bluuebunny/crossref_metadata_2025 huggingface dataset:
Differences in Survival by Histologic Type of Pancreatic Cancer
Authors: Fesinmeyer Megan Dann , Austin Melissa A. , Li Christopher I. , De Roos Anneclaire J. , Bowen Deborah J.
Published: September 2005

Objective: Although pancreatic cancer has an extremely high case fatality rate, little is known about differences in mortality by histologic types. We examined median survival and risk of mortality for endocrine pancreatic tumors and two types of exocrine tumors, adenocarcinomas, and mucinous tumors.

Method: This analysis included 35,276 pancreatic cancer cases reported to the nine population-based cancer registries participating in the Surveillance, Epidemiology, and End Results program from 1973 to 2000. Survival among cases with pancreatic adenocarcinomas, mucinous tumors, and endocrine tumors were compared using Kaplan-Meier plots. Comparative risks of mortality were evaluated using multivariate adjusted Cox regression models.

Results: Endocrine pancreatic cancer cases had a median survival of 27 months compared with a median survival of 4 months for adenocarcinoma and mucinous tumor cases. Compared with adenocarcinoma cases, endocrine tumor cases had a 0.28-fold lower risk of mortality [95% confidence interval (95% CI), 0.26-0.30], and mucinous tumor cases had a 0.88-fold lower risk (95% CI, 0.84-0.91). These results were similar for men and women. Within histologic types, advanced tumor stage, older diagnosis age, surgery, and Black race were associated with increased risks of mortality, whereas female sex and more recent year of diagnosis were associated with decreased risks.

Conclusion: This study confirms the clinical observation that patients with endocrine pancreatic cancer survive longer than patients with exocrine tumors. A better understanding of these differences could contribute to identifying the underlying causes of pancreatic cancer and to improving survival rates across all histologic types.
Maternal Hormone Levels and Risk of Cryptorchism among Populations at High and Low Risk of Testicular Germ Cell Tumors
Authors: McGlynn Katherine A. , Graubard Barry I. , Nam Jun-Mo , Stanczyk Frank Z. , Longnecker Matthew P. , Klebanoff Mark A.
Published: September 2005

Cryptorchism is one of the few well-described risk factors for testicular cancer. It has been suggested that both conditions are related to increased in utero estrogen exposure. The evidence supporting the “estrogen hypothesis” has been inconsistent, however. An alternative hypothesis suggests that higher in utero androgen exposure may protect against the development of cryptorchism and testicular cancer. In order to examine both hypotheses, we studied maternal hormone levels in two populations at diverse risks of testicular cancer; Black Americans (low-risk) and White Americans (high-risk). The study population of 200 mothers of cryptorchid sons and 200 mothers of noncryptorchid sons was nested within the Collaborative Perinatal Project, a cohort study of pregnant women and their children. Third trimester serum levels of estradiol (total, free, bioavailable), estriol, testosterone (total, free, bioavailable), sex hormone–binding globulin, α-fetoprotein, and the ratios of estradiols to testosterones were compared between the case and control mothers. The results found no significant differences in the levels of testosterone (total, free, bioavailable), α-fetoprotein, sex hormone–binding globulin, or in the ratios of estrogens to androgens. Total estradiol, however, was significantly lower in the cases versus the controls (P = 0.03) among all mothers and, separately, among White mothers (P = 0.05). Similarly, estriol was significantly lower among all cases (P = 0.05) and among White cases (P = 0.05). These results do not support either the estrogen or the androgen hypothesis. Rather, lower estrogens in case mothers may indicate that a placental defect increases the risk of cryptorchism and, possibly, testicular cancer.
Social and Behavioral Correlates of Cigarette Smoking among Mid-Atlantic Latino Primary Care Patients
Authors: Cox Lisa Sanderson , Feng Shibao , Cañar Janet , Ford Maureen McGlinchey , Tercyak Kenneth P.
Published: September 2005

Tobacco use is the leading preventable cause of death for the U.S. Hispanic population. The goal of this study was to identify social and behavioral correlates of smoking behavior among urban, multiethnic Latino primary care patients seen in community clinics. Spanish-language interviews were completed with 141 current smokers and 158 former and nonsmokers. Twenty countries of origin were represented. Eighty-three percent of participants were from Central or South America and 71% spoke primarily Spanish. Current smokers were more likely than nonsmokers or former smokers to originate from South America (38% versus 26%) and to be single (63% versus 42%). Current smokers also were more likely to use alcohol on a regular basis (59% versus 31%) and to experience daily symptoms of depression (29% versus 19%). Logistic regression analysis suggested a moderating effect of depression on the relationship between alcohol use and smoking, such that current users of alcohol who reported depression were more likely to smoke (82%) than were current users of alcohol who did not report depression (56%). As both social and behavioral factors were uniquely associated with smoking, country of origin, marital status, and comorbid alcohol use and depression should be considered in designing and implementing tobacco control interventions targeted to this community.
Insulin-Like Growth Factor Pathway Polymorphisms Associated with Body Size in Hispanic and Non-Hispanic White Women
Authors: Sweeney Carol , Murtaugh Maureen A. , Baumgartner Kathy B. , Byers Tim , Giuliano Anna R. , Herrick Jennifer S. , Wolff Roger , Caan Bette J. , Slattery Martha L.
Published: September 2005

Polymorphisms affecting insulin-like growth factors (IGF), their binding proteins (IGFBP), insulin receptor substrates (IRS), and other IGF regulatory molecules may affect growth, obesity, and obesity-related diseases, including cancer. The objective of this study was to better describe the associations between several IGF pathway variants and body size. Hispanic (n = 462) and non-Hispanic White (n = 1,702) women were recruited as controls in collaborative population-based case-control studies in Arizona, New Mexico, Colorado, Utah, and California. Body size measurements were taken by trained interviewers; genotypes were determined for the IGF1 CA repeat, the IGFBP3 −202 C > A substitution, the IRS1 G972R and IRS2 G1057D substitutions, and the vitamin D receptor (VDR) BsmI and FokI polymorphisms. Two associations were observed that were consistent in both Hispanics and non-Hispanic Whites: IGF1 CA repeat alleles of length other than 19 were associated with higher mean waist-to-hip ratios (WHR), P = 0.01, and women who carried an IGFBP3 A allele, compared with women with the CC genotype, more often reported high birthweight (odds ratio, 1.9; 95% confidence interval, 1.1-3.2). We observed trends for associations between IGFBP3 A allele and taller height, IRS1R allele, and smaller WHR, and VDR FokI ff genotype and larger WHR; each of these trends was present in only one ethnic group, and heterogeneity of effect by ethnicity was detected. These results provide evidence that IGF pathway polymorphisms have functional effects on growth and central obesity and indicate that genotype-phenotype relationships are ethnic specific.
Identifying Susceptibility Genes for Prostate Cancer—A Family-Based Association Study of Polymorphisms in CYP17, CYP19, CYP11A1, and LH-β
Authors: Douglas Julie A. , Zuhlke Kimberly A. , Beebe-Dimmer Jennifer , Levin Albert M. , Gruber Stephen B. , Wood David P. , Cooney Kathleen A.
Published: September 2005

Polymorphisms in genes that code for enzymes or hormones involved in the synthesis and metabolism of androgens are compelling biological candidates for prostate cancer. Four such genes, CYP17, CYP19, CYP11A1, and LH-β, are involved in the synthesis and conversion of testosterone to dihydrotestosterone and estradiol. In a study of 715 men with and without prostate cancer from 266 familial and early-onset prostate cancer families, we examined the association between prostate cancer susceptibility and common single-nucleotide polymorphisms in each of these four candidate genes. Family-based association tests revealed a significant association between prostate cancer and a common single-nucleotide polymorphism in CYP17 (P = 0.004), with preferential transmission of the minor allele to unaffected men. Conditional logistic regression analysis of 461 discordant sibling pairs from these same families reaffirmed the association between the presence of the minor allele in CYP17 and prostate cancer risk (odds ratio, 0.51; 95% confidence interval, 0.28-0.92). These findings suggest that variation in or around CYP17 predicts susceptibility to prostate cancer. Family-based association tests may be especially valuable in studies of genetic variation and prostate cancer risk because this approach minimizes confounding due to population substructure, which is of particular concern for prostate cancer given the tremendous variation in the worldwide incidence of this disease.
Crypt-Restricted Loss and Decreased Protein Expression of Cytochrome c Oxidase Subunit I as Potential Hypothesis-Driven Biomarkers of Colon Cancer Risk
Authors: Payne Claire M. , Holubec Hana , Bernstein Carol , Bernstein Harris , Dvorak Katerina , Green Sylvan B. , Wilson Megan , Dall'Agnol Monique , Dvorakova Barbora , Warneke James , Garewal Harinder
Published: September 2005

There is an increasing demand for the development of intermediate biomarkers to assess colon cancer risk. We previously determined that a live cell bioassay, which assesses apoptosis resistance in the nonneoplastic colonic mucosa, detects ∼50% of patients with colon cancer. A hypothesis-driven biomarker that reflects apoptosis resistance in routine formalin-fixed, paraffin-embedded tissue would be easier to use. Cytochrome c oxidase is a critical enzyme that controls mitochondrial respiration and is central to apoptosis. We did an immunohistochemical study of cytochrome c oxidase subunit I expression in 46 colonic mucosal samples from 16 patients who had undergone a colonic resection. These included five patients without evidence of colonic neoplasia (three normal and two diverticulitis), three patients with tubulovillous adenomas, and eight patients with colonic adenocarcinomas. Analysis of aberrancies in expression of cytochrome c oxidase subunit I showed that, compared with nonneoplasia, the patients with neoplasia had a higher mean incidence of crypts having decreased expression (1.7 versus 22.8, P = 0.03) and a higher mean incidence having crypt-restricted loss (0.6 versus 3.2, P = 0.06). The percentage with segmented loss was low and was similar in the two groups. Combining these results, the mean % normal (i.e., with none of the three types of abnormality) was 96.7 in nonneoplasia versus only 73.2 in patients with neoplasia (P = 0.02). It should be noted that a defect in cytochrome c oxidase subunit I immunostaining was not detected in all biopsy samples from each patient for whom some abnormality was found, indicating a “patchiness” in the cytochrome c oxidase subunit I field defect. As a result of this “patchiness,” the increased variability in the incidence of crypt-restricted loss of cytochrome c oxidase subunit I expression was a statistically significant feature of the neoplasia group. Crypt-restricted loss of cytochrome c oxidase subunit I has not been previously reported in colonic mucosa and is presumably the result of a crypt-restricted stem cell mutation. Decreased cytochrome c oxidase subunit I expression also significantly correlated with apoptosis resistance, a factor known to contribute to carcinogenesis. The results suggest, however, that aberrant cytochrome c oxidase subunit I expression may be a better biomarker than loss of apoptosis competence for increased colon cancer risk.
Alcohol, ALDH2, and Esophageal Cancer: A Meta-analysis Which Illustrates the Potentials and Limitations of a Mendelian Randomization Approach
Authors: Lewis Sarah J. , Davey Smith George
Published: September 2005

Mendelian randomization, the use of common polymorphisms as surrogates for measuring exposure levels in epidemiologic studies, provides one method of assessing the causal nature of some environmental exposures. This can be illustrated by looking at the association between the ALDH2 polymorphism and esophageal cancer. Alcohol drinking is considered a risk factor for esophageal cancer, and exposure to high levels of acetaldehyde, the principal metabolite of alcohol, may be responsible for the increased cancer risk. The ability to metabolize acetaldehyde is encoded by the ALDH2 gene, which is polymorphic in some populations. The ALDH2*2 allele produces an inactive protein subunit, which is unable to metabolize acetaldehyde. An individual's genotype at this locus may influence their esophageal cancer risk through two mechanisms, first through influencing alcohol intake and second through influencing acetaldehyde levels. We have carried out a meta-analysis of studies looking at the ALDH2 genotype and esophageal cancer and found that risk was reduced among *2*2 homozygotes [odds ratio (OR), 0.36; 95% confidence interval (95% CI), 0.16-0.80] and increased among heterozygotes (OR, 3.19; 95% CI, 1.86-5.47) relative to *1*1 homozygotes. This provides strong evidence that alcohol intake increases the risk of esophageal cancer and individuals whose genotype results in markedly lower intake, because they have an adverse reaction to alcohol are thus protected. This meta-analysis also provides evidence that acetaldehyde plays a carcinogenic role in esophageal cancer. The two different processes operating as a result of the ALDH2 genotype have implications for the interpretation of studies using the Mendelian randomization paradigm.
Familial Lung Cancer and Aggregation of Smoking Habits: A Simulation of the Effect of Shared Environmental Factors on the Familial Risk of Cancer
Authors: Lorenzo Bermejo Justo , Hemminki Kari
Published: September 2005

Background: Tobacco smoking is the principal cause of lung cancer. The risk of lung cancer in the offspring of lung cancer patients is about twice higher than the risk in the general population. The present study investigated the contribution of shared smoking habits to the familial clustering of lung cancer.

Methods: We estimated the relative risk of lung cancer attributable to smoking according to the extent to which smokers transmit their smoking habits to the offspring (heritability of smoking), the prevalence of smoking in the general population, and the risk of lung cancer for smokers compared with nonsmokers.

Findings: The relative risk of lung cancer for the offspring of lung cancer patients attributable to smoking was 1.19 when published data on smoking practice were modeled (i.e., assuming that the heritability of smoking was 0.5, the smoking prevalence 40%, and the odds ratio of lung cancer for smokers versus nonsmokers was 20).

Interpretation: Most familial cases of lung cancer cannot be attributed to shared smoking habits. The example of smoking can be used for other familial cancers, for which no strong environmental risk factors are usually known, to infer the primary role for heritable genes.
Fruits and Vegetables and Ovarian Cancer Risk in a Pooled Analysis of 12 Cohort Studies
Authors: Koushik Anita , Hunter David J. , Spiegelman Donna , Anderson Kristin E. , Arslan Alan A. , Beeson W. Lawrence , van den Brandt Piet A. , Buring Julie E. , Cerhan James R. , Colditz Graham A. , Fraser Gary E. , Freudenheim Jo L. , Genkinger Jeanine M. , Goldbohm R. Alexandra , Hankinson Susan E. , Koenig Karen L. , Larsson Susanna C. , Leitzmann Michael , McCullough Marjorie L. , Miller Anthony B. , Patel Alpa , Rohan Thomas E. , Schatzkin Arthur , Smit Ellen , Willett Walter C. , Wolk Alicja , Zhang Shumin M. , Smith-Warner Stephanie A.
Published: September 2005

Because fruits and vegetables are rich in bioactive compounds with potential cancer-preventive actions, increased consumption may reduce the risk of ovarian cancer. Evidence on the association between fruit and vegetable intake and ovarian cancer risk has not been consistent. We analyzed and pooled the primary data from 12 prospective studies in North America and Europe. Fruit and vegetable intake was measured at baseline in each study using a validated food-frequency questionnaire. To summarize the association between fruit and vegetable intake and ovarian cancer, study-specific relative risks (RR) were estimated using the Cox proportional hazards model, and then combined using a random-effects model. Among 560,441 women, 2,130 cases of invasive epithelial ovarian cancer occurred during a maximum follow-up of 7 to 22 years across studies. Total fruit intake was not associated with ovarian cancer risk—the pooled multivariate RR for the highest versus the lowest quartile of intake was 1.06 [95% confidence interval (95% CI), 0.92-1.21; P value, test for trend = 0.73; P value, test for between-studies heterogeneity = 0.74]. Similarly, results for total vegetable intake indicated no significant association (pooled multivariate RR, 0.90; 95% CI, 0.78-1.04, for the highest versus the lowest quartile; P value, test for trend = 0.06; P value, test for between-studies heterogeneity = 0.31). Intakes of botanically defined fruit and vegetable groups and individual fruits and vegetables were also not associated with ovarian cancer risk. Associations for total fruits and vegetables were similar for different histologic types. These results suggest that fruit and vegetable consumption in adulthood has no important association with the risk of ovarian cancer.
Relative and Absolute Risks of Cigarette Smoking on Major Histologic Types of Lung Cancer in Korean Men
Authors: Yun Young Ho , Lim Min Kyung , Jung Kyu Won , Bae Jong-Myon , Park Sang Min , Shin Soon Ae , Lee Jin Soo , Park Jae-Gahb
Published: September 2005

Objectives: Most prospective cohort studies of lung cancer focus on the relative risk rather than the absolute risk of smoking.

Methods: This prospective study included 437,976 Korean men (cohort for the National Health Insurance Cooperation Study), ≥40 years old, who were free of cancer and smoking-related chronic disease at the time of enrollment. Based on new incidence cases, relative risk and excess risk, and their 95% confidence intervals (95% CI), were estimated with the standard Poisson regression model after adjustment for age or other demographic factors and other confounders.

Results: During the 6-year follow-up period of 3,142,451 person-years, 1,357 new lung cancer cases were identified. Based on the multivariate-adjusted relative risk for current smokers, the strongest association with smoking was shown for small-cell lung cancer (relative risk, 21.7; 95% CI, 8.0-58.5) followed by squamous cell carcinoma (relative risk, 11.7; 95% CI, 7.1-19.4) and then adenocarcinoma (relative risk, 2.1; 95% CI, 1.6-2.7). In current smokers with ≥40 pack-years of exposure, excess risk was highest for squamous cell carcinoma (excess risk, 33.8; 95% CI, 10.2-109.8) followed by adenocarcinoma (excess risk, 26.7; 95% CI, 10.3-64.4), and then small-cell carcinoma (excess risk, 16.3; 95% CI, 1.8-144.3).

Conclusions: In Korean men, cigarette smoking was as important a risk factor for adenocarcinoma as it was for squamous cell and small-cell lung cancer.
Multivitamin and Alcohol Intake and Folate Receptor α Expression in Ovarian Cancer
Authors: Kelemen Linda E. , Sellers Thomas A. , Keeney Gary L. , Lingle Wilma L.
Published: September 2005

Folate receptor α (FRα) expression in epithelial ovarian cancer may be related to folate intake. We examined this association using multivitamin intake, a proxy for folic acid, and assessed whether the relation was modified by alcohol intake, a folate agonist. Cases (n = 148) with suspected epithelial ovarian cancer, of ages ≥20 years, were seen at Mayo Clinic, Minnesota, between 2000 and 2004; those with tumor specimens (n = 108) were included in analyses. Outpatient controls (n = 148) without cancer and with at least one ovary intact were matched to cases by age (within 5 years) and state of residence. Multivitamin (≥4 pills/wk) and weekly alcohol (≥5 drinks) intakes were assessed. Tumor specimens were analyzed immunohistochemically for FRα. Multivariable rate ratios (RR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression. In case-control analysis, the RRs of multivitamin intake with absent/weak/moderate and strong-expressing FRα tumors were 0.30 (95% CI, 0.12-0.70) and 0.47 (95% CI, 0.24-0.91), respectively. For alcohol, the associations were 0.84 (95% CI, 0.24-2.86) and 1.65 (95% CI, 0.69-3.93), respectively. In case-case analysis, the RR associated with developing strong-expressing versus other FRα tumors was 3.13 (95% CI, 1.14-8.65) for multivitamins and 1.58 (95% CI, 0.45-5.60) for alcohol. The data did not support evidence for an interaction between multivitamin and alcohol intake with risk of developing a strong-expressing FRα tumor. The association of multivitamin intake with ovarian cancer may depend on FRα expression level.
Repeated Sequences in CASPASE-5 and FANCD2 but not NF1 Are Targets for Mutation in Microsatellite-Unstable Acute Leukemia/Myelodysplastic Syndrome
Authors: Offman Judith , Gascoigne Karen , Bristow Fiona , Macpherson Peter , Bignami Margherita , Casorelli Ida , Leone Giuseppe , Pagano Livio , Sica Simona , Halil Ozay , Cummins David , Banner Nicholas R. , Karran Peter
Published: September 2005

Microsatellite instability (MSI) in tumors is diagnostic for inactive DNA mismatch repair. It is widespread among some tumor types, such as colorectal or endometrial carcinoma, but is rarely found in leukemia. Therapy-related acute myeloid leukemia/myelodysplastic syndrome (tAML/MDS) is an exception, and MSI is frequent in tAML/MDS following cancer chemotherapy or organ transplantation. The development of MSI+ tumors is associated with an accumulation of insertion/deletion mutations in repetitive sequences. These events can cause inactivating frameshifts or loss of expression of key growth control proteins. We examined established MSI+ cell lines and tAML/MDS cases for frameshift-like mutations of repetitive sequences in several genes that have known, or suspected, relevance to leukemia. CASPASE-5, an acknowledged frameshift target in MSI+ gastrointestinal tract tumors, was frequently mutated in MSI+ cell lines (67%) and in tAML/MDS (29%). Frameshift-like mutations were also observed in the NF1 and FANCD2 genes that are associated with genetic conditions conferring a predisposition to leukemia. Both genes were frequent targets for mutation in MSI+ cell lines and colorectal carcinomas. FANCD2 mutations were also common in MSI+ tAML/MDS, although NF1 mutations were not observed. A novel FANCD2 polymorphism was also identified.
Vascular Hypertrophy in Angiotensin II–Induced Hypertension Is Mediated by Vascular Smooth Muscle Cell–Derived H
2
O
2
Authors: Zhang Yong , Griendling Kathy K. , Dikalova Anna , Owens Gary K. , Taylor W. Robert
Published: September 2005

Angiotensin II induces the development of vascular hypertrophy and hypertension. An increasing number of studies have demonstrated that reactive oxygen species are involved in many of the vascular responses to angiotensin II. However, the role of specific cell types and the precise identity of the functionally relevant reactive oxygen species remain unclear. In this study, we established a line of transgenic mice with vascular smooth muscle cell (SMC)–specific overexpression of the human catalase gene to explicitly test the functional role of vascular smooth muscle–derived hydrogen peroxide in the hypertensive and hypertrophic responses to angiotensin II in vivo. Catalase overexpression was confirmed by increased expression of catalase mRNA and protein, as well as by an increase in catalase enzymatic activity. The catalase transgenic mice were viable, had no change in basal hydrogen peroxide release (0.36±0.03 versus 0.37±0.14 μmol/L), and showed no overt developmental abnormality. In response to angiotensin II treatment, catalase transgenic mice exhibited lower hydrogen peroxide release compared with control animals. There was no effect on the hypertensive response to angiotensin II (147±10 versus 148±12 mm Hg). However, angiotensin II–induced aortic wall hypertrophy was dramatically attenuated in the catalase transgenic mice (wall thickness 32.4±2.0 versus 43.2±7.6 μm;
P
<0.001). These results demonstrate that vascular SMC–derived hydrogen peroxide plays an important role in angiotensin II–induced hypertrophy of the arterial wall.
Blood Pressure–Dependent Inhibition of Renin Secretion Requires A1 Adenosine Receptors
Authors: Schweda Frank , Segerer Florian , Castrop Hayo , Schnermann Jürgen , Kurtz Armin
Published: September 2005

Renal perfusion pressure (RPP) regulates renin release with a reduction of RPP stimulating and an elevation inhibiting renin secretion. The precise sensing and effector mechanisms by which changes in arterial pressure are linked to the exocytosis of renin are not well-defined. The present experiments were designed to study the potential role of adenosine as a mediator of this renal baroreceptor mechanism. In isolated perfused mouse kidneys a stepwise reduction of RPP from 90 mm Hg to 65 and 40 mm Hg stimulated renin secretion rates (RSR) 1.4-fold and 3.6-fold, whereas stepwise elevations of RPP from 90 mm Hg to 115 and 140mm Hg suppressed RSR to 64% or 40% of baseline. Inactivation of A1 adenosine receptors by either pharmacological blockade (DPCPX 1μmol/L) or genetic deletion (A1AR
−/−
mice) did not modify the stimulation of renin release by a low RPP, but completely prevented the suppression of renin secretion by higher perfusion pressures. In vivo, the induction of arterial hypertension by either acute (single subcutaneous injection) or chronic (osmotic minipump for 72 hours) application of phenylephrine significantly reduced plasma renin concentration (PRC) in wild-type mice to ≈40% of control, whereas it did not significantly affect PRC in A1AR
−/−
mice. Together these data demonstrate that A1 adenosine receptors are indispensable for the inhibition of renin secretion by an increase in blood pressure, suggesting that formation and action of adenosine is responsible for baroreceptor-mediated inhibition of renin release. In contrast, the stimulation of the renin system by a low blood pressure appears to follow different pathways.
Human Urotensin II Accelerates Foam Cell Formation in Human Monocyte-Derived Macrophages
Authors: Watanabe Takuya , Suguro Toshiaki , Kanome Tomoko , Sakamoto Yu-ichiro , Kodate Syuusuke , Hagiwara Tamio , Hongo Shigeki , Hirano Tsutomu , Adachi Mitsuru , Miyazaki Akira
Published: September 2005

Human urotensin II (U-II), the most potent vasoconstrictor peptide identified to date, and its receptor (UT) are involved in hypertension and atherosclerosis. Acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) converts intracellular free cholesterol into cholesterol ester (CE) for storage in lipid droplets and plays an important role in the formation of macrophage-derived foam cells in atherosclerotic lesions. We examined the effects of U-II on ACAT-1 expression and CE accumulation in human monocyte-derived macrophages. U-II increased ACAT activity in a concentration-dependent manner after 7 days in monocyte primary culture. Immunoblotting analysis showed that U-II at 25 nmol/L increased ACAT-1 protein expression level by 2.5-fold, which was completely abolished by anti–U-II antibody, selective UT receptor antagonists (urantide and 4-aminoquinoline), a G-protein inactivator (GDP-β-S), a c-Src protein tyrosine kinase inhibitor (PP2), a protein kinase C (PKC) inhibitor (rottlerin), a mitogen-activated protein kinase kinase (MEK) inhibitor (PD98059), or a Rho kinase (ROCK) inhibitor (Y27632). Northern blotting analysis indicated that among the 4 ACAT-1 mRNA transcripts (2.8-, 3.6-, 4.3-, and 7.0-kb), the 2.8- and 3.6-kb transcript levels were selectively upregulated by ≈1.7-fold by U-II (25 nmol/L). Further, U-II (25 nmol/L) significantly increased acetylated LDL (acetyl-LDL)–induced CE accumulation in monocyte-derived macrophages but not scavenger receptor class A (SR-A) function as assessed by endocytic uptake of [
125
I]acetyl-LDL. Our results suggest that U-II may play a novel role in the formation of macrophage-derived foam cells by upregulating ACAT-1 expression via the UT receptor/G-protein/c-Src/PKC/MEK and ROCK pathways but not by SR-A, thus contributing to the relatively rapid development of atherosclerosis in hypertension.
Relaxin Increases Cardiac Output and Reduces Systemic Arterial Load in Hypertensive Rats
Authors: Debrah Dan O. , Conrad Kirk P. , Jeyabalan Arundhathi , Danielson Lee A. , Shroff Sanjeev G.
Published: September 2005

Chronic administration of recombinant human relaxin (rhRLX) to conscious, normotensive rats (male and female) increases cardiac output (CO) and global arterial compliance (AC
g
) and reduces systemic vascular resistance (SVR) with no change in mean arterial pressure (MAP). Effects (magnitude and temporal pattern) of relaxin on systemic hemodynamics and arterial properties in hypertensive animal models are not known. Accordingly, the major goal of the present study was to determine the cardiovascular effects of rhRLX in hypertensive rats using 2 models: Long–Evans rats chronically administered angiotensin II (AII) and spontaneously hypertensive rats (SHR). CO and systemic arterial load, as quantified by SVR and AC
g
, were obtained using methods reported previously by us. In rats with AII-induced hypertension, acute rhRLX administration (up to 6 hours) significantly increased CO and AC
g
(24.9±3.9 and 34.3±12.6% above baseline, respectively) and significantly decreased SVR (17.2±3.5%) without changing MAP. In contrast, acute rhRLX administration to SHR and normotensive rats for up to 6 hours failed to produce any significant changes in CO, AC
g
, SVR, or MAP. However, chronic rhRLX administration (1 to 7 days) to SHR yielded significant changes (24.0±8.1 and 22.3±6.6% increases in CO and AC
g
, respectively, and a 13.3±5.3% decrease in SVR, with no change in MAP). In conclusion, rhRLX increases CO and reduces arterial load in hypertensive rats without reducing MAP. However, the time course of response to rhRLX treatment is dependent on the model of hypertension such that rats characterized by AII-mediated hypertension responded more rapidly to rhRLX administration than SHR.
Androgen Receptor–Mediated Regulation of the α-Subunit of the Epithelial Sodium Channel in Human Kidney
Authors: Quinkler Marcus , Bujalska Iwona J. , Kaur Kirren , Onyimba Claire U. , Buhner Sabine , Allolio Bruno , Hughes Susan V. , Hewison Martin , Stewart Paul M.
Published: September 2005

Rodents studies suggest that androgens are involved in sex-specific differences in blood pressure. In humans, there is no difference in blood pressure between boys and girls, but after puberty, blood pressure increases more in men than in women. We investigated androgen-dependent regulation of the α-subunit of the epithelial sodium channel (αEnaC) in human kidney and in the human renal cell line immortalized human renal proximal tubular cell line (HKC-8). We used microarray technique to analyze androgen-dependent gene regulation and performed quantitative RT-PCR for verification. Promoter constructs for human αENaC were used in transfection studies to analyze the regulation by testosterone. We investigated the in vivo effect of testosterone on αENaC in a rat model and used the mouse collecting duct cell line M-1 for transepithelial electrophysiological measurements. The androgen receptor (AR) was expressed in male kidney and HKC-8 cells. αENaC mRNA expression increased 2- to 3-fold after treatment with testosterone in HKC-8 cells. The induction by testosterone was completely blocked by adding the AR antagonist flutamide. Analysis of the αENaC promoter sequence identified a putative AR response element (ARE) located 140 nucleotides upstream from the transcription start site. HKC-8 cell transfection studies showed that testosterone directly upregulated gene expression via this ARE. In vivo, testosterone treatment of orchiectomized rats resulted in an increased renal αENaC mRNA expression. In testosterone-treated mouse M-1 cells, amiloride caused a significant stronger decrease in short circuit current than in control cells. These data show that αENaC expression is directly regulated by androgens in vitro and in vivo and highlight a potential mechanism explaining the reported gender differences in blood pressure.
Sinus Venosus Atrial Septal Defect
Authors: Jost Christine H. Attenhofer , Connolly Heidi M. , Danielson Gordon K. , Bailey Kent R. , Schaff Hartzell V. , Shen Win-Kuang , Warnes Carole A. , Seward James B. , Puga Francisco J. , Tajik A. Jamil
Published: September 2005

Background—

Sinus venosus atrial septal defect (SVASD) differs from secundum atrial septal defect by its atrial septal location and its association with anomalous pulmonary venous connection (APVC). Data on long-term outcome after surgical repair are limited.

Methods and Results—

We reviewed outcomes of 115 patients (mean age±SD 34±23 years) with SVASD who had repair from 1972 through 1996. APVC was present in 112 patients (97%). Early mortality was 0.9%. Complete follow-up was obtained for 108 patients (95%) at 144±99 months. Symptomatic improvement was noted in 83 patients (77%), and deterioration was noted in 17 patients (16%). At follow-up, 7 (6%) of 108 patients had sinus node dysfunction, a permanent pacemaker, or both, and 15 (14%) of 108 patients had atrial fibrillation. Older age at repair was predictive of postoperative atrial fibrillation (
P
=0.033). No reoperations were required during follow-up. Survival was not different from expected for an age- and sex-matched population. Clinical improvement was more common with older age at surgery (
P
=0.014). Older age at repair (
P
=0.008) and preoperative New York Heart Association class III or IV (
P
=0.038) were independent predictors of late mortality.

Conclusions—

Operation for SVASD is associated with low morbidity and mortality, and postoperative subjective clinical improvement occurs irrespective of age at surgery. Postoperative atrial fibrillation appears to be related to older age at operation. SVASD repair achieves survival similar to that of a matched population and should be considered whenever repair may impact survival or symptoms.
New Locus for Autosomal Dominant Mitral Valve Prolapse on Chromosome 13
Authors: Nesta Francesca , Leyne Maire , Yosefy Chaim , Simpson Charles , Dai Daisy , Marshall Jane E. , Hung Judy , Slaugenhaupt Susan A. , Levine Robert A.
Published: September 2005

Background—

Mitral valve prolapse (MVP) is a common disorder associated with mitral regurgitation, endocarditis, heart failure, and sudden death. To date, 2 MVP loci have been described, but the defective genes have yet to be discovered. In the present study, we analyzed a large family segregating MVP, and identified a new locus,
MMVP3
. This study and others have enabled us to explore mitral valve morphological variations of currently uncertain clinical significance.

Methods and Results—

Echocardiograms and blood samples were obtained from 43 individuals who were classified by the extent and pattern of displacement. Genotypic analyses were performed with polymorphic microsatellite markers. Evidence of linkage was obtained on chromosome 13q31.3-q32.1, with a peak nonparametric linkage score of 18.41 (
P
<0.0007). Multipoint parametric analysis gave a logarithm of odds score of 3.17 at marker
D13S132
. Of the 6 related individuals with mitral valve morphologies not meeting diagnostic criteria but resembling fully developed forms, 5 carried all or part of the haplotype linked to MVP.

Conclusions—

The mapping of a new MVP locus to chromosome 13 confirms the observed genetic heterogeneity and represents an important step toward gene identification. Furthermore, the genetic analysis provides clinical lessons with regard to previously nondiagnostic morphologies. In the familial context, these may represent early expression in gene carriers. Early recognition of gene carriers could potentially enhance the clinical evaluation of patients at risk of full expression, with the ultimate aim of developing interventions to reduce progression.
Impaired Impulse Propagation in
Scn5a
-Knockout Mice
Authors: van Veen Toon A.B. , Stein Mera , Royer Anne , Le Quang Khaï , Charpentier Flavien , Colledge William H. , Huang Christopher L.-H. , Wilders Ronald , Grace Andrew A. , Escande Denis , de Bakker Jacques M.T. , van Rijen Harold V.M.
Published: September 2005

Background—

The
SCN5A
sodium channel is a major determinant for cardiac impulse propagation. We used epicardial mapping of the atria, ventricles, and septae to investigate conduction velocity (CV) in
Scn5a
heterozygous young and old mice.

Methods and Results—

Mice were divided into 4 groups: (1) young (3 to 4 months) wild-type littermates (WT); (2) young heterozygous
Scn5a
-knockout mice (HZ); (3) old (12 to 17 months) WT; and (4) old HZ. In young HZ hearts, CV in the right but not the left ventricle was reduced in agreement with a rightward rotation in the QRS axes; fibrosis was virtually absent in both ventricles, and the pattern of connexin43 (Cx43) expression was similar to that of WT mice. In old WT animals, the right ventricle transversal CV was slightly reduced and was associated with interstitial fibrosis. In old HZ hearts, right and left ventricle CVs were severely reduced both in the transversal and longitudinal direction; multiple areas of severe reactive fibrosis invaded the myocardium, accompanied by markedly altered Cx43 expression. The right and left bundle-branch CVs were comparable to those of WT animals. The atria showed only mild fibrosis, with heterogeneously disturbed Cx40 and Cx43 expression.

Conclusions—

A 50% reduction in
Scn5a
expression alone or age-related interstitial fibrosis only slightly affects conduction. In aged HZ mice, reduced
Scn5a
expression is accompanied by the presence of reactive fibrosis and disarrangement of gap junctions, which results in profound conduction impairment.
Functional Roles of Ca
v
1.3(α
1D
) Calcium Channels in Atria
Authors: Zhang Zhao , He Yuxia , Tuteja Dipika , Xu Danyan , Timofeyev Valeriy , Zhang Qian , Glatter Kathryn A. , Xu Yanfang , Shin Hee-Sup , Low Reginald , Chiamvimonvat Nipavan
Published: September 2005

Background—

Previous data suggest that L-type Ca
2+
channels containing the Ca
v
1.3(α
1D
) subunit are expressed mainly in neurons and neuroendocrine cells, whereas those containing the Ca
v
1.2(α
1C
) subunit are found in the brain, vascular smooth muscle, and cardiac tissue. However, our previous report as well as others have shown that Ca
v
1.3 Ca
2+
channel–deficient mice (
Ca

v

1.3
−/−
) demonstrate sinus bradycardia with a prolonged PR interval. In the present study, we extended our study to examine the role of the Ca
v
1.3(α
1D
) Ca
2+
channel in the atria of
Ca

v

1.3
−/−
mice.

Methods and Results—

We obtained new evidence to demonstrate that there is significant expression of Ca
v
1.3 Ca
2+
channels predominantly in the atria compared with ventricular tissues. Whole-cell L-type Ca
2+
currents (
I
Ca,L
) recorded from single, isolated atrial myocytes from
Ca

v

1.3
−/−
mice showed a significant depolarizing shift in voltage-dependent activation. In contrast, there were no significant differences in the
I
Ca,L
recorded from ventricular myocytes from wild-type and null mutant mice. We previously documented the hyperpolarizing shift in the voltage-dependent activation of Ca
v
1.3 compared with Ca
v
1.2 Ca
2+
channel subunits in a heterologous expression system. The lack of Ca
v
1.3 Ca
2+
channels in null mutant mice would result in a depolarizing shift in the voltage-dependent activation of
I
Ca,L
in atrial myocytes. In addition, the
Ca

v

1.3
-null mutant mice showed evidence of atrial arrhythmias, with inducible atrial flutter and fibrillation. We further confirmed the isoform-specific differential expression of Ca
v
1.3 versus Ca
v
1.2 by in situ hybridization and immunofluorescence confocal microscopy.

Conclusions—

Using gene-targeted deletion of the Ca
v
1.3 Ca
2+
channel, we established the differential distribution of Ca
v
1.3 Ca
2+
channels in atrial myocytes compared with ventricles. Our data represent the first report demonstrating important functional roles for Ca
v
1.3 Ca
2+
channel in atrial tissues.
Targeting Adhesion Molecules as a Potential Mechanism of Action for Intravenous Immunoglobulin
Authors: Gill Varinder , Doig Christopher , Knight Derrice , Love Emma , Kubes Paul
Published: September 2005

Background—

Intravenous immunoglobulin (IVIg) therapy has been shown to have therapeutic benefit in more than 50 inflammatory and immune-related diseases; however, the potential benefit of IVIg in cardiovascular disease is more limited, in part because our understanding of the mechanisms underlying the effects of IVIg in innate immunity is incomplete.

Methods and Results—

In this study, a systematic assessment of the role of IVIg in leukocyte recruitment was completed with an in vitro flow-chamber system and in vivo intravital microscopy in a feline ischemia-reperfusion model system. IVIg treatment of blood resulted in a profound decrease in recruitment of either immobilized P-selectin or E-selectin due to direct effects of IVIg on the leukocyte (not substratum). Similar results were observed on endothelium treated with histamine, which induces P-selectin–dependent rolling and β
2
-integrin–dependent adhesion. IVIg reduced P-selectin glycoprotein ligand-1 (PSGL-1) antibody binding to PSGL-1 on leukocytes. Use of a β
2
-integrin–dependent static assay to bypass selectin-dependent recruitment revealed some inhibitory effectiveness (60%), which suggests that the majority of the effects of IVIg were due to selectin inhibition, with some inhibition of integrin function. In vivo intravital microscopy revealed a potent inhibitory effect of IVIg on P-selectin–dependent rolling and β
2
-integrin–dependent adhesion that led to reduced leukocyte recruitment and vascular dysfunction in postischemic microvessels.

Conclusions—

Our data demonstrate that IVIg has direct inhibitory effects on leukocyte recruitment in vitro and in vivo through inhibition of selectin and integrin function.
Effect of Fish Oil on Heart Rate in Humans
Authors: Mozaffarian Dariush , Geelen Anouk , Brouwer Ingeborg A. , Geleijnse Johanna M. , Zock Peter L. , Katan Martijn B.
Published: September 2005

Background—

The effect of fish oil on heart rate (HR), a major risk factor for sudden death, is not well established. We calculated this effect in a meta-analysis of randomized, double-blind, placebo-controlled trials in humans.

Methods and Results—

Randomized trials of fish oil that evaluated HR were identified through MEDLINE (1966 through January 2005), hand-searching of references, and contact with investigators for unpublished results. Two investigators independently extracted trial data. A pooled estimate was calculated from random-effects meta-analysis. Predefined stratified meta-analyses and meta-regression were used to explore potential heterogeneity. Of 197 identified articles, 30 met inclusion criteria. Evidence for publication bias was not present. In the overall pooled estimate, fish oil decreased HR by 1.6 bpm (95% CI, 0.6 to 2.5;
P
=0.002) compared with placebo. Between-trial heterogeneity was evident (Q test,
P
<0.001). Fish oil reduced HR by 2.5 bpm (
P
<0.001) in trials with baseline HR ≥69 bpm (median) but had little effect (0.04-bpm reduction;
P
=0.56) in trials with baseline HR <69 bpm (
P
for interaction=0.03). Fish oil reduced HR by 2.5 bpm (
P
<0.001) in trials with duration ≥12 weeks but had less effect (0.7-bpm reduction;
P
=0.27) in trials with duration <12 weeks (
P
for interaction=0.07). HR reduction with fish oil intake did not significantly vary by fish oil dose (range, 0.81 to 15 g/d), type of HR measure, population age, population health, parallel versus crossover design, type of control oil, or study quality by Delphi criteria (
P
for interaction >0.25 for each).

Conclusions—

In randomized controlled trials in humans, fish oil reduces HR, particularly in those with higher baseline HR or longer treatment duration. These findings provide firm evidence that fish oil consumption directly or indirectly affects cardiac electrophysiology in humans. Potential mechanisms such as effects on the sinus node, ventricular efficiency, or autonomic function deserve further investigation.
Private Sources of U.S. Foreign Policy: William Pawley and the 1954 Coup d'État in Guatemala
Authors: Holland Max
Published: September 2005

As a wealthy American businessman and former ambassador, William Pawley was a key actor in PBSUCCESS, the covert operation that brought down the government of Jacobo Arbenz Guzmán in Guatemala in 1954.The anti-Arbenz rebels, led by Colonel Carlos Castillo Armas, could not have defeated the Guatemalan army on their own. The key to a successful coup was getting the army to act on their behalf, and in this regard, control of the air was vital. Pawley, owing to his knowledge of Latin America and experience in aviation, played a central role in ensuring that the rebels enjoyed air superiority during their move against the president. At a more abstract level, Pawley exempli fied the role non-governmental actors played in the formulation and implementation of U.S. foreign policy during the Cold War. The “state-private network,” as it has been dubbed, remains a rich vein for scholarly investigation.
From Non-alignment to Neutrality: Austria's Transformation during the First East-West Détente, 1953–1958
Authors: Gehler Michael
Published: September 2005

This article deals with Austria during the first phase of détente from 1953 to 1958, a period in which the country was still formally under Four-Power control. The article recounts and analyzes the conclusion of the Austrian State Treaty (and Austria's accompanying declaration of neutrality) in 1955 and the positions taken by Austria during the crises in East Germany in 1953, Hungary in 1956, and Lebanon in 1958. Austria's neutrality was spurred not so much by the Cold War as by the East-West “thaw” after Stalin's death. Neutrality helped usher in a remarkably successful period of national self-assertion that facilitated Austria's efforts at nation building.
“Reenacting the Story of Tantalus”: Eisenhower, Dulles, and the Failed Rhetoric of Liberation
Authors: Tudda Chris
Published: September 2005

This article examines Dwight Eisenhower's and John Foster Dulles's publicly declared goal to achieve the “liberation” of Eastern Europe, a goal that they claimed would replace the Truman administration's “passive” containment policy.But the evidence shows that Eisenhower and Dulles were unwilling to risk war with the Soviet Union and believed that liberation, if actually pursued, would induce the Soviet Union to react violently to perceived threats in Eastern Europe. Hence, in top-secret meetings and conversations, Eisenhower and Dulles rejected military liberation, despite their public pronouncements. Instead, they secretly pursued a tricky, risky, and long-term strategy of radio broadcasts and covert action designed to erode, rather than overthrow, Soviet power in Eastern Europe. In public, they continued to embrace liberation policy even when confronted with testimony from U.S. allies that the rhetorical diplomacy of liberation had not worked. This reliance on rhetoric failed to deter the Soviet Union from quashing rebellions in East Germany in 1953 and Hungary in 1956. If anything, the Eisenhower administration's rhetorical liberation policy may have encouraged, at least to some degree, these revolts.