bluuebunny/crossref_metadata_2025 huggingface dataset:
Coexpression of Fragile Histidine Triad and c-kit Is Relevant for Prediction of Survival in Patients with Small Cell Lung Cancer
Authors: Rehfeld Nina , Geddert Helene , Atamna Abedelsalam , Gabbert Helmut E. , Steidl Ulrich , Fenk Roland , Kronenwett Ralf , Haas Rainer , Rohr Ulrich-Peter
Published: November 2006

Background: In a retrospective analysis of 195 patients with small cell lung cancer (SCLC), we examined the prognostic value of a coexpression of fragile histidine triad (FHIT) protein and c-kit on patient's survival.

Methods: As assessed by immunohistochemistry using formalin-fixed, paraffin-embedded tissue sections, tumors of 195 patients with SCLC were evaluated for FHIT and c-kit coexpression.

Results: Coexpression of FHIT and c-kit was observed in 53.3%; a positive expression of either FHIT or c-kit was found in 40.5%. Complete lack of FHIT and c-kit (6.2%) was associated with a significantly shorter survival time for the patients with a mean of 122 ± 45 days compared with 468 ± 89 days for patients with lung cancer coexpressing FHIT and c-kit (P = 0.0011). The proportion of FHIT- and c-kit-positive cells within a tumor was also related to survival time. Patients with tumors with a proportion between 0% to 25% of FHIT- and c-kit-positive cells had the worst survival of 157 ± 34 days compared with 496 ± 95 days for patients showing >25% FHIT- and c-kit-positive cells (P = 0.0002). Further, variables associated with shorter survival times were low performance status, elevated lactate dehydrogenase level, and advanced tumor stage according to tumor-node-metastasis classification. Multivariate analysis using Cox regression model, including 11 variables, confirmed the prognostic significance of a combined expression of FHIT and c-kit next to tumor stage, performance status, and lactate dehydrogenase level.

Conclusions: Differential FHIT and c-kit expression was of prognostic relevance for survival in patients with SCLC and therefore provide useful variables for therapeutic decisions. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2232–8)
Body Size, Mammographic Density, and Breast Cancer Risk
Authors: Boyd Norman F. , Martin Lisa J. , Sun Limei , Guo Helen , Chiarelli Anna , Hislop Greg , Yaffe Martin , Minkin Salomon
Published: November 2006

Background: Greater weight and body mass index (BMI) are negatively correlated with mammographic density, a strong risk factor for breast cancer, and are associated with an increased risk of breast cancer in postmenopausal women, but with a reduced risk in premenopausal women. We have examined the associations of body size and mammographic density on breast cancer risk.

Method: We examined the associations of body size and the percentage of mammographic density at baseline with subsequent risk of breast cancer among 1,114 matched case-control pairs identified from three screening programs. The effect of each factor on risk of breast cancer was examined before and after adjustment for the other, using logistic regression.

Results: In all subjects, before adjustment for mammographic density, breast cancer risk in the highest quintile of BMI, compared with the lowest, was 1.04 [95% confidence interval (CI), 0.8-1.4]. BMI was associated positively with breast cancer risk in postmenopausal women, and negatively in premenopausal women. After adjustment for density, the risk associated with BMI in all subjects increased to 1.60 (95% CI, 1.2-2.2), and was positive in both menopausal groups. Adjustment for BMI increased breast cancer risk in women with 75% or greater density, compared with 0%, increased from 4.25 (95% CI, 1.6-11.1) to 5.86 (95% CI, 2.2-15.6).

Conclusion: BMI and mammographic density are independent risk factors for breast cancer, and likely to operate through different pathways. The strong negative correlated between them will lead to underestimation of the effects on risk of either pathway if confounding is not controlled. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2086–92)
Prognostic Value of PAI1 in Invasive Breast Cancer: Evidence That Tumor-Specific Factors Are More Important Than Genetic Variation in Regulating PAI1 Expression
Authors: Sternlicht Mark D. , Dunning Alison M. , Moore Dan H. , Pharoah Paul D.P. , Ginzinger David G. , Chin Koei , Gray Joe W. , Waldman Frederic M. , Ponder Bruce A.J. , Werb Zena
Published: November 2006

Plasminogen activator inhibitor-1 (PAI1) can promote cancer progression, and its protein expression in tumors is an independent indicator of poor prognosis in many forms of cancer. Here, we show that high PAI1 mRNA levels also predict for shorter overall survival in two independent breast cancer data sets, highlighting the importance of its transcriptional regulation. The −675insG (4G/5G) single-nucleotide polymorphism in the PAI1 gene promoter has been shown to influence PAI1 transcription, with the 4G allele eliciting higher reporter gene expression in vitro and higher levels of circulating PAI1 in vivo. Nevertheless, its genotypic distribution in 2,539 British women with invasive breast cancer was virtually identical to that seen in 1,832 matched controls (P = 0.72), and annual mortality rates for 4G4G, 4G5G, and 5G5G cases were 2.6%, 2.8%, and 3.1% per year, respectively (P = 0.10). Thus, there was no association with breast cancer incidence or outcome, and in a separate set of breast cancers, the 4G/5G single-nucleotide polymorphism showed no association with PAI1 mRNA expression (P = 0.85). By contrast, connective tissue growth factor (CTGF), which can regulate PAI1 expression in culture, was associated with PAI1 expression in three independent cohorts (P ≪ 0.0001). In addition, PAI1 gene copy number differences in the tumors were correlated with PAI1 mRNA expression (P = 0.0005) and seemed to affect expression independently of CTGF. Thus, local factors, such as CTGF and genomic amplification, seem to be more important than germ line genetic variation in influencing PAI1 expression and its untoward effects in breast cancer. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2107–14)
Synergy between Cigarette Smoking and Human Papillomavirus Type 16 in Cervical Cancer In situ Development
Authors: Gunnell Anthony S. , Tran Trung N. , Torrång Anna , Dickman Paul W. , Sparén Pär , Palmgren Juni , Ylitalo Nathalie
Published: November 2006

Background: A majority of studies have implicated the involvement of cigarette smoking in cervical cancer development, although its mechanism of action remains unclear. We conducted a large population-based case-control study to address the potential interaction between smoking and human papillomavirus type 16 (HPV-16) in development of cervical cancer in situ (CIS).

Methods: Information on risk factors for CIS was collected via interview, and archival cervical smears were tested for HPV-16 DNA presence in cases (n = 375) and controls (n = 363). Adjusted odds ratios (OR) for the effects of smoking, HPV-16 presence/absence, and load at first smear (taken, on average, 9 years before diagnosis) were calculated.

Results: The risk for CIS among current smokers who were HPV-16 positive at time of first smear was >14-fold [adjusted OR, 14.4; confidence interval (95% CI), 5.6-36.8] compared with HPV-16-negative current smokers. In contrast, the risk for CIS among HPV-16-positive nonsmokers was only 6-fold (adjusted OR, 5.6; 95% CI, 2.7-11.5), compared with HPV-16-negative nonsmokers. HPV-16-positive smokers with high viral load at time of first smear exhibited a high risk for CIS (adjusted OR, 27.0; 95% CI, 6.5-114.2) compared with HPV-16-negative smokers. Within nonsmokers, however, high HPV-16 load contributed only a 6-fold increased risk compared with HPV-16-negative nonsmokers (adjusted OR, 5.9; 95% CI, 2.4-14.6). Interaction was observed (P = 0.03) between duration of smoking and HPV-16 presence in CIS development.

Conclusion: Results suggest a synergistic effect between smoking and both HPV-16 status and HPV-16 viral load, which may occur almost a decade before CIS detection. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2141–7)
Identifying and Screening Patients at Risk of Second Cancers
Authors: Vogel Victor G.
Published: November 2006

Background: The average age of the U.S. population is increasing, and cancer incidence increases with age. Both improved early detection of first malignancies and effective primary oncologic therapy have led to prolonged survival, and the risk of secondary malignancies has consequently increased. A few anatomic sites are at increased risk for second malignancies within the same organ: breast, colon and rectum, lung, head and neck (or upper aerodigestive malignancies), prostate, and the uterine cervix. Some of the cancers also incur a risk for a second malignancy at another anatomic site. In addition, there are well-described clinical genetic syndromes that, as unique clinical entities, predispose to second malignant tumors.

Methods/Results: In this review, we focus on issues related to the risk of second malignancies among patients with primary breast, colon, lung and head and neck, prostate, and cervical cancers that comprise the most common sites of primary malignancy among patients in the United States. We review recent data related to both established and new screening strategies at these sites.

Conclusions: There is some evidence that screening will improve outcomes among patients who may develop second malignancies, although the data are limited. The optimal screening modalities and strategies to reduce mortality from second malignancies remain to be defined for most tumor sites. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2027–32)
Risk of Squamous Cell Carcinoma of the Upper Aerodigestive Tract in Cancer-Free Alcoholic Japanese Men: An Endoscopic Follow-up Study
Authors: Yokoyama Akira , Omori Tai , Yokoyama Tetsuji , Sato Yasuo , Mizukami Takeshi , Matsushita Sachio , Higuchi Susumu , Maruyama Katsuya , Ishii Hiromasa , Hibi Toshifumi
Published: November 2006

Asian case-control studies have shown a strong relationship between the development of squamous cell carcinoma (SCC) of the esophagus and alcohol consumption combined with inactive aldehyde dehydrogenase-2 (ALDH2*1/*2), less-active alcohol dehydrogenase-1B (ADH1B*1/*1), high mean corpuscular volume (MCV), and self-reported facial flushing in response to alcohol. However, little is known about whether these risk factors prospectively influence cancer development in cancer-free alcoholics. Between 1993 and 2005, 808 Japanese alcoholic men diagnosed as cancer-free by an initial endoscopic screening examination received follow-up examinations ranging from 1 to 148 months (median, 31 months) later, and SCC of the upper aerodigestive tract was diagnosed in 53 of them (esophagus in 33 and oropharyngolarynx in 30). Cox proportional hazards analysis showed that the age-adjusted relative hazard for SCC was 11.55 [95% confidence interval (95% CI), 5.73-23.3] in ALDH2*1/*2 heterozygotes compared with ALDH2*1/*1 homozygotes, 2.02 (95% CI, 1.02-4.02) in ADH1B*1/*1 homozygotes compared with ADH1B*1/*2 heterozygotes or *2/*2 homozygotes, 2.64 (95% CI, 1.49-4.67) in patients with flushing compared with those who had never experienced flushing, 2.91 (95% CI, 1.63-5.20) in those with an MCV ≥ 106 compared with those with an MCV < 106, 2.52 (95% CI, 1.22-5.22) in those who smoked ≥30 cigarettes per day compared with those who smoked 0 to 19 cigarettes per day, 7.26 (95% CI, 3.99-13.23) in those with esophageal dysplasia compared with those without distinct iodine-unstained lesions ≥5 mm, and 0.28 (95% CI, 0.09-0.85) in those with body mass index ≥ 23.2 (highest quartile) compared with those with body mass index < 19.0 (lowest quartile). These predictors are useful for selecting appropriately patients for careful follow-up examinations. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2209–15)
CYP17Genotypes Differ in Salivary 17-β Estradiol Levels: A Study Based on Hormonal Profiles from Entire Menstrual Cycles
Authors: Jasienska Grazyna , Kapiszewska Maria , Ellison Peter T. , Kalemba-Drozdz Malgorzata , Nenko Ilona , Thune Inger , Ziomkiewicz Anna
Published: November 2006

Variation in the levels of sex-steroid hormones results from differences in developmental conditions, adult lifestyle, and genetic polymorphism. Genes involved in sex-steroid biosynthesis have been implicated to influence levels of hormones in premenopausal women, but the results were inconclusive. We tested variation among women in levels of salivary estradiol (E2) corresponding to CYP17 genotypes. CYP17 encodes cytochrome P450c17α, which mediates two enzymes important in E2 synthesis. In contrast to the earlier studies that relied on one or a few samples for assessing the E2 levels of an individual woman, our study is based on daily collected saliva samples for one entire menstrual cycle. Sixty Polish women, ages 24 to 36 years, with regular menstrual cycles and no reported fertility problems participated in the study. Women with A2/A2 genotype had 54% higher mean E2 levels than women with A1/A1 genotype (P = 0.0001) and 37% higher than women with A1/A2 genotype (P = 0.0008). Heterozygous A1/A2 women had 13 % higher E2 levels than homozygous A1/A1 women (but this difference was significant only in a nonparametric test). Levels of E2 during the day with highest E2 (day −1) were 72% higher in A2/A2 compared with A1/A1 (P = 0.01) and 52 % higher compared with A1/A2 (P = 0.03). Our results suggest that CYP17 genotype may serve as a biomarker of endocrine function in women of reproductive age. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2131–5)
Genes Involved in DNA Repair and Nitrosamine Metabolism and Those Located on Chromosome 14q32 Are Dysregulated in Nasopharyngeal Carcinoma
Authors: Dodd Lori E. , Sengupta Srikumar , Chen I-How , den Boon Johan A. , Cheng Yu-Juen , Westra William , Newton Michael A. , Mittl Beth F. , McShane Lisa , Chen Chien-Jen , Ahlquist Paul , Hildesheim Allan
Published: November 2006

Polymorphisms in nitrosamine metabolism, DNA repair, and immune response genes have been associated with nasopharyngeal carcinoma (NPC). Studies have suggested chromosomal regions involved in NPC. To shed light on NPC etiology, we evaluated host gene expression patterns in 31 NPC and 10 normal nasopharyngeal tissue specimens using the Affymetrix Human Genome U133 Plus 2.0 Array. We focused on genes in five a priori biological pathways and chromosomal locations. Rates of differential expression within these prespecified lists and overall were tested using a bootstrap method. Differential expression was observed for 7.6% of probe sets overall. Elevations in rate of differential expression were observed within the DNA repair (13.7%; P = 0.01) and nitrosamine metabolism (17.5%; P = 0.04) pathways. Differentially expressed probe sets within the DNA repair pathway were consistently overexpressed (93%), with strong effects observed for PRKDC, PCNA, and CHEK1. Differentially expressed probe sets within the nitrosamine metabolism pathway were consistently underexpressed (100%), with strong effects observed for NQ01, CYP2B6, and CYP2E1. No significant evidence of increases in rate of differential expression was seen within the immune/inflammatory pathway. A significant elevation in rate of differential expression was noted for chromosome 4p15.1-4q12 (13.0%; P = 0.04); both overexpression and underexpression were evident (38% and 62%, respectively). An elevation in the rate of differential expression on chromosome 14q32 was observed (11.3%; P = 0.06) with a consistent pattern of gene underexpression (100%; P < 0.0001). These effects were similar when excluding late-stage tumors. Our results suggest that nitrosamine activation and DNA repair are important in NPC. The consistent down-regulation of expression on chromosome 14q32 suggests loss of heterozygosity in this region. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2216–25)
A Prospective Investigation of Height and Prostate Cancer Risk
Authors: Sequoia Jacqueline S.P. , Wright Margaret E. , McCarron Peter , Pietinen Pirjo , Taylor Philip R. , Virtamo Jarmo , Albanes Demetrius
Published: November 2006

Greater adult height, which reflects a combination of early nutrition, exposure to androgens, growth hormones, and other factors during growth and development, as well as heredity, has been associated with increased prostate cancer risk in several observational studies, but findings have been inconsistent. We examined this relationship in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. At baseline, 29,119 Finnish male smokers 50 to 69 years old had height and weight measured by trained personnel, provided information on demographic, smoking, medical, and other characteristics, and completed an extensive diet history questionnaire. A total of 1,346 incident prostate cancer cases were identified during a follow-up period of up to 17.4 years (median, 14.1 years). In age-adjusted Cox proportional hazards models, the hazard ratios and 95% confidence intervals for prostate cancer according to increasing quintiles of height [≤168, 169-171, 172-175, 176-178, and >178 cm] were 1.00 (reference), 1.11 (0.93-1.32), 1.11 (0.95-1.31), 1.30 (1.01-1.55), and 1.14 (0.96-1.35); Ptrend = 0.04. In analyses stratified by disease stage (available for 916 cases), a strong dose-response relationship was observed between greater height and advanced, but not earlier-stage, disease [tumor-node-metastasis stage III-IV, hazard ratio and 95% confidence interval for increasing quintiles of height: 1.77 (1.18-2.65), 1.82 (1.25-2.65), 1.93 (1.29-2.90), and 2.02 (1.37-2.97); Ptrend = 0.0008, Pinteraction = 0.002]. Our study provides additional evidence that increased height is a risk factor for prostate cancer and suggests that taller men are particularly susceptible to advanced disease. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2174–8)
Effects of Parity on Pregnancy Hormonal Profiles Across Ethnic Groups with a Diverse Incidence of Breast Cancer
Authors: Arslan Alan A. , Zeleniuch-Jacquotte Anne , Lukanova Annekatrin , Afanasyeva Yelena , Katz Joseph , Levitz Mortimer , Del Priore Giuseppe , Toniolo Paolo
Published: November 2006

Epidemiologic evidence suggests that a full-term pregnancy may affect maternal risk of breast cancer later in life. The objective of this cross-sectional study was to compare circulating levels of maternal hormones affecting breast differentiation (human chorionic gonadotropin and prolactin) and proliferation [α-fetoprotein, insulin-like growth factor I (IGF-I), and estradiol] between women at a low to moderate risk (Asians and Hispanics), as compared with women at a high risk for breast cancer (Caucasians and African-Americans). Between May 2002 and December 2004, a total of 586 pregnant women were approached during a routine prenatal visit. Among them, 450 women (206 Caucasian, 126 Asian, 88 Hispanic, and 30 African-American) met the inclusion criteria and signed the informed consent. Only singleton pregnancies were considered. Blood samples were drawn during the second trimester of pregnancy. Laboratory analyses were done using the IMMULITE 2000 immunoassay system. Gestational age standardized mean levels of estradiol, IGF-I, and prolactin were significantly higher in Hispanic women compared with Caucasian women. Mean concentration of IGF-I was significantly higher in African-American women compared with Caucasian and Asian women. No significant differences in pregnancy hormone levels were observed between Caucasian and Asian (predominantly second-generation Chinese) women in this study. Irrespective of ethnicity, women who had their first pregnancy had substantially higher mean levels of α-fetoprotein, human chorionic gonadotropin, estradiol, and prolactin compared with women who previously had at least one full-term pregnancy. These data suggest that circulating pregnancy hormone levels may explain some of the ethnic differences in breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2123–30)
Reproductive Factors, Oral Contraceptive Use, and Human Papillomavirus Infection: Pooled Analysis of the IARC HPV Prevalence Surveys
Authors: Vaccarella Salvatore , Herrero Rolando , Dai Min , Snijders Peter J.F. , Meijer Chris J.L.M. , Thomas Jaiye O. , Hoang Anh Pham Thi , Ferreccio Catterina , Matos Elena , Posso Hector , de Sanjosé Silvia , Shin Hai-Rim , Sukvirach Sukhon , Lazcano-Ponce Eduardo , Ronco Guglielmo , Rajkumar Raj , Qiao You-Lin , Muñoz Nubia , Franceschi Silvia ,   and IARC HPV Prevalence Surveys Study Group
Published: November 2006

High parity, early age at first full-term pregnancy (FTP), and long-term oral contraceptive (OC) use increase cervical cancer risk, but it is unclear whether these variables are also associated with increased risk of acquisition and persistence of human papillomavirus (HPV) infection, the main cause of cervical cancer. Information on reproductive and menstrual characteristics and OC use were collected from 14 areas worldwide, among population-based, age-stratified random samples of women aged 15 years or older. HPV testing was done using PCR-based enzyme immunoassay. Unconditional logistic regression was used to estimate the odds ratios (OR) of being HPV-positive according to reproductive and menstrual factors and corresponding 95% confidence intervals (CI). When more than two groups were compared, floating CIs (FCI) were estimated. A total of 15,145 women (mean age, 40.9 years) were analyzed. Women with ≥5 FTPs (OR, 0.90; 95% FCI, 0.76-1.06) showed a similar risk of being HPV-positive compared with women with only one FTP (OR, 1.00; 95% FCI, 0.86-1.16). However, nulliparous women showed an OR of 1.40 (95% CI, 1.16-1.69) compared with parous women. Early age at first FTP was not significantly related to HPV positivity. HPV positivity was similar for women who reported ≥10 years of use of OCs (OR, 1.16; 95% FCI, 0.85-1.58) and never users of OCs (OR, 1.00; 95% FCI, 0.90-1.12). Our study suggests, therefore, that high parity, early age at first FTP, and long-term OC use are not associated with HPV prevalence, but rather these factors might be involved in the transition from HPV infection to neoplastic cervical lesions. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2148–53)
Alleviating the Burden of Cancer: A Perspective on Advances, Challenges, and Future Directions
Authors: Schottenfeld David , Beebe-Dimmer Jennifer
Published: November 2006

The control of the burden of cancer would be achievable by promoting health-maintaining lifestyle behavioral practices in conjunction with facilitated access to affordable and effective periodic screening and early detection examinations combined with comprehensive treatment services. In a global population exceeding six billion in the year 2002, there were ∼10.9 million new cancer cases, 6.7 million cancer deaths, and 22.4 million persons surviving from cancer diagnosed in the previous 5 years. In 2020, the world's population is projected to increase to 7.5 billion and will experience 15 million new cancer cases and 12 million cancer deaths. This perspective on advances, challenges, and future directions in cancer epidemiology and prevention reviews the conceptual foundation for multistep carcinogenesis, causal mechanisms associated with chronic inflammation and the microenvironment of the cancer cell, and obesity, energy expenditure, and insulin resistance. Strategic priorities in global cancer control initiatives should embrace these fundamental concepts by targeting tobacco and alcohol consumption, the increasing prevalence of obesity and metabolic sequelae, and persistent microbial infections. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2049–55)
Inositol Phosphoglycan P-Type in Preeclampsia
Authors: Williams Philip J. , Gumaa Khalid , Scioscia Marco , Redman Christopher W. , Rademacher Thomas W.
Published: November 2006

A state of insulin resistance has been demonstrated in active preeclampsia, and women with clinical evidence of insulin resistance are at higher risk to develop this syndrome during pregnancy. Recently, inositol phosphoglycan P-type, a putative second messenger of insulin action, has been implicated in the pathophysiology of preeclampsia and is increased in the placenta, amniotic fluid, and maternal urine of preeclamptic women compared with normal pregnant women. We report here a case–control study to assess the potential of urinary levels of inositol phosphoglycan P-type as a screening test for preeclampsia. Twenty-seven preeclamptic women and 47 healthy pregnant women were recruited. A polyclonal antibody-based ELISA was developed to detect levels of inositol phosphoglycan P-type in urine. Its content in urinary specimens was found to be 30-fold higher in preeclamptic subjects than control subjects (329.1±21.8 versus 9.2±1.5;
P
<0.001), with a higher level in all of the preeclamptic cases. For 6 women who developed preeclampsia, >1 gestational date sample of urine was available, and retrospective analysis showed a significant time-related increase of the urinary level of inositol phosphoglycan P-type ≤7 weeks before clinical diagnosis of preeclampsia. Urinary level of inositol phosphoglycan P-type increased after diagnosis indicating a possible pathophysiological threshold level and steeply decreased after delivery.
Endothelial Dysfunction
Authors: Germain Alfredo M. , Romanik Mary Carmen , Guerra Irene , Solari Sandra , Reyes María Soledad , Johnson Richard J. , Price Karen , Karumanchi S. Ananth , Valdés Gloria
Published: November 2006

We tested the hypothesis that endothelial dysfunction could cause placentation-related defects, persist after the complicated pregnancy, and probably cause cardiovascular disease later in life. Brachial arterial reactivity and factors related to endothelial dysfunction, such as circulating cholesterol, uric acid, nitrites,
l
-arginine, asymmetrical dimethylarginine, vascular endothelial growth factor, and soluble vascular endothelial growth factor receptor-1, in women with previous healthy pregnancies (n=22), patients with severe preeclampsia (n=25), or patients with recurrent pregnancy loss (n=29), at day 10 of the luteal phase of an ovulatory cycle an average of 11 to 27 months after pregnancy were evaluated. Both groups with placentation defects had a significant decrease in endothelium-dependent dilatation, a higher rate of endothelial dysfunction, lower serum nitrites, and higher cholesterol as compared with control subjects; subjects with previous preeclampsia additionally had higher normal blood pressures and a greater parental prevalence of cardiovascular disease. Patients with recurrent pregnancy loss also demonstrated a significantly lower endothelium-independent vasodilatation. A trend to an inverse correlation was found between serum cholesterol serum and endothelial-mediated vasodilatation in the whole study population. Uric acid,
l
-arginine, asymmetrical dimethylarginine, vascular endothelial growth factor, and soluble vascular endothelial growth factor receptor-1 were similar in all of the groups. We postulate that endothelial dysfunction may represent a link between preeclampsia and increased cardiovascular disease latter in life and propose that women with unexplained recurrent miscarriages are also at increased cardiovascular risk. The identification and correction of endothelial dysfunction detected during the reproductive stage on obstetric outcome and on cardiovascular diseases needs to be elucidated.
Multilocus Analyses of Renin–Angiotensin–Aldosterone System Gene Variants on Blood Pressure at Rest and During Behavioral Stress in Young Normotensive Subjects
Authors: Ge Dongliang , Zhu Haidong , Huang Ying , Treiber Frank A. , Harshfield Gregory A. , Snieder Harold , Dong Yanbin
Published: November 2006

The renin–angiotensin–aldosterone system (RAAS) is a proteolytic cascade that regulates and maintains blood pressure (BP). This study aimed to explore the interactive and integrative effects of multiple RAAS polymorphisms on BP at rest and during behavioral stress in a normotensive population. A total of 920 young white and black twins (age: 12 to 30 years; 45% blacks) was subjected to three 10-minute stress tasks. Thirteen potential functional polymorphisms from 4 major RAAS genes were genotyped. We performed multilocus prediction allowing for genetic modification effects (gene–gene, gene–gender, gene–ethnicity, and gene–body mass index) using Multivariate Adaptive Regression Splines and generalized estimating equations. Single polymorphism analyses showed modest effects of M235T (angiotensinogen) and A-239T (angiotensin I–converting enzyme;
P
value range: 0.005 to 0.036), accounting for ≈1% of the total variance of systolic BP at rest and during stress. Compared with this, the best multilocus models revealed multiple independent genetic modification effects (gene–gene, gene–gender, and gene–body mass index;
P
value range: 0.003 to 0.009), accounting for 2.5% and 7.3% of the total variance for systolic BP levels at rest and during stress, respectively. Our data support the hypothesis that multiple RAAS genetic modifications account for BP variation. We conclude that the RAAS genetic modifications may contribute more to the dynamic BP regulation in response to behavioral stress compared with the static BP value. In addition, we reported a gene–gene interaction between M235T (angiotensinogen) and A1159G (angiotensin I–converting enzyme) on stress systolic BP levels. We proposed a viable approach to test for the multiple genetic contributions to BP and hypertension.
Autonomic Contribution to Blood Pressure and Metabolism in Obesity
Authors: Shibao Cyndya , Gamboa Alfredo , Diedrich Andre , Ertl Andrew C. , Chen Kong Y. , Byrne Daniel W. , Farley Ginnie , Paranjape Sachin Y. , Davis Stephen N. , Biaggioni Italo
Published: November 2006

Obesity is associated with alterations in the autonomic nervous system that may contribute to the increase in blood pressure and resting energy expenditure present in this condition. To test this hypothesis, we induced autonomic withdrawal with the ganglionic blocker trimethaphan in 10 lean (32±3 years) and 10 obese (35±3 years) subjects. Systolic blood pressure fell more in obese compared with lean subjects (−17±3 versus −11±1 mm Hg;
P
=0.019) because of a greater decrease in total peripheral resistance (−310±41 versus 33±78 dynes/sec/cm
−5
;
P
=0.002). In contrast, resting energy expenditure decreased less in obese than in lean subjects, (−26±21 versus −86±15 kcal per day adjusted by fat-free mass;
P
=0.035). We confirmed that the autonomic contribution to blood pressure was greater in obesity after including additional subjects with a wider range of blood pressures. Systolic blood pressure decreased −28±4 mm Hg (95% CI: −38 to −18.0; n=8) in obese hypertensive subjects compared with lean (−9±1 mm Hg; 95% CI: −11 to −6; n=22) or obese normotensive subjects (−14±2 mm Hg; 95% CI: −18 to −10; n=20). After removal of autonomic influences, systolic blood pressure remained higher in obese hypertensive subjects (109±3 versus 98±2 mm Hg in lean and 103±2 mm Hg in obese normotensive subjects;
P
=0.004) suggesting a role for additional factors in obesity-associated hypertension. In conclusion, sympathetic activation induced by obesity is an important determinant to the blood pressure elevation associated with this condition but is not effective in increasing resting energy expenditure. These results suggest that the sympathetic nervous system could be targeted in the treatment of obesity-associated hypertension.
Outcome After Implantation of a Cardioverter-Defibrillator in Patients With Brugada Syndrome
Authors: Sacher Frédéric , Probst Vincent , Iesaka Yoshito , Jacon Peggy , Laborderie Julien , Mizon-Gérard Frédérique , Mabo Philippe , Reuter Sylvain , Lamaison Dominique , Takahashi Yoshihide , O’Neill Mark D. , Garrigue Stéphane , Pierre Bertrand , Jaïs Pierre , Pasquié Jean-Luc , Hocini Mélèze , Salvador-Mazenq Michèle , Nogami Akihiko , Amiel Alain , Defaye Pascal , Bordachar Pierre , Boveda Serge , Maury Philippe , Klug Didier , Babuty Dominique , Haïssaguerre Michel , Mansourati Jacques , Clémenty Jacques , Le Marec Hervé
Published: November 2006

Background—

Brugada syndrome is an arrhythmogenic disease characterized by an increased risk of sudden cardiac death (SCD) by ventricular fibrillation. At present, an implantable cardioverter-defibrillator (ICD) is the recommended therapy in high-risk patients. This multicenter study reports the outcome of a large series of patients implanted with an ICD for Brugada syndrome.

Methods and Results—

All patients (n=220, 46±12 years, 183 male) with a type 1 Brugada ECG pattern implanted with an ICD in 14 centers between 1993 and 2005 were investigated. ICD indication was based on resuscitated SCD (18 patients, 8%), syncope (88 patients, 40%), or positive electrophysiological study in asymptomatic patients (99 patients, 45%). The remaining 15 patients received an ICD because of a family history of SCD or nonsustained ventricular arrhythmia. During a mean follow-up of 38±27 months, no patient died and 18 patients (8%) had appropriate device therapy (10±15 shocks/patient, 26±33 months after implantation). The complication rate was 28%, including inappropriate shocks, which occurred in 45 patients (20%, 4±3 shocks/patient, 21±20 months after implantation). The reasons for inappropriate therapy were lead failure (19 patients), T-wave oversensing (10 patients), sinus tachycardia (10 patients), and supraventricular tachycardia (9 patients). Among implantation parameters, high defibrillation threshold, high pacing threshold, and low R-wave amplitude occurred, respectively, in 12%, 27%, and 15% of cases.

Conclusion—

In this large Brugada syndrome population, a low incidence of arrhythmic events was found, with an annual event rate of 2.6% during a follow-up of >3 years, in addition to a significant risk of device-related complications (8.9%/year). Inappropriate shocks were 2.5 times more frequent than appropriate ones.
Intracellular Calcium and Vulnerability to Fibrillation and Defibrillation in Langendorff-Perfused Rabbit Ventricles
Authors: Hwang Gyo-Seung , Hayashi Hideki , Tang Liang , Ogawa Masahiro , Hernandez Heidy , Tan Alex Y. , Li Hongmei , Karagueuzian Hrayr S. , Weiss James N. , Lin Shien-Fong , Chen Peng-Sheng
Published: November 2006

Background—

The role of intracellular calcium (Ca
i
) in defibrillation and vulnerability is unclear.

Methods and Results—

We simultaneously mapped epicardial membrane potential and Ca
i
during shock on T-wave episodes (n=104) and attempted defibrillation episodes (n=173) in 17 Langendorff-perfused rabbit ventricles. Unsuccessful and type B successful defibrillation shocks were followed by heterogeneous distribution of Ca
i
, including regions of low Ca
i
surrounded by elevated Ca
i
(“Ca
i
sinkholes”) 31±12 ms after shock. The first postshock activation then originated from the Ca
i
sinkhole 53±14 ms after the shock. No sinkholes were present in type A successful defibrillation. A Ca
i
sinkhole also was present 39±32 ms after a shock on T that induced ventricular fibrillation, followed 22±15 ms later by propagated wave fronts that arose from the same site. This wave propagated to form a spiral wave and initiated ventricular fibrillation. Thapsigargin and ryanodine significantly decreased the upper limit of vulnerability and defibrillation threshold. We studied an additional 7 rabbits after left ventricular endocardial cryoablation, resulting in a thin layer of surviving epicardium. Ca
i
sinkholes occurred 31±12 ms after the shock, followed in 19±7 ms by first postshock activation in 63 episodes of unsuccessful defibrillation. At the Ca
i
sinkhole, the rise of Ca
i
preceded the rise of epicardial membrane potential in 5 episodes.

Conclusions—

There is a heterogeneous postshock distribution of Ca
i
. The first postshock activation always occurs from a Ca
i
sinkhole. The Ca
i
prefluorescence at the first postshock early site suggests that reverse excitation-contraction coupling might be responsible for the initiation of postshock activations that lead to ventricular fibrillation.
Clinical Features and Outcomes of Childhood Dilated Cardiomyopathy
Authors: Daubeney Piers E. F. , Nugent Alan W. , Chondros Patty , Carlin John B. , Colan Steven D. , Cheung Michael , Davis Andrew M. , Chow C.W. , Weintraub Robert G.
Published: November 2006

Background—

Despite considerable mortality, population-based prognostic factors for childhood dilated cardiomyopathy are lacking.

Methods and Results—

A population-based cohort study was undertaken of all children in Australia who presented with cardiomyopathy at age 0 to 10 years between January 1, 1987, and December 31, 1996. A single cardiologist analyzed all cardiac investigations, and a single pathologist analyzed histopathological material. There were 184 subjects with dilated cardiomyopathy. Positive viral identification or lymphocytic myocarditis was found in 30 (68.2%) of 44 cases with available early histology and 8 of 9 cases presenting with sudden death. Freedom from death or transplantation was 72% (95% CI, 65% to 78%) 1 year after presentation and 63% (95% CI, 55% to 70%) at 5 years. By proportional hazards regression analysis, risk factors for death or transplantation comprised age >5 years at presentation (hazard ratio 5.6, 95% CI, 2.6 to 12.0), familial dilated cardiomyopathy (hazard ratio, 2.9; 95% CI, 1.5 to 5.6), lower initial fractional shortening
z
score (hazard ratio per
z
-score unit, 0.75; 95% CI, 0.65 to 0.87), and failure to increase fractional shortening
z
score during follow-up (hazard ratio per unit increase, 0.68; 95% CI, 0.58 to 0.79). At follow-up, 78 (44.6%) of 175 cases diagnosed during life have no symptoms and are not taking any cardiac medication.

Conclusions—

Early mortality is high in childhood dilated cardiomyopathy, but the clinical status of long-term survivors is good. This population-based study identifies children at risk of adverse events.
Extending the Horizon in Chronic Heart Failure
Authors: Inglis Sally C. , Pearson Sue , Treen Suzette , Gallasch Tamara , Horowitz John D. , Stewart Simon
Published: November 2006

Background—

The long-term impact of chronic heart failure management programs over the typical life span of affected individuals is unknown.

Methods and Results—

The effects of a nurse-led, multidisciplinary, home-based intervention (HBI) in a typically elderly cohort of patients with chronic heart failure initially randomized to either HBI (n=149) or usual postdischarge care (UC) (n=148) after a short-term hospitalization were studied for up to 10 years of follow-up (minimum 7.5 years of follow-up). Study end points were all-cause mortality, event-free survival (event was defined as death or unplanned hospitalization), recurrent hospital stay, and cost per life-year gained. Median survival in the HBI cohort was almost twice that of UC (40 versus 22 months;
P
<0.001), with fewer deaths overall (HBI, 77% versus 89%; adjusted relative risk, 0.74; 95% CI, 0.53 to 0.80;
P
<0.001). HBI was associated with prolonged event-free survival (median, 7 versus 4 months;
P
<0.01). HBI patients had more unplanned readmissions (560 versus 550) but took 7 years to overtake UC; the rates of readmission (2.04±3.23 versus 3.66±7.62 admissions;
P
<0.05) and related hospital stay (14.8±23.0 versus 28.4±53.4 days per patient per year;
P
<0.05) were significantly lower in the HBI group. HBI was associated with 120 more life-years per 100 patients treated compared with UC (405 versus 285 years) at a cost of $1729 per additional life-year gained when we accounted for healthcare costs including the HBI.

Conclusions—

In altering the natural history of chronic heart failure relative to UC (via prolonged survival and reduced frequency of recurrent hospitalization), HBI is a remarkably cost- and time-effective strategy over the longer term.
Pathogen-Sensing Plasmacytoid Dendritic Cells Stimulate Cytotoxic T-Cell Function in the Atherosclerotic Plaque Through Interferon-α
Authors: Niessner Alexander , Sato Kayoko , Chaikof Elliot L. , Colmegna Ines , Goronzy Jörg J. , Weyand Cornelia M.
Published: November 2006

Background—

Unstable atherosclerotic plaque is characterized by an infiltrate of inflammatory cells. Both macrophages and T cells have been implicated in mediating the tissue injury leading to plaque rupture; however, signals regulating their activation remain unidentified. Infectious episodes have been suspected to render plaques vulnerable to rupture. We therefore explored whether plasmacytoid dendritic cells (pDCs) that specialize in sensing bacterial and viral products can regulate effector functions of plaque-residing T cells and thus connect host infection and plaque instability.

Methods and Results—

pDCs were identified in 53% of carotid atheromas (n=30) in which they localized to the shoulder region and produced the potent immunoregulatory cytokine interferon (INF)-α. IFN-α transcript concentrations in atheroma tissues correlated strongly with plaque instability (
P
<0.0001). Plaque-residing pDCs responded to pathogen-derived motifs, CpG-containing oligodeoxynucleotides binding to toll-like receptor 9, with enhanced IFN-α transcription (
P
=0.03) and secretion (
P
=0.007). IFN-α emerged as a potent regulator of T-cell function, even in the absence of antigen recognition. Specifically, IFN-α induced a 10-fold increase of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) on the surface of CD4 T cells (
P
<0.0001) and enabled them to effectively kill vascular smooth muscle cells (
P
=0.0003).

Conclusions—

pDCs in atherosclerotic plaque sense microbial motifs and amplify cytolytic T-cell functions, thus providing a link between host-infectious episodes and acute immune-mediated complications of atherosclerosis.
The Next Tsunami? Preparing for a Disorderly Correction of Global Imbalances
Authors: Eichengreen Barry
Published: November 2006

This paper makes the case that Asian countries should start preparing now for a disorderly correction of global imbalances. It points to six measures they should take: allowing their currencies to appreciate against the dollar as a way of limiting their dependence on the U.S. market; accelerating regional trade initiatives to support their export sectors; using fiscal policy to sustain domestic demand; developing their financial markets; allowing intraregional exchange rates to move to accommodate differences in the impact of the shock and the scope for offsetting action; and enhancing regional cooperation to address free-rider and firstmover problems that might otherwise discourage these adjustments.
“Economizing” on Government in Economic Development
Authors: Garnaut Ross
Published: November 2006

The human resources and institutional capacity to deliver services through the public sector are scarce in developing countries with no traditions of an overarching state and in which the world's poor people are increasingly concentrated. This makes economizing on interventions by government a central aspect of economic development. The paper discusses a range of expedients for economizing on government.
Correlation, Contagion, and Asian Evidence
Authors: Dungey Mardi , Fry Renée , Martin Vance L.
Published: November 2006

This paper examines the empirical literature on financial market contagion in Asia during the 1997–98 financial crises with respect to existing tests of contagion. Empirical evidence shows that contagion affects both developed and emerging markets and does not seem to vary with the relative fundamental economic health or trade and financial linkages of the Asian economies. Contagion occurs across both asset types and geographical borders and tends to have larger effects in equity markets than in currency and bond markets. There is evidence to support the hypothesis that contagion is regional and transmitted through developed markets. A discussion of the behavior of correlation coefficients in the presence of contagion and financial crises suggests that they are not a reliable metric for detecting contagion.
Is the Log Export Ban an Efficient Instrument for Economic Development and Environmental Protection? The Case of Indonesia
Authors: Resosudarmo Budy P. , Yusuf Arief Anshory
Published: November 2006

The effectiveness of a log export ban policy in achieving the twin goals of conservation and economic development has been vigorously debated by many researchers and policymakers for the last two decades or so. Despite the abundance of work focusing on this issue that demonstrates the perversity of such policies, many countries around the world still implement them. This paper will first review the economic and political arguments in regard to the pros and cons of this policy. Second, it will review the Indonesian experience in implementing a log export ban policy in the 1980s and 2000s. Third, using a computable general equilibrium model, this paper will predict the anticipated impact of implementing a log export ban policy on the national economy and on household incomes for various socioeconomic groups.
Automatic Evaluation of Information Ordering: Kendall's Tau
Authors: Lapata Mirella
Published: November 2006

This article considers the automatic evaluation of information ordering, a task underlying many text-based applications such as concept-to-text generation and multidocument summarization. We propose an evaluation method based on Kendall's τ, a metric of rank correlation. The method is inexpensive, robust, and representation independent. We show that Kendall's τ correlates reliably with human ratings and reading times.
Unsupervised Multilingual Sentence Boundary Detection
Authors: Kiss Tibor , Strunk Jan
Published: November 2006

In this article, we present a language-independent, unsupervised approach to sentence boundary detection. It is based on the assumption that a large number of ambiguities in the determination of sentence boundaries can be eliminated once abbreviations have been identified. Instead of relying on orthographic clues, the proposed system is able to detect abbreviations with high accuracy using three criteria that only require information about the candidate type itself and are independent of context: Abbreviations can be defined as a very tight collocation consisting of a truncated word and a final period, abbreviations are usually short, and abbreviations sometimes contain internal periods. We also show the potential of collocational evidence for two other important subtasks of sentence boundary disambiguation, namely, the detection of initials and ordinal numbers. The proposed system has been tested extensively on eleven different languages and on different text genres. It achieves good results without any further amendments or language-specific resources. We evaluate its performance against three different baselines and compare it to other systems for sentence boundary detection proposed in the literature.