part students had little sense of themselves as able to influence the rules beyond either obedience or rule-breaking. The second half of this paper focuses on student subjectivity. While students sometimes felt able to negotiate the rules through positioning themselves as workers or students in the future, or as teenagers in the process of development, it was when they identified themselves as social actors and rights holders in the present that they were most able to challenge school rules they found to be unfair.
Putting the Age of Criminal and Tort Liability into Context: A Dialogue between Law and Psychology
Authors: Ferreira Nuno
Published: April 2008

The concepts of 'liability age' and 'capacity responsibility' have been widely dissected by researchers in various fields. However, their application to both criminal and tort liability of children remains inconsistent. Furthermore, rarely has an interdisciplinary approach adequately dealt with these concepts and their impact on legal norms. This text investigates the notion of criminal and tort liability age in connection with the notion of capacity responsibility, in relation to children, and further questions the adequacy of the relevant legal norms. This endeavour to improve the applicable legal norms is supported by an analysis of the pertinent findings in the field of psychology, particularly in respect of the moral development of children. Informed by an excursion through the ideas of Piaget, Kohlberg, and Gilligan, among others, regarding the moral development of children, the text also serves to assess the impact of concepts of moral responsibility and maturity, in relation to the development of the legal norms, which determine the age of liability of children. The text concludes with a proposal for a criminal and tort liability age framework, based upon indicative/presumptive age milestones, and an integrated approach to all relevant circumstances in casu.
Rights Conceptions of Maltreated Children Living in State Care
Authors: Ruck Martin , Peterson-Badali Michele , Bone Janet
Published: April 2008

Although research on children's thinking about children's rights has increased over the past few decades, there has been virtually no study of children with maltreatment histories who live in state care. This group is particularly vulnerable, having suffered profound violations of their right to security at the hands of their caregivers and often residing in non-kinship settings. We examined conceptions and attitudes about nurturance and self-determination rights in 100 10-18-year-old maltreated children living in state care in Toronto, Canada. Participants demonstrated a more accurate definition of a right than typically-developing youth in previous studies. Rights that were salient related predominantly to participants' current – rather than historical – circumstances. However, compared to nonmaltreated children in previous research, there was a greater focus on rights related to protection and access to basic needs, which suggests that basic issues of protection and provision are still quite relevant in their lives. While type of maltreatment did not relate to participants' thinking about rights, differences emerged between youth living in foster care and group homes. In general, rights that appeared salient to participants had an aspirational quality in that they related to opportunities or benefits that they deemed important but may not have experienced. Theoretical and practical implications of the results are discussed.
Public Justifiability and Children
Authors: Beckman Ludvig
Published: April 2008

The idea that everyone should be able, at least in principle, to accept a society's basic political principles is a central element of the liberal idea of political legitimacy. In this article, the implications of this idea for the political status of children are examined and two arguments are made. The first is that our political institutions and principles should be able to meet with the approval of children in order for them to be justified in accordance with the liberal principle of political legitimacy. The second argument is that this would be best achieved by considering what principles we – the adults – could not reasonably reject were we to adopt the child's perspective.
The United States and the International Criminal Court: Avoiding Jurisdiction Through Bilateral Agreements in Reliance on Article 98
Authors: Bogdan Attila
Published: April 2008

State-parties to the International Criminal Court Statute have a general obligation to cooperate with the Court. The duty to cooperate represents the functional cornerstone of the Court's existence. A narrow exception to this duty is contained in Article 98 of the Statute, which provides for limited circumstances in which the Court must refrain from seeking a surrender of an individual to the Court. Following rules of treaty interpretation, as well as an examination of the legislative history of the ICC Statute, the article explores the scope of Article 98, the provision the United States relied on in concluding a series of bilateral agreements that are primarily aimed at preventing the surrender of any U.S. nationals to the ICC. The article considers the issue of what impact, if any, the agreements have in the context of extradition, and the U.S.' legal ability to fulfill the commitments made in the "Article 98" agreements.
Prosecutor v.Gacumbitsi: The New Definition for Prosecuting Rape Under International Law
Authors: Cole Alison
Published: April 2008

The Gacumbitsi judgement of the Appeals Chamber of the International Criminal Tribunal for Rwanda is the first appellate case to address the apparent contradiction in the prior jurisprudence of the ad hoc Tribunals on the definition of rape. The Trial Chamber in the Akayesu judgement defined rape as a physical invasion of a sexual nature under coercive circumstances, whereas the later Appeals Chamber judgment of Kunarac introduced the requirement of consent. As well as addressing the role of consent in defining and proving rape at trial, the Appeals Chamber in Gacumbitsi also considered appeals of fact on specific allegations of rape, providing guidance on establishing crime base and linkage evidence to hold superiors responsible for rape under individual and command responsibility theory. After setting out the developments in the case law on the definition of rape, the author considers the contribution of the Gacumbitsi judgement, and argues that the Akayesu approach is most consistent with the framework of international criminal law.
UN Ad Hoc Tribunals Under Time Pressure – Completion Strategy and Referral Practice of the ICTY and ICTR from the Perspective of the Defence
Authors: Dieckmann Jens , Kerll Christina
Published: April 2008

The ICTY and ICTR have been put under an enormous time pressure to comply with the deadlines scheduled by the so-called Completion Strategy, which was announced by the United Nations Security Council in its Resolutions 1503 and 1534. This strategy called upon the two ad hoc Tribunals to focus on the trials of the most senior leaders and transfer intermediary- and lower-level accused to competent national jurisdictions in order to complete all trial activities at first instance by 2008 and all of its work by 2010. Rules 11bis of the ICTY and ICTR Rules of Procedure and Evidence were consequently amended to provide for the referral of indictments to national courts. While the ICTY to date has issued ten Referral Bench decisions and seven appellate decisions in Rule 11bis cases, the ICTR has only just initiated its referral practice. It is therefore time to examine the ICTY's jurisprudence on referrals as they will have a large impact on referral cases presented before the ICTR. This article critically analyses the development of the Tribunals' case law on referral cases from the point of view of the Defence. It provides an exhaustive overview of the jurisprudence in Rule 11bis proceedings, and examines the extent to which this jurisprudence has developed reasonable responses to the strict guidelines of the UN Security Council.
Victim Participation During the Pre-Trial Stage at the International Criminal Court
Authors: Guhr
Published: April 2008

The article deals with the first decisions of the International Criminal Court in regard to victim participation in the criminal proceedings. Victim participation is one of the novelties of the Rome Statute of the International Criminal Court. With the aim of integrating a restorative element into the proceedings, the victims are given both the opportunity to be heard and to claim reparations. The first decisions are examined with a view to the impact they could have on the proceedings. Beyond the specific decisions, various problems that may arise in relation to victim participation are discussed.
Military Criminal Responsibilities for Targeting Suspected Terrorists within (International) Armed Conflicts: Towards a Uniform Framework
Authors: Knoops Geert-Jan Alexander
Published: April 2008

This article examines a new form of counterterrorism measures exercised by states namely preventative targeting of alleged terrorists. The analysis conducted in this article is based on a judgment of the Israeli Supreme court of 13 December 2006 where this issue was addressed in the context of an international armed conflict. The author critically assesses the various aspects of this judgment in view of contemporary principles of contemporary international (criminal) law. In particular, it focuses on the main question whether this form of counter terrorism complies with the underlying principle of Common Article 3 of the Geneva conventions, namely the requirement of "the passing of sentences and the carrying out of executions without previous judgment pronounced by a regularly constituted court, affording all the judicial guarantees which are recognized as indispensable by civilized peoples."
Prospects for Ratification and Implementation of the Rome Statute by the Czech Republic
Authors: Křivánek David
Published: April 2008

The Czech Republic is the only European Union member state not to have ratified the Rome Statute of the International Criminal Court. Although the Czech Republic is a like-minded state and the government can generally be said to support the ratification, there are several reasons why this has not yet happened. This paper elucidates these reasons. It gives an overview of the relevant provisions of Czech constitutional law as well as both material and procedural criminal law and shows current Czech procedures regarding international cooperation. In this evaluation, it is highlighted that most existing provisions or those currently undergoing revision would soon enable the Czech Republic to ratify and implement the Rome Statute. The reasons why this has not yet happened are shown to be not as much legal as they are political.
The Principle of Complementarity in the Cases of the Sudanese Nationals Ahmad Harun and Ali Kushayb before the International Criminal Court
Authors: Pichon Jakob
Published: April 2008

In April 2007, the Pre-Trial Chamber I of the International Criminal Court (ICC) issued its first arrest warrants with regard to the situation in Darfur. Addressees of these measures are the Minister for Humanitarian Affairs and former Minister for the Interior Ahmad Harun and the alleged Janjaweed leader Ali Kushayb, who both at the time of writing have not yet been surrendered to the ICC. On the contrary: Sudan consistently invokes its national sovereignty and its ability to prosecute its nationals itself. However, with regard to Harun and Kushayb, there is reason to hold strong doubts as to Sudan's ability and willingness to seriously prosecute them. Therefore, this article assesses the admissibility of these two cases before the ICC, focusing on the principle of complementarity. For this the article starts with an overview of those aspects of the principle of complementarity which are relevant for the situation in Darfur. A thorough analysis of the status of the Sudanese judicial system both before and after the adoption of the Interim National Constitution of Sudan in 2005 follows, before, finally, the application of the principle of complementarity to the two cases is assessed against the results found.
Equal Standards? On the Dialectics between National Jurisdictions and the International Criminal Court
Authors: van der Wilt Harmen
Published: April 2008

The Rome Statute contains a body of legal standards on elements of the offences, concepts of criminal responsibility and defences of unprecedented detail. Whereas these standards serve the International Criminal Court as normative framework, the principle of complementarity implies that domestic jurisdictions are to take the lead in the adjudication of international crimes.This article addresses the question whether domestic legislators and courts are bound to meticulously apply the international standards, or whether they are left some leeway to apply their own (criminal) law. The article starts with a survey of the actual performance of national jurisdictions. Current international law does not explicitly compel states to copy the international standards; at most one might argue that the codification of international criminal law and the principle of complementarity encourage harmonization.Capitalizing on the concept of 'open texture of law' and the methodology of casuistry, the present author argues that a certain measure of diversity in the interpretation and application of international standards is inevitable and even desirable. However, as a general rule, states have less freedom of interpretation in respect of the elements of crimes than in the application of concepts of responsibility and defences.
The International Criminal Court's Office of the Prosecutor: Navigating between Independence and Accountability?
Authors: Verhoeven Sten , Wouters Jan , Demeyere Bruno
Published: April 2008

This contribution critically appraises the institutional position which is held by the International Criminal Court's Office of the Prosecutor. Especially, it will be asked whether and to what extent the latter is « independent » in its activities, or whether and to what extent other actors – both inside and outside the Court – can hamper the Office of the Prosecutor's margin to independently manoeuver. Against the background of the debates preceding the Rome Statute's adoption, where it was feared that the Office of the Prosecutor would become an actor that would no longer be controllable by anyone, the logical counterpart of the first question will necessarily need to assess to what extent the Office of the Prosecutor has been rendered instutionally accountable. Throughout, particular emphasis will be put on the oversight which can be exercised by the Pre-Trial Chamber. This, together with other practical factors which can constrain the Prosecutor's scope of action, leads to the conclusion that many checks and balances seriously hamper the realities of the theoretical affirmation that the Office of the Prosecutor would be an institutionally independent actor.
War Crimes in International Versus Non-International Armed Conflicts: "New Wine in Old Wineskins"?
Authors: de Beco Gauthier
Published: April 2008

This note discusses the distinction between international and non-international armed conflicts in the prosecution of war crimes before the International Criminal Court. It analyses the international humanitarian law applicable to both kinds of conflict, and the way in which the International Criminal Tribunal for the former Yugoslavia succeeded in prosecuting war crimes committed in non-international armed conflicts. It also studies the two war crimes regimes provided for in the Rome Statute of the International Criminal Court. The note then examines how Pre-Trial Chamber I dealt with this issue in its Decision on the confirmation of charges against Thomas Lubanga Dyilo and the problems it faced in doing so. It concludes with a plea for the abolition of the distinction between international and non-international armed conflicts with respect to war crimes in the Rome Statute of the International Criminal Court.