bluuebunny/crossref_metadata_2025 huggingface dataset:
Height and Prostate Cancer Risk: A Large Nested Case-Control Study (ProtecT) and Meta-analysis
Authors: Zuccolo Luisa , Harris Ross , Gunnell David , Oliver Steven , Lane Jane Athene , Davis Michael , Donovan Jenny , Neal David , Hamdy Freddie , Beynon Rebecca , Savovic Jelena , Martin Richard Michael
Published: September 2008

Background: Height, a marker of childhood environmental exposures, is positively associated with prostate cancer risk, perhaps through the insulin-like growth factor system. We investigated the relationship of prostate cancer with height and its components (leg and trunk length) in a nested case-control study and with height in a dose-response meta-analysis.

Methods: We nested a case-control study within a population-based randomized controlled trial evaluating treatments for localized prostate cancer in British men ages 50 to 69 years, including 1,357 cases detected through prostate-specific antigen testing and 7,990 controls (matched on age, general practice, assessment date). Nine bibliographic databases were searched systematically for studies on the height-prostate cancer association that were pooled in a meta-analysis.

Results: Based on the nested case-control, the odds ratio (OR) of prostate-specific antigen–detected prostate cancer per 10 cm increase in height was 1.06 [95% confidence interval (95% CI): 0.97-1.16; ptrend = 0.2]. There was stronger evidence of an association of height with high-grade prostate cancer (OR: 1.23; 95% CI: 1.06-1.43), mainly due to the leg component, but not with low-grade disease (OR: 0.99; 95% CI: 0.90-1.10). In general, associations with leg or trunk length were similar. A meta-analysis of 58 studies found evidence that height is positively associated with prostate cancer (random-effects OR per 10 cm: 1.06; 95% CI: 1.03-1.09), with a stronger effect for prospective studies of more advanced/aggressive cancers (random-effects OR: 1.12; 95% CI: 1.05-1.19).

Conclusion: These data indicate a limited role for childhood environmental exposures—as indexed by adult height—on prostate cancer incidence, while suggesting a greater role for progression, through mechanisms requiring further investigation. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2325–36)
Serum Calcium and Incident and Fatal Prostate Cancer in the National Health and Nutrition Examination Survey
Authors: Skinner Halcyon G. , Schwartz Gary G.
Published: September 2008

We examined the association between serum calcium levels and the risk for prostate cancer using a prospective cohort, the National Health and Nutrition Examination Survey (NHANES) and the NHANES Epidemiologic Follow-up Study. Eighty-five incident cases of prostate cancer and 25 prostate cancer deaths occurred over 46,188 person-years of follow-up. Serum calcium was determined an average of 9.9 years before the diagnosis of prostate cancer. Comparing men in the top with men in the bottom tertile of serum calcium, the multivariable-adjusted relative hazard for fatal prostate cancer was 2.68 (95% confidence interval, 1.02-6.99; Ptrend = 0.04). For incident prostate cancer, the relative risk for the same comparison was 1.31 (95% confidence interval, 0.77-2.20; Ptrend = 0.34). These results support the hypothesis that high serum calcium or a factor strongly associated with it (e.g., high serum parathyroid hormone) increases the risk for fatal prostate cancer. Our finding of a >2.5-fold increased risk for men in the highest tertile of serum calcium is comparable in magnitude with the risk associated with family history and could add significantly to our ability to identify men at increased risk for fatal prostate cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2302–5)
Domestic and Farm-Animal Exposures and Risk of Non-Hodgkin's Lymphoma in a Population-Based Study in the San Francisco Bay Area
Authors: Tranah Gregory J. , Bracci Paige M. , Holly Elizabeth A.
Published: September 2008

Objective: To assess the association between animal exposures and non-Hodgkin's lymphoma (NHL).

Methods: Exposure data were collected from 1,591 cases and 2,515 controls during in-person interviews in a population-based case-control study of NHL in the San Francisco Bay Area. Odds ratios (OR) and 95% confidence intervals (95% CI) were adjusted for potential confounders.

Results: Pet owners had a reduced risk of NHL (OR, 0.71; 95% CI, 0.52-0.97) and diffuse large-cell lymphoma large cell (DLCL; OR, 0.58; 95% CI, 0.39-0.87) compared with those who never had owned a pet. Ever having owned dogs and/or cats was associated with reduced risk of all NHL (OR, 0.71; 95% CI, 0.54-0.94) and of DLCL (OR, 0.60; 95% CI, 0.42-0.86). Longer duration of cat ownership (Ptrend = 0.008), dog ownership (Ptrend = 0.04), and dog and/or cat ownership (Ptrend = 0.004) was inversely associated with risk of NHL. Ownership of pets other than cats and dogs was associated with a reduced risk of NHL (OR, 0.64; 95% CI, 0.55-0.74) and DLCL (OR, 0.58; 95% CI, 0.47-0.71). Exposure to cattle for ≥5 years was associated with an increased risk of NHL (OR, 1.6; 95% CI, 1.0-2.5) as was exposure to pigs for all NHL (OR, 1.8; 95% CI, 1.2-2.6) and for DLCL (OR, 2.0; 95% CI, 1.2-3.4).

Conclusions: The association between animal exposure and NHL warrants further investigation in pooled analyses. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2382–7)
Association of Prostate-Specific Antigen Promoter Genotype with Clinical and Histopathologic Features of Prostate Cancer
Authors: Cramer Scott D. , Sun Jielin , Zheng S. Lilly , Xu Jianfeng , Peehl Donna M.
Published: September 2008

The serum test for the secreted protease prostate-specific antigen (PSA) is the most widely used screening tool for prostate cancer. The PSA gene contains multiple functional and nonfunctional single nucleotide polymorphisms (SNP) in its promoter. We showed previously that the rs925013 G/A SNP, but not the rs266882 G/A SNP, was significantly associated with serum PSA in healthy men. In this study, we evaluated the association of the PSA promoter genotype with clinical data in a cohort of 1,224 men with prostate cancer. Previous work with a subset of this cohort has shown that percent high-grade (Gleason grades 4 and 5) cancer was the strongest predictor of biochemical recurrence (PSA relapse). We found a statistically significant association (P < 0.05) of the rs925013 SNP with several clinical and histomorphologic variables. The G allele was associated with higher serum PSA at diagnosis, higher percent Gleason grade 3 cancer, and lower percent high-grade and Gleason grade 4 cancer. The rs266882 SNP was modestly associated with PSA at diagnosis in a dominant model but was not associated with cancer grade. Neither SNP was associated with biochemical recurrence. The statistically significant predictors of biochemical recurrence were tumor location in the peripheral zone [odds ratio (OR), 10.71; 95% confidence interval (95% CI), 3.15-36.49], presence of any Gleason grade 4/5 cancer (OR, 4.26; 95% CI, 1.30-14.00), presence of any intraductal cancer (OR, 1.03; 95% CI, 1.00-1.04), and serum PSA at diagnosis (OR, 2.04; 95% CI, 1.50-2.77). (Cancer Epidemiol Biomarkers Prev 2008;17(9):2451–7)
Estrogen plus Progestin and Risk of Benign Proliferative Breast Disease
Authors: Rohan Thomas E. , Negassa Abdissa , Chlebowski Rowan T. , Lasser Norman L. , McTiernan Anne , Schenken Robert S. , Ginsberg Mindy , Wassertheil-Smoller Sylvia , Page David L.
Published: September 2008

Women with benign proliferative breast disease are at increased risk of subsequent breast cancer. Estrogens and progesterone exert proliferative effects on mammary epithelium, and combined hormone replacement therapy has been associated with increased breast cancer risk. We tested the effect of conjugated equine estrogen plus progestin on the risk of benign proliferative breast disease in the Women's Health Initiative (WHI) randomized controlled trial. In the WHI trial of estrogen plus progestin, 16,608 postmenopausal women were randomly assigned either to 0.625 mg/day of conjugated equine estrogen plus 2.5 mg/day of medroxyprogesterone acetate or to placebo. Baseline and annual breast exams and mammograms were required. The trial was terminated early (average follow-up, 5.5 years). We identified women who had had a biopsy for benign breast disease, and subjected histologic sections from the biopsies to standardized review. Overall, 178 incident cases of benign proliferative breast disease were ascertained in the estrogen plus progestin group and 99 in the placebo group. The use of estrogen plus progestin was associated with a 74% increase in the risk of benign proliferative breast disease [hazard ratio, 1.74; 95% confidence interval (CI), 1.35-2.25]. For benign proliferative breast disease without atypia the hazard ratio was 2.00 (95% CI, 1.50-2.66), while for atypical hyperplasia it was 0.76 (95% CI, 0.38-1.52). The risk varied little by levels of baseline characteristics. The results of this study suggest that the use of estrogen plus progestin may increase the risk of benign proliferative breast disease. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2337–43)
Placental Weight and Risk of Invasive Epithelial Ovarian Cancer with an Early Age of Onset
Authors: Cnattingius Sven , Eloranta Sandra , Adami Hans-Olov , Axelsson Ove , Dickman Paul W. , Hsieh Chung-cheng , Mucci Lorelei A. , Trichopoulos Dimitrios , Lambe Mats , Johansson Anna L.V.
Published: September 2008

Background: Epithelial ovarian cancer is associated with reproductive factors, but we lack knowledge if hormonal factors during pregnancy influence the mother's risk. Because pregnancy hormones are primarily produced by the placenta, placental weight may be an indirect marker of hormone exposure during pregnancy.

Methods: In a nationwide Swedish cohort study, we included women with singleton births from 1982 to 1989. Women were followed for occurrence of invasive epithelial ovarian cancer, death, or emigration through 2004. Hazard ratios (HR) with 95% confidence intervals (95% CI) from Cox models were used to estimate associations between pregnancy exposures and epithelial ovarian cancer.

Results: Among 395,171 women with information on placental weight in their first recorded birth, 316 women developed invasive epithelial ovarian cancer. Mean age at diagnosis was 44 years. Compared with women with a placental weight of 500 to 699 g, women with a high (≥700 g) placental weight had an increased risk of developing epithelial ovarian cancer (HR, 1.47; 95% CI, 1.14-1.90). Compared with women with term pregnancies (40-41 weeks), women with post-term (≥42 weeks) pregnancies had an increased risk of developing epithelial ovarian cancer (HR, 1.48; 95% CI, 1.00-2.19). These associations were slightly stronger when we included information about women's overall first birth, and slightly weaker when we included information about last recorded birth or ever last birth from 1982 to 1989.

Conclusions: Because pregnancy hormone levels increase with placental weight, our study supports the hypothesis that hormone exposures during pregnancy influence the risk of invasive epithelial ovarian cancer among young women. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2344–9)
Physical Activity in Relation to Total, Advanced, and Fatal Prostate Cancer
Authors: Moore Steven C. , Peters Tricia M. , Ahn Jiyoung , Park Yikyung , Schatzkin Arthur , Albanes Demetrius , Ballard-Barbash Rachel , Hollenbeck Albert , Leitzmann Michael F.
Published: September 2008

Physical activity has been inconsistently related to total prostate cancer and few studies have examined whether this association varies by disease aggressiveness. We examined physical activity in relation to total, advanced, and fatal prostate cancer in the NIH-AARP Diet and Health Study. At baseline (1995-1996), 293,902 men ages 50 to 71 years completed a questionnaire inquiring about current frequency of vigorous exercise of at least 20 min of duration, as well as frequency of exercise during adolescence (ages 15-18). We used proportional hazards regression to calculate multivariate relative risks (RR) and 95% confidence intervals (95% CI). During up to 8.2 years of follow-up, 17,872 prostate cancer cases were identified, including 1,942 advanced and 513 fatal cases. Comparing frequent (5+ times per week) versus infrequent (less than once per week) vigorous exercise, exercise at baseline was not associated with risk of total prostate cancer (RR, 1.01; 95% CI, 0.96-1.07; Ptrend = 0.78), advanced prostate cancer (RR, 1.14; 95% CI, 0.97-1.33; Ptrend = 0.25), or fatal prostate cancer (RR, 0.90; 95% CI, 0.67-1.20; Ptrend = 0.12). Increasing level of vigorous exercise during adolescence was associated with a small 3% reduction in total prostate cancer risk (frequent versus infrequent exercise during adolescence: RR, 0.97; 95% CI, 0.91-1.03; Ptrend = 0.03) but was not associated with risk of advanced prostate cancer (RR, 0.95; 95% CI, 0.78-1.14; Ptrend = 0.18) or fatal prostate cancer (RR, 0.96; 95% CI, 0.67-1.36; Ptrend = 0.99). Neither vigorous exercise at baseline nor exercise during adolescence was related to risk of total, advanced, or fatal prostate cancer in this large prospective cohort. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2458–66)
Tumor Necrosis Factor Alpha Extended Haplotypes and Risk of Gastric Carcinoma
Authors: Canedo Paulo , Durães Cecília , Pereira Fábio , Regalo Gonçalo , Lunet Nuno , Barros Henrique , Carneiro Fátima , Seruca Raquel , Rocha Jorge , Machado José C.
Published: September 2008

The tumor necrosis factor α (TNFA)-308*A allele has been found to confer an increased risk of gastric carcinoma. Inconsistency in risk estimates across populations lead us to hypothesize about the presence of an alternative causal locus in the same chromosomal region. A suitable approach is to determine the tumor necrosis factor haplotypic structure in order to clarify whether the association between the *A allele and the increased risk of gastric carcinoma is etiologic or secondary to linkage disequilibrium. Firstly, we assessed the association between the TNFA-308G>A polymorphism and the risk of gastric carcinoma in a population from Northern Portugal (508 gastric carcinoma patients, 713 controls); secondly, we genotyped five microsatellite loci (TNFa, b, c, d, e) flanking the TNFA-308G>A locus to establish the haplotypic structure associated with this single-nucleotide polymorphism in cases (122 patients) and controls (169 individuals). We found a significant association between the *A allele and increased risk of gastric carcinoma (odds ratio, 1.7; 95% confidence interval, 1.3-2.2) confirming previous results in our population. Regarding the *A allele–associated haplotypes, the most relevant difference was found for the H1A haplotype present in 33.1% of the cases and 12.5% of the controls. We also observed haplotypes associated with the *A allele that were found only in cases or controls. A population differentiation test showed that the gastric carcinoma and the control groups were significantly different for the *A allele haplotypic structure. This suggests that the association between the TNFA-308G>A polymorphism and increased risk of gastric carcinoma is dependent on linkage disequilibrium with an as yet unidentified locus. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2416–20)
Mitochondrial Genetic Polymorphisms Do Not Predict Survival in Patients with Pancreatic Cancer
Authors: Halfdanarson Thorvardur R. , Wang Liang , Bamlet William R. , de Andrade Mariza , McWilliams Robert R. , Cunningham Julie M. , Petersen Gloria M.
Published: September 2008

Pancreatic cancer is a highly lethal malignancy, and the majority of patients succumb to the disease within 2 years. We evaluated the role of variants of mitochondrial DNA and mitochondrial haplogroups in predicting prognosis of patients with pancreatic cancer. A total of 24 mitochondrial single nucleotide polymorphisms were genotyped in 990 patients with pancreatic cancer. After adjusting for covariates and multiple comparisons, no association between any of the mitochondrial single nucleotide polymorphisms or haplogroups and survival was observed. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2512–3)
Age-Incidence Curves of Nasopharyngeal Carcinoma Worldwide: Bimodality in Low-Risk Populations and Aetiologic Implications
Authors: Bray Freddie , Haugen Marion , Moger Tron A. , Tretli Steinar , Aalen Odd O. , Grotmol Tom
Published: September 2008

The distinct geographic variation in the global incidence of nasopharyngeal carcinoma reflects a complex etiology involving viral, environmental, and genetic components. The high to intermediate rates observed in endemic areas contrast markedly with the uniformly low rates seen in much of the world. An interesting epidemiologic observation is the early peak in age-incidence curves observed in certain geographically disparate populations, suggestive of distinct causal entities and the possible exhaustion of susceptible individuals from the population at a certain age. The aim of this study was to systematically evaluate the age-incidence profiles of NPC worldwide on partitioning populations according to level of risk, in an effort to provide clues about the importance of early-in-life factors and genetic susceptibility. Using data from 23 high-quality population-based cancer registries for the period 1983-1997, a key finding was the consistent pattern of bimodality that emerged across low-risk populations, irrespective of geographic location. Continual increases in NPC risk by age up to a first peak in late adolescence/early adulthood (ages 15-24 years) were observed, followed by a second peak later in life (ages 65-79 years). No such early peak in NPC incidence by age group was evident among the high-risk populations studied. These findings are discussed according to existing lines of biological and epidemiologic evidence related to level of population risk, age at diagnosis, and histologic subtype. A modified model for NPC tumor development is proposed on the basis of these observations. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2356–65)
Tamoxifen Treatment in Danish Breast Cancer Patients and 5-Year Risk of Arterial Atherosclerotic Events: A Null Association
Authors: Hernandez Rohini K. , Sørensen Henrik Toft , Jacobsen Jacob , Pedersen Lars , Lash Timothy L.
Published: September 2008

Although the effectiveness of tamoxifen in preventing the recurrence of breast cancer is well established, associations between tamoxifen and the occurrence of atherosclerotic events are not as clear. Breast cancer patients taking tamoxifen have lower serum cholesterol and other lipid levels than those not taking tamoxifen, suggesting that tamoxifen might prevent atherosclerotic events, but the existing studies are conflicting. We examined the relation between tamoxifen and incident hospitalization of angina pectoris, acute myocardial infarction, heart failure, and stroke. The study population of 16,289 women was identified from the Danish Breast Cancer Cooperative Group nationwide clinical database and includes women diagnosed with stage I or II estrogen receptor–positive breast cancer between 1990 and 2004 at ages 45 to 69. Use of a large population-based sample with complete outcome ascertainment allowed us to calculate precise measures of risks, risk ratios, and adjusted hazard ratios comparing tamoxifen-treated patients with untreated patients. We found strong evidence for null associations for each of the four outcomes of interest during the first year and first 5 years after the start of therapy. These findings are important in risk/benefit analyses as tamoxifen therapy in postmenopausal women is being replaced with aromatase inhibitors. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2509–11)
Genetic variants associated with carboplatin-induced cytotoxicity in cell lines derived from Africans
Authors: Huang R. Stephanie , Duan Shiwei , Kistner Emily O. , Hartford Christine M. , Dolan M. Eileen
Published: September 2008

To gain a better understanding of the genetic variants associated with carboplatin-induced cytotoxicity in individuals of African descent, we present a step-wise approach integrating genotypes, gene expression, and sensitivity of HapMap cell lines to carboplatin. Cell lines derived from 30 trios of African descent (YRI) were used to develop a preclinical model to identify genetic variants and gene expression that contribute to carboplatin-induced cytotoxicity. Cytotoxicity was determined as cell growth inhibition at increasing concentrations of carboplatin for 72 h. Gene expression of 89 HapMap YRI cell lines was determined using the Affymetrix GeneChip Human Exon 1.0 ST Array. Single nucleotide polymorphism genotype and the percent survival at different treatment concentrations along with carboplatin IC50 were linked through whole genome association. A second association test was done between single nucleotide polymorphism genotype and gene expression, and linear regression was then used to capture those genes whose expression correlated to drug sensitivity phenotypes. This approach allows us to identify genetic variants that significantly associate with sensitivity to the cytotoxic effects of carboplatin through their effect on gene expression. We found a gene (GPC5) whose expression is important in all carboplatin treatment concentrations as well as many genes unique to either low (e.g., MAPK1) or high (e.g., BRAF, MYC, and BCL2L1) concentrations of drug. Our whole genome approach enables us to evaluate the contribution of genetic and gene expression variation to a wide range of cellular phenotypes. The identification of concentration specific genetic signatures allows for potential integration of pharmacokinetics, pharmacodynamics, and pharmacogenetics in tailoring chemotherapy. [Mol Cancer Ther 2008;7(9):3038–46]
Gene expression profiling-based identification of cell-surface targets for developing multimeric ligands in pancreatic cancer
Authors: Balagurunathan Yoganand , Morse David L. , Hostetter Galen , Shanmugam Vijayalakshmi , Stafford Phillip , Shack Sonsoles , Pearson John , Trissal Maria , Demeure Michael J. , Von Hoff Daniel D. , Hruby Victor J. , Gillies Robert J. , Han Haiyong
Published: September 2008

Multimeric ligands are ligands that contain multiple binding domains that simultaneously target multiple cell-surface proteins. Due to cooperative binding, multimeric ligands can have high avidity for cells (tumor) expressing all targeting proteins and only show minimal binding to cells (normal tissues) expressing none or only some of the targets. Identifying combinations of targets that concurrently express in tumor cells but not in normal cells is a challenging task. Here, we describe a novel approach for identifying such combinations using genome-wide gene expression profiling followed by immunohistochemistry. We first generated a database of mRNA gene expression profiles for 28 pancreatic cancer specimens and 103 normal tissue samples representing 28 unique tissue/cell types using DNA microarrays. The expression data for genes that encode proteins with cell-surface epitopes were then extracted from the database and analyzed using a novel multivariate rule-based computational approach to identify gene combinations that are expressed at an efficient binding level in tumors but not in normal tissues. These combinations were further ranked according to the proportion of tumor samples that expressed the sets at efficient levels. Protein expression of the genes contained in the top ranked combinations was confirmed using immunohistochemistry on a pancreatic tumor tissue and normal tissue microarrays. Coexpression of targets was further validated by their combined expression in pancreatic cancer cell lines using immunocytochemistry. These validated gene combinations thus encompass a list of cell-surface targets that can be used to develop multimeric ligands for the imaging and treatment of pancreatic cancer. [Mol Cancer Ther 2008;7(9):3071–80]
HER receptor signaling confers resistance to the insulin-like growth factor-I receptor inhibitor, BMS-536924
Authors: Haluska Paul , Carboni Joan M. , TenEyck Cynthia , Attar Ricardo M. , Hou Xiaonan , Yu Chunrong , Sagar Malvika , Wong Tai W. , Gottardis Marco M. , Erlichman Charles
Published: September 2008

We have reported previously the activity of the insulin-like growth factor-I (IGF-IR)/insulin receptor (InsR) inhibitor, BMS-554417, in breast and ovarian cancer cell lines. Further studies indicated treatment of OV202 ovarian cancer cells with BMS-554417 increased phosphorylation of HER-2. In addition, treatment with the pan-HER inhibitor, BMS-599626, resulted in increased phosphorylation of IGF-IR, suggesting a reciprocal cross-talk mechanism. In a panel of five ovarian cancer cell lines, simultaneous treatment with the IGF-IR/InsR inhibitor, BMS-536924 and BMS-599626, resulted in a synergistic antiproliferative effect. Furthermore, combination therapy decreased AKT and extracellular signal-regulated kinase activation and increased biochemical and nuclear morphologic changes consistent with apoptosis compared with either agent alone. In response to treatment with BMS-536924, increased expression and activation of various members of the HER family of receptors were seen in all five ovarian cancer cell lines, suggesting that inhibition of IGF-IR/InsR results in adaptive up-regulation of the HER pathway. Using MCF-7 breast cancer cell variants that overexpressed HER-1 or HER-2, we then tested the hypothesis that HER receptor expression is sufficient to confer resistance to IGF-IR-targeted therapy. In the presence of activating ligands epidermal growth factor or heregulin, respectively, MCF-7 cells expressing HER-1 or HER-2 were resistant to BMS-536924 as determined in a proliferation and clonogenic assay. These data suggested that simultaneous treatment with inhibitors of the IGF-I and HER family of receptors may be an effective strategy for clinical investigations of IGF-IR inhibitors in breast and ovarian cancer and that targeting HER-1 and HER-2 may overcome clinical resistance to IGF-IR inhibitors. [Mol Cancer Ther 2008;7(9):2589–98]
Functional Incapacity and Physical and Psychological Symptoms: How They Interconnect in Chronic Fatigue Syndrome
Authors: Priebe Stefan , Fakhoury Walid K.H. , Henningsen Peter
Published: September 2008

Background: It has been argued that perceived functional incapacity might be a primary characteristic of chronic fatigue syndrome (CFS) and could be explained by physical symptoms. If so, it could be expected to be closely associated with physical, but not psychological symptoms. The study tests this hypothesis. Sampling and Methods: The sample consisted of 73 patients, with a diagnosis of CFS according to the Oxford criteria, randomly selected from clinics in the Departments of Immunology and Psychiatry at St. Bartholomew’s Hospital, London. The degree of fatigue experienced by patients was assessed using the Chalder Fatigue Questionnaire and a visual analogue scale. Self-rated instruments were used to measure physical and social functioning, quality of life, and physical and psychological symptoms. Results: Principal-component analysis of all scale scores revealed 2 distinct components, explaining 53% of the total variance. One component was characterized by psychological symptoms and generic quality of life indicators, whilst the other component was made up of physical symptoms, social and physical functioning and indicators of fatigue. Conclusions: The findings suggest that perceived functional incapacity is a primary characteristic of CFS, which is manifested and/or explained by physical symptoms.
The Phenomenology of the Psychotic Break and Huxley’s Trip: Substance Use and the Onset of Psychosis
Authors: Nelson Barnaby , Sass Louis A.
Published: September 2008

Background: While considerable research attention has been devoted to the causal relationship between substance use and psychosis, the phenomenology of the association between the two has largely been ignored. This is a significant shortcoming, because it blinds researchers to the possibility that there may be elements of the subjective experience of substance use and psychosis that contribute to their apparent relationship in empirical studies. Sampling and Methods: The current paper examines the phenomenology of the onset of psychosis and the phenomenology of substance intoxication through consideration of two texts: Sass’s account of the phenomenology of psychosis onset and Huxley’s account of the experience of hallucinogenic intoxication. Sass’s account of psychosis onset includes four components: Unreality, Fragmentation, Mere Being, and Apophany. Results: The analysis reveals significant parallels – and also some differences – between this account and the phenomenology of substance intoxication. Conclusions: We discuss the implications of this for the causal relationship between psychosis and substance use and suggest several ways of understanding the overlapping phenomenologies. This includes the suggestion of a shared factor, perhaps best described as psychotic-like experience, which seems to involve a breakdown of the sign-referent relationship and relationship with the common-sense, practical world. However, in the onset of psychosis, this breakdown is primarily experienced as a sense of alienation from self and world, whereas in the hallucinogenic state a sense of mystical union and revelation seems predominant. Further research may extend this analysis by looking at experiences with other drugs, particularly cannabis, and by examining the phenomenology of psychotic disorder beyond the first episode.
DSM-IV Personality Disorders and Their Axis I Correlates in the South African Population
Authors: Suliman S. , Stein D.J. , Williams D.R. , Seedat S.
Published: September 2008

Background: The prevalence of personality disorders (PD) in the South African population is largely unknown. Thus, we undertook to estimate prevalence, demographic correlates, co-morbidity and treatment rates of DSM-IV PD among South Africans. Sampling and Methods: A three-stage probability sample design was used. Of the 4,433 interviews obtained, based on quality control criteria, 4,315 interviews were retained for analysis. All participants were screened for PD and axis I disorders with the World Health Organisation Composite International Diagnostic Interview. The multiple imputation method was then used to estimate prevalence. Results: The multiple imputation prevalence estimate in the total sample was 6.8%. All three PD clusters were significantly co-morbid with each other and with other axis I disorders. Male gender was the only significant predictor of PD. Of note was the finding that less than one fifth of participants with a possible PD diagnosis had received treatment for a mental health or substance abuse problem in the previous 12 months. Conclusion: The high co-morbidity of PD with axis I disorders in South Africa is consistent with previous reports elsewhere. However, more research is indicated to determine the reasons for the higher prevalence of cluster A disorders than of cluster B and C disorders in this population.
Association of Physical and Social Anhedonia with Depression in the Acute Phase of Schizophrenia
Authors: Kollias Costas T. , Kontaxakis Vassilis P. , Havaki-Kontaxaki Beata J. , Stamouli Sophia , Margariti Maria , Petridou Eleni
Published: September 2008

Background/Aims: Researchers have shown interest in the association between anhedonia and depression in schizophrenia. The aim of the current study was to investigate the relationship between physical and social anhedonia with depression in a sample of inpatients with schizophrenia in the acute phase of their illness. Methods: Sixty-two patients with acute schizophrenia consecutively admitted at the Eginition Hospital, Department of Psychiatry, University of Athens were assessed using the revised Physical Anhedonia Scale, the revised Social Anhedonia Scale and the Calgary Depression Scale for Schizophrenia. Results: The Calgary Depression Scale for Schizophrenia score correlated with both physical anhedonia and social anhedonia ratings. The revised Social Anhedonia Scale score significantly correlated to self-depreciation, guilty ideas of reference, pathological guilt, early wakening, suicidality and observed depression. The revised Physical Anhedonia Scale score significantly correlated with depressive mood, self-depreciation, pathological guilt and observed depression. Self-depreciation, pathological guilt and observed depression were correlated with both social and physical anhedonia. Conclusion: Depression in schizophrenia and anhedonia may overlap, and it could therefore be difficult to clinically differentiate them, especially in acute schizophrenia patients.
Plasma Nuclear DNA and Mitochondrial DNA as Prognostic Markers in Corrosive Injury Patients
Authors: Chou Chu-Chung , Fang Hsin-Yuan , Chen Yao-Li , Wu Chin-Yen , Siao Fu-Yuan , Chou Ming-Jen
Published: September 2008

Study Objectives: Ingestion of a corrosive substance produces an injury to the gastrointestinal tract and it is often difficult to evaluate the severity and prognosis of this injury. Increased concentrations of plasma nuclear DNA and mitochondrial DNA (mtDNA) have been found to be associated with the area of corrosion. This study examined the level of plasma DNA as it relates to the severity of corrosive injury. Methods: Forty-eight consecutive patients were enrolled prospectively. The concentrations of plasma nuclear DNA and mtDNA were measured by real-time quantitative polymerase chain reaction assay at presentation to the emergency room and 12 h later. Result: The median age of the patients enrolled was 55 years (20 men and 28 women) with an overall mortality rate of 21%. Nineteen patients underwent operative intervention secondary to perforation. Findings included significantly elevated plasma nuclear DNA and mtDNA in the mortality group at presentation and 12 h after injury compared to the survival group. Conclusion: The concentrations of plasma nuclear DNA and mtDNA were elevated within 4 h after corrosive injury. The elevated concentrations of plasma nuclear DNA and mtDNA could be useful prognostic markers to correlate with the clinical outcome in corrosive patients.
Differential Impact of Msx1 and Msx2 Homeogenes on Mouse Maxillofacial Skeleton
Authors: Berdal Ariane , Molla Muriel , Hotton Dominique , Aïoub Muhanad , Lézot Frédéric , Néfussi Jean-Raphaël , Goubin Gérard
Published: September 2008

Craniofacial development involves a large number of genes involved in a complex time- and site-specific cascade of cellular crosstalk. Msx homeobox genes are expressed very early and have been implicated in multiple signaling processes. However, little is known about their role in postnatal growth and at adult stages. The aim of this study was to compare the patterns of expression of Msx1 and Msx2 during postnatal growth and homeostasis. We used transgenic mice with a knock-in for Msx1 or Msx2. Msx expression was analyzed on whole-mount experiments on heterozygous mice. The results were confirmed by quantitative RT-PCR on mandible and tibia samples. Steady-state levels of Msx2 mRNA were determined at 2 ages, at postnatal day 14 and after 3 months, corresponding to phases of growth and homeostasis, respectively. Consistent with previous findings, the expression profiles of Msx1 and Msx2 overlapped during embryonic development. By contrast, marked differences in the patterns of expression of these 2 genes were observed during the growth phase. Msx1 was found to be expressed in basal bone during postnatal growth. Msx1 was not expressed in alveolar bone, whereas Msx2 was strongly and continually expressed. Msx2 was present in all growth plate cartilages, as previously shown for Msx1. Autopods displayed different patterns of expression during the mouse life cycle, with continuous expression of Msx1 only. Interestingly, both secretory cells (osteoblasts) and cells involved in bone resorption (osteoclasts) were found to be involved in Msx molecular pathways, their precise involvement depending on the anatomical site. The observed patterns correspond to specific sites during growth and constitute landmarks in our understanding of growth-related oral facial dysmorphologies.
Perinatal Outcome of Fetal Atrioventricular Block
Authors: Lopes Lilian M. , Tavares Gláucia Maria Penha , Damiano Ana Paula , Lopes Marco Antônio Borges , Aiello Vera Demarchi , Schultz Regina , Zugaib Marcelo
Published: September 2008

Background—

Fetal atrioventricular (AV) block is an uncommon lesion with significant mortality. Because of the rarity of this disorder, the natural course, extensive evaluation of untreated fetuses, and late follow-up remain unclear.

Methods and Results—

Of the 116 consecutive cases of fetal AV block studied from 1988 to 2006, only 1 was terminated, and 75% were live births. Fifty-nine cases of AV block were associated with major structural heart disease, mainly left atrial isomerism (n=40), with only 26% of neonatal survivors. Of the 57 fetuses with normal cardiac anatomy, 41 (72%) were positive for maternal antinuclear antibodies, and 32 of these seropositive mothers did not receive any treatment. This untreated group had live-birth and 1-year infant survival rates of 93% and 90%, respectively. Five fetuses from seronegative mothers showed regression to sinus rhythm during pregnancy. The presence of major structural heart disease, hydrops, an atrial rate ≤120 bpm, and a ventricular rate ≤55 bpm were identified as risk factors for mortality. Logistic regression analysis of the whole group showed that the presence of structural heart disease was the only independent predictor of death (
P
<0.001).

Conclusions—

This long-term study confirms that fetal AV block has a poor outcome when associated with structural heart disease and that spontaneous regression of AV block is possible in seronegative forms. The survival rate of >90% of our untreated patients with isolated forms of AV block raises concerns about any decision to intervene with immunosuppressive agents.
Combined Statin and Niacin Therapy Remodels the High-Density Lipoprotein Proteome
Authors: Green Pattie S. , Vaisar Tomas , Pennathur Subramaniam , Kulstad J. Jacob , Moore Andrew B. , Marcovina Santica , Brunzell John , Knopp Robert H. , Zhao Xue-Qiao , Heinecke Jay W.
Published: September 2008

Background—

Boosting low high-density lipoprotein (HDL) levels is a current strategy for preventing clinical events that result from cardiovascular disease. We previously showed that HDL
3
of subjects with coronary artery disease is enriched in apolipoprotein E and that the lipoprotein carries a distinct protein cargo. This observation suggests that altered protein composition might affect the antiatherogenic and antiinflammatory properties of HDL. We hypothesized that an intervention that increases HDL levels—combined statin and niacin therapy—might reverse these changes.

Methods and Results—

HDL
3
isolated from 6 coronary artery disease subjects before and 1 year after combination therapy was analyzed by liquid chromatography–Fourier transform–mass spectrometry. Alterations in protein composition were detected by spectral counting and confirmed with extracted ion chromatograms. We found that combination therapy decreased the abundance of apolipoprotein E in HDL
3
while increasing the abundance of other macrophage proteins implicated in reverse cholesterol transport. Treatment-induced decreases in apolipoprotein E levels of HDL
3
were validated biochemically in a second group of 18 coronary artery disease subjects. Interestingly, the changes in HDL
3
proteome with niacin/statin treatment resulted in a protein composition that more closely resembled that of HDL
3
in healthy control subjects.

Conclusions—

Combined statin and niacin therapy partially reverses the changes in the protein composition seen in HDL
3
in coronary artery disease subjects. Our observations raise the possibility that quantifying the HDL proteome could provide insights into the therapeutic efficacy of antiatherosclerotic interventions.
Dose Effect of Clopidogrel Reloading in Patients Already on 75-mg Maintenance Dose
Authors: Collet Jean-Philippe , Silvain Johanne , Landivier Antoine , Tanguy Marie-Laure , Cayla Guillaume , Bellemain Anne , Vignolles Nicolas , Gallier Sophie , Beygui Farzin , Pena Ana , Montalescot Gilles
Published: September 2008

Background—

Clopidogrel loading has mostly been studied in clopidogrel-naïve patients. Whether clopidogrel-treated patients readmitted for an acute coronary syndrome or percutaneous coronary intervention can benefit from a new load of clopidogrel and at what dose remain unknown. Our aim was to evaluate the impact of 3 different strategies of administration of a loading dose of 900 mg clopidogrel in patients already treated with a maintenance dose of 75 mg clopidogrel for at least 7 days on residual platelet aggregation.

Methods and Results—

Patients treated long term by clopidogrel 75 mg/d were assigned to receive a first loading dose of 300, 600, or 900 mg clopidogrel and 4 hours later a second loading dose of 600, 300, or 0 mg, respectively, to achieve a total loading dose of 900 mg in all patients. Platelet aggregation was evaluated at baseline, at 4 hours after the initial load (and before second load), and at 24 hours using light transmission aggregometry with 20 μmol ADP and the point-of-care assay VerifyNow P2Y
12
. The primary objective of the study was to evaluate the inhibition (relative change) of residual platelet aggregation (percentage of IRPA) between 600- and 900-mg first loading at 4 hours. IRPA at 24 hours also was evaluated as a secondary objective, as well as the rate of suboptimal response at 4 hours defined as IRPA <10%. We included 166 consecutive patients with acute coronary syndromes (n=80, 48%) or stable coronary artery disease (n=86, 52%). Baseline characteristics were similar in the 3 dose groups. A significant stepwise increase was found in percentage IRPA assessed at 4 hours in patients initially assigned to 300 versus 600 versus 900 mg (30.7% versus 40.3% versus 64.0%, respectively;
P
=0.0024). The difference in percentage IRPA at 4 hours was not significant between 300 and 600 mg but was significant between 600 and 900 mg and between 300 and 900 mg. Percentage IRPA assessed at 24 hours when all patients had received 900 mg did not differ between the 3 loading regimens. The rates of suboptimal response (IRPA <10% at 4 hours) were 23.6%, 20.4%, and 5.3% with 300, 600, and 900 mg, respectively (
P
=0.02 for all).

Conclusions—

In patients treated long term with 75 mg clopidogrel, a new loading dose of 900 mg improves IRPA and reduces poor and/or slow response to clopidogrel significantly more than that obtained with 300 or 600 mg.
Hot Flashes and Subclinical Cardiovascular Disease
Authors: Thurston Rebecca C. , Sutton-Tyrrell Kim , Everson-Rose Susan A. , Hess Rachel , Matthews Karen A.
Published: September 2008

Background—

Although evidence suggests adverse vascular changes among women with hot flashes, it is unknown whether hot flashes are associated with subclinical cardiovascular disease. The aim of this study was to examine relations between menopausal hot flashes and indices of subclinical cardiovascular disease. We hypothesized that women with hot flashes would show reduced flow-mediated dilation and greater coronary artery and aortic calcification compared with women without hot flashes.

Methods and Results—

The Study of Women’s Health Across the Nation Heart Study (2001 to 2003) is an ancillary study to the Study of Women’s Health Across the Nation, a community-based cohort study. Participants were 492 women (35% black, 65% white) 45 to 58 years of age who were free of clinical cardiovascular disease and had a uterus and at least 1 ovary. Measures included a brachial artery ultrasound to assess flow-mediated dilation, electron beam tomography to assess coronary artery and aortic calcification, reported hot flashes (any/none, previous 2 weeks), and a blood sample for measurement of estradiol concentrations. Cross-sectional associations were evaluated with linear regression and partial proportional odds models. Hot flashes were associated with significantly lower flow-mediated dilation (β=−1.01; SE, 0.41;
P
=0.01) and greater coronary artery (odds ratio, 1.48; 95% confidence interval, 1.04 to 2.12) and aortic (odds ratio, 1.55; 95% confidence interval, 1.10 to 2.19) calcification in age- and race-adjusted models. Significant associations between hot flashes and flow-mediated dilation (β=−0.97; SE, 0.44;
P
=0.03) and aortic calcification (odds ratio, 1.63; 95% confidence interval, 1.07 to 2.49) remained in models adjusted for cardiovascular disease risk factors and estradiol.

Conclusions—

Women with hot flashes had reduced flow-mediated dilation and greater aortic calcification. Hot flashes may mark adverse underlying vascular changes among midlife women.
Trimetazidine, a Metabolic Modulator, Has Cardiac and Extracardiac Benefits in Idiopathic Dilated Cardiomyopathy
Authors: Tuunanen Helena , Engblom Erik , Naum Alexandru , Någren Kjell , Scheinin Mika , Hesse Birger , Juhani Airaksinen K.E. , Nuutila Pirjo , Iozzo Patricia , Ukkonen Heikki , Opie Lionel H. , Knuuti Juhani
Published: September 2008

Background—The anti-ischemic agent trimetazidine improves ejection fraction in heart failure that is hypothetically linked to inhibitory effects on cardiac free fatty acid (FFA) oxidation. However, FFA oxidation remains unmeasured in humans. We investigated the effects of trimetazidine on cardiac perfusion, efficiency of work, and FFA oxidation in idiopathic dilated cardiomyopathy.

Methods and Results—Nineteen nondiabetic patients with idiopathic dilated cardiomyopathy on standard medication were randomized to single-blind trimetazidine (n=12) or placebo (n=7) for 3 months. Myocardial perfusion, FFA, and total oxidative metabolism were measured using positron emission tomography with [15O]H2O, [11C]acetate, and [11C]palmitate. Cardiac function was assessed echocardiographically; insulin sensitivity was assessed by the homeostasis model assessment index. Trimetazidine increased ejection fraction from 30.9±8.5% to 34.8±12% (P=0.027 versus placebo). Myocardial FFA uptake was unchanged, and β-oxidation rate constant decreased only 10%. Myocardial perfusion, oxidative metabolism, and work efficiency remained unchanged. Trimetazidine decreased insulin resistance (glucose: 5.9±0.7 versus 5.5±0.6 mmol/L,P=0.047; insulin: 10±6.9 versus 7.6±3.6 mU/L,P=0.031; homeostasis model assessment index: 2.75±2.28 versus 1.89±1.06,P=0.027). The degree of β-blockade and trimetazidine interacted positively on ejection fraction. Plasma high-density lipoprotein concentrations increased 11% (P<0.001).

Conclusions—In idiopathic dilated cardiomyopathy with heart failure, trimetazidine increased cardiac function and had both cardiac and extracardiac metabolic effects. Cardiac FFA oxidation modestly decreased and myocardial oxidative rate was unchanged, implying increased oxidation of glucose. Trimetazidine improved whole-body insulin sensitivity and glucose control in these insulin-resistant idiopathic dilated cardiomyopathy patients, thus hypothetically countering the myocardial damage of insulin resistance. Additionally, the trimetazidine-induced increase in ejection fraction was associated with greater β1-adrenoceptor occupancy, suggesting a synergistic mechanism.