Three-dimensional finite element analysis of the effect of alveolar cleft bone graft on the maxillofacial biomechanical stabilities of unilateral complete cleft lip and palate.

BACKGROUND: The objective is to clarify the effect of alveolar cleft bone graft on maxillofacial biomechanical stabilities, the key areas when bone grafting and in which should be supplemented with bone graft once bone resorption occurred in UCCLP (unilateral complete cleft lip and palate). METHODS: Maxillofacial CAD (computer aided design) models of non-bone graft and full maxilla cleft, full alveolar cleft bone graft, bone graft in other sites of the alveolar cleft were acquired by processing the UCCLP maxillofacial CT data in three-dimensional modeling software. The maxillofacial bone EQV (equivalent) stresses and bone suture EQV strains under occlusal states were obtained in the finite element analysis software. RESULTS: Under corresponding occlusal states, the EQV stresses of maxilla, pterygoid process of sphenoid bone on the corresponding side and anterior alveolar arch on the non-cleft side were higher than other maxillofacial bones, the EQV strains of nasomaxillary, zygomaticomaxillary and pterygomaxillary suture on the corresponding side were higher than other maxillofacial bone sutures. The mean EQV strains of nasal raphe, the maximum EQV stresses of posterior alveolar arch on the non-cleft side, the mean and maximum EQV strains of nasomaxillary suture on the non-cleft side in full alveolar cleft bone graft model were all significantly lower than those in non-bone graft model. The mean EQV stresses of bilateral anterior alveolar arches, the maximum EQV stresses of maxilla and its alveolar arch on the cleft side in the model with bone graft in lower 1/3 of the alveolar cleft were significantly higher than those in full alveolar cleft bone graft model. CONCLUSIONS: For UCCLP, bilateral maxillae, pterygoid processes of sphenoid bones and bilateral nasomaxillary, zygomaticomaxillary, pterygomaxillary sutures, anterior alveolar arch on the non-cleft side are the main occlusal load-bearing structures before and after alveolar cleft bone graft. Alveolar cleft bone graft mainly affects biomechanical stabilities of nasal raphe and posterior alveolar arch, nasomaxillary suture on the non-cleft side. The areas near nasal floor and in the middle of the alveolar cleft are the key sites when bone grafting, and should be supplemented with bone graft when the bone resorbed in these areas.

[Changes of postoperative velopharyngeal function in children with cleft palate under 5 years old].

OBJECTIVE: To demonstrate the regularity of velopharyngeal function recovery after primary cleft palatoplasty and its correlation with different surgical procedures, ages, cleft types, and follow-up times. METHODS: Patients with cleft palate under 5 years old who had more than two follow-up records were included in this study, and consecutive evaluations of postoperative velopharyngeal function were performed. Univariate and multivariate logistic regression analysis were used to reveal the regularity of postoperative velopharyngeal function and the possible influencing factors. RESULTS: A total of 165 patients were included. Inconsistent functions of the velopharyngeal closure were observed in 31 patients, of which velopharyngeal insufficiency (VPI) in the first follow-up converted to velopharyngeal competence (VPC) in the second follow-up, accounting for 18.79% of the total, and 134 patients had consistent velopharyngeal function. The patients in the group who had consistent velopharyngeal function were younger than those in the group who were inconsistent, and the differences between the two groups were statistically significant. The younger the operation age, the patient's velopharyngeal function was more likely to stabilize at the first follow-up. At the time of the first follow-up in 15, 28, and 40 months, the probability that the patients had stable postoperative velopharyngeal function was 80%, 90%, and 95%, respectively. CONCLUSIONS: The recovery of velopharyn-geal function after surgery is a dynamic process. The velopharyngeal status of patients can be converted from VPI to VPC. Meanwhile, VPC cannot switch to VPI. The follow-up time is the most important factor affecting the consistency of the evaluation of velopharyngeal function. Choosing appro-priate follow-up time is the key to obtain the stable evaluation of velopharyngeal function.

The Association Between Bleeding and the Incidence of Warfarin Discontinuation in Patients with Atrial Fibrillation.

AIM: While bleeding is a well-known complication of warfarin use and is thought to be a contributory cause of treatment discontinuation, studies quantifying this association are limited. The objective of this study was to quantify the association between bleeding events and subsequent warfarin discontinuation in patients with nonvalvular atrial fibrillation (NVAF). METHODS: A nested case-control analysis was conducted within a cohort of patients with NVAF newly treated with warfarin. All patients who discontinued warfarin (at least 60 days from last day of warfarin supply) during follow-up were identified as cases and matched with up to 10 controls on age, sex, and duration of follow-up. The index date was defined as the date of warfarin treatment discontinuation of the cases. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of warfarin treatment discontinuation associated with a bleeding event in the 60 days before the index date. RESULTS: The cohort included 24,243 patients who initiated warfarin treatment, of whom 13,482 discontinued treatment during follow-up (cases). Bleeding was associated with an increased risk of warfarin treatment discontinuation (3.55% vs. 0.85%; OR, 4.31; 95% CI, 3.87-4.81). When including only bleeds as the first listed diagnosis, the unadjusted OR was 4.64 (95% CI, 4.10-5.26), and the adjusted OR was 4.65 (95% CI, 4.10-5.27). CONCLUSIONS: Bleeding was significantly associated with warfarin discontinuation, and thus, the selection of an effective treatment regimen associated with a lower bleeding rate could be a desirable treatment approach.

Benefit-Risk Assessment, Communication, and Evaluation (BRACE) throughout the life cycle of therapeutic products: overall perspective and role of the pharmacoepidemiologist.

PURPOSE: Optimizing a therapeutic product's benefit-risk profile is an on-going process throughout the product's life cycle. Different, yet related, benefit-risk assessment strategies and frameworks are being developed by various regulatory agencies, industry groups, and stakeholders. This paper summarizes current best practices and discusses the role of the pharmacoepidemiologist in these activities, taking a life-cycle approach to integrated Benefit-Risk Assessment, Communication, and Evaluation (BRACE). METHODS: A review of the medical and regulatory literature was performed for the following steps involved in therapeutic benefit-risk optimization: benefit-risk evidence generation; data integration and analysis; decision making; regulatory and policy decision making; benefit-risk communication and risk minimization; and evaluation. Feedback from International Society for Pharmacoepidemiology members was solicited on the role of the pharmacoepidemiologist. The case example of natalizumab is provided to illustrate the cyclic nature of the benefit-risk optimization process. RESULTS: No single, globally adopted benefit-risk assessment process exists. The BRACE heuristic offers a way to clarify research needs and to promote best practices in a cyclic and integrated manner and highlight the critical importance of cross-disciplinary input. Its approach focuses on the integration of BRACE activities for risk minimization and optimization of the benefit-risk profile. CONCLUSION: The activities defined in the BRACE heuristic contribute to the optimization of the benefit-risk profile of therapeutic products in the clinical world at both the patient and population health level. With interdisciplinary collaboration, pharmacoepidemiologists are well suited for bringing in methodology expertise, relevant research, and public health perspectives into the BRACE process.

Pitfalls in meta-analyses on adverse events reported from clinical trials.

In recent years, comparative effectiveness research has been more aggressively pursued as a means to improve health care, including systematic reviews and meta-analyses to inform health policy decision making. Because most clinical trials have pre-specified approaches to collecting data on efficacy, the value of systematic reviews and meta-analyses in assessing efficacy outcomes is generally accepted. In contrast, collection of data on adverse events is seldom well structured. Hence, the methodological considerations for comparing adverse events from such non-aligned sources differ substantially from those for comparing efficacy endpoints. We address several important pitfalls in performing systematic reviews and meta-analyses on adverse events in clinical trials, and we offer recommendations for remedies. Some pitfalls arise from the fact that adverse events often are not the primary endpoints in clinical trials, hence incomplete reporting, inconsistent event definitions, various level of effort in reporting unexpected adverse events, and inappropriate use of statistical testing. Others are posed by certain important characteristics of adverse events data. The very concept of "adverse events" may skew the ascertainment, attribution, and reporting of the events. In addition, problems for meta-analysis methods arise in situations involving zero or rare events and withdrawal or loss to follow-up because of adverse events. We highlight recent initiatives that may improve the assessment and cross-study summary of adverse events. We anticipate that future guidance for conducting systematic reviews and meta-analyses will evolve to address the important methodological pitfalls we highlight here, and the practice of assessing the totality of evidence on drug safety will be improved.

Single nucleotide polymorphisms in obesity-related genes and all-cause and cause-specific mortality: a prospective cohort study.

BACKGROUND: The aim of this study was to examine the associations between 16 specific single nucleotide polymorphisms (SNPs) in 8 obesity-related genes and overall and cause-specific mortality. We also examined the associations between the SNPs and body mass index (BMI) and change in BMI over time. METHODS: Data were analyzed from 9,919 individuals who participated in two large community-based cohort studies conducted in Washington County, Maryland in 1974 (CLUE I) and 1989 (CLUE II). DNA from blood collected in 1989 was genotyped for 16 SNPs in 8 obesity-related genes: monoamine oxidase A (MAOA), lipoprotein lipase (LPL), paraoxonase 1 and 2 (PON1 and PON2), leptin receptor (LEPR), tumor necrosis factor-alpha (TNFalpha), and peroxisome proliferative activated receptor-gamma and -delta (PPARG and PPARD). Data on height and weight in 1989 (CLUE II baseline) and at age 21 were collected from participants at the time of blood collection. All participants were followed from 1989 to the date of death or the end of follow-up in 2005. Cox proportional hazards regression was used to obtain the relative risk (RR) estimates and 95% confidence intervals (CI) for each SNP and mortality outcomes. RESULTS: The results showed no patterns of association for the selected SNPs and the all-cause and cause-specific mortality outcomes, although statistically significant associations (p < 0.05) were observed between PPARG rs4684847 and all-cause mortality (CC: reference; CT: RR 0.99, 95% CI 0.89, 1.11; TT: RR 0.60, 95% CI 0.39, 0.93) and cancer-related mortality (CC: reference; CT: RR 1.01, 95% CI 0.82, 1.25; TT: RR 0.22, 95% CI 0.06, 0.90) and TNFalpha rs1799964 and cancer-related mortality (TT: reference; CT: RR 1.23, 95% CI 1.03, 1.47; CC: RR 0.83, 95% CI 0.54, 1.28). Additional analyses showed significant associations between SNPs in LEPR with BMI (rs1137101) and change in BMI over time (rs1045895 and rs1137101). CONCLUSION: Findings from this cohort study suggest that the selected SNPs are not associated with overall or cause-specific death, although several LEPR SNPs may be related to BMI and BMI change over time.

Genetic polymorphisms of estrogen receptors alpha and beta and the risk of developing prostate cancer.

Estrogen may be involved in the development of prostate cancer. The association between genetic polymorphisms of estrogen receptors alpha (ESR1) and beta (ESR2) and prostate cancer risk was examined in a nested case-control study in Washington County, Maryland. Incident prostate cancer cases (n = 269) were matched to one or two controls (n = 440) by age, sex, race, and date of blood donation. Associations between estrogen receptor genotypes or dietary intake and the development of prostate cancer were examined in conditional logistic regression models. Results from this study showed that six single base-pair polymorphisms (SNPs) of ESR1 (rs1801132, rs2077647, rs746432, rs2273206, rs851982, rs2228480) and four SNPs of ESR2 (rs4986938, rs928554, rs8018687, rs number not available for ESR2 5696 bp 3' of STP A>G) were not significantly associated with prostate cancer risk, either by allelic or genotypic frequencies. However, an interactive association with BMI was observed in the relationship between prostate cancer risk and genotypes of ESR2 38 bp 3' of STP G>A (rs4986938) (p = 0.031). An interaction between intake level of phytoestrogen and genotypes of ESR1 Ex1-192G>C (rs746432) and between intake level of phytoestrogen and genotypes of ESR1 Ex8+229G>A (rs2228480) and risk of prostate cancer was observed (p = 0.0009 and p = 0.044, respectively). In conclusion, selected genetic polymorphisms of ESR1 and ESR2, overall, were not associated with prostate cancer risk. However, a variation in risk by BMI and phytoestrogen intake was implicated.

The risk of developing lung cancer associated with antioxidants in the blood: ascorbic acids, carotenoids, alpha-tocopherol, selenium, and total peroxyl radical absorbing capacity.

Lung cancer cases diagnosed during the period 1975 through 1993 and matched controls were identified in the rosters of Washington County, Maryland residents who had donated blood for a serum bank in 1974 or 1989. Plasma from participants in the 1989 project was assayed for ascorbic acid; serum or plasma was assayed for participants in either project for alpha- and beta-carotene, cryptoxanthin, lutein/zeaxanthin, lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity. Among the total group of 258 cases and 515 controls, serum/plasma concentrations were significantly lower among cases than controls for cryptoxanthin, beta-carotene, and lutein/zeaxanthin with case-control differences of -25.5, -17.1, and -10.1%, respectively. Modest nonsignificant case-control differences in a protective direction were noted for alpha-carotene and ascorbic acid. There were only trivial differences for lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity. Findings are reported for males and females and for persons who had never smoked cigarettes, former smokers, and current smokers at baseline. These results and those from previous studies suggest that beta-carotene is a marker for some protective factor(s) against lung cancer; that cryptoxanthin, alpha-carotene, and ascorbic acid need to be investigated further as potentially protective factors or associates of a protective factor; and that lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity are unlikely to be associated with lung cancer risk. Until specific preventive factors are identified, the best protection against lung cancer is still the avoidance of airborne carcinogens, especially tobacco smoke; second best is the consumption of a diet rich in fruits and vegetables.

A community-based study of cigarette smoking behavior in relation to variation in three genes involved in dopamine metabolism: Catechol-O-methyltransferase (COMT), dopamine beta-hydroxylase (DBH) and monoamine oxidase-A (MAO-A).

OBJECTIVE: Cigarette smoking behavior may be influenced by catechol-O-methlyltransferase (COMT), dopamine beta-hydroxylase (DBH), and monamine oxidase-A (MAO-A), genes that play roles in dopamine metabolism. The association between common polymorphisms of these genes and smoking behavior was assessed among 10,059 Caucasian volunteers in Washington County, MD in 1989. METHODS: Age-adjusted logistic regression was used to measure the association between variants of these single nucleotide polymorphisms and smoking initiation and persistent smoking. RESULTS: Overall, no association was seen between each genotype and smoking behavior. However, among younger (<54 years) women, the COMT GG genotype was positively associated with smoking initiation (OR=1.3; 95% CI: 1.0 1.5), and the MAO-A TT genotype was inversely associated with persistent smoking (OR=0.7; 95% CI: 0.4, 1.0). Men who smoked fewer than 10 cigarettes per day were more likely to be persistent smokers if they had the COMT GG (OR=1.7; 95% CI: 1.0, 2.9) or the DBH GG (OR=1.6; 95% CI: 1.0, 2.5) genotypes. CONCLUSION: Overall the results of this large community-based study do not provide evidence to support the presence of important associations between variants of COMT, DBH, or MAO-A and smoking initiation or persistent smoking.

Single nucleotide polymorphisms in inflammation-related genes and mortality in a community-based cohort in Washington County, Maryland.

The purpose of this study was to examine the associations between single nucleotide polymorphisms (SNPs) in genes controlling inflammatory processes and mortality. Data were analyzed from 9,933 individuals who participated in two large community-based cohort studies conducted in Washington County, Maryland, in 1974 and 1989, designated "CLUE I" and "CLUE II," respectively. DNA from blood collected in 1989 was genotyped for 47 SNPs in 23 inflammation-related genes, including interferon-gamma (IFNgamma), lymphotoxin-alpha (LTalpha), tumor necrosis factor-alpha (TNFalpha), C-reactive protein (CRP), peroxisome proliferator-activated receptor (PPAR), and the human endothelial nitric oxide synthase (eNOS). All participants were followed from 1989 to the date of death or to June 20, 2005. The results showed no observable patterns of association for the SNPs and the all-cause and cause-specific mortality outcomes, although statistically significant associations were observed between at least one mortality outcome and SNPs in eNOS (reference SNP (rs) 1799983), PPARG (rs4684847), CRP (rs2794521), IFNgamma (rs2069705), TNFalpha (rs1799964), and LTalpha (rs2229094). Additionally, three of the four examined CRP SNPs were strongly associated with CRP serum concentration among those with CRP measurements. The authors' findings from this community-based prospective cohort study suggest that the selected SNPs are not associated with overall or cause-specific death, although CRP genotypes may be associated with systemic inflammation.

Genetic polymorphisms of peroxisome proliferator-activated receptors and the risk of cardiovascular morbidity and mortality in a community-based cohort in washington county, Maryland.

The primary aim of this study was to examine prospectively the associations between 5 peroxisome proliferator-activated receptor (PPAR) single nucleotide polymorphisms (SNPs) and cardiovascular morbidity and mortality in a community-based cohort study in Washington County, Maryland. Data were analyzed from 9,364 Caucasian men and women participating in CLUE-II. Genotyping on 5 PPAR polymorphisms was conducted using peripheral DNA samples collected in 1989. The followup period was from 1989 to 2003. The results showed that there were no statistically significant associations between the PPAR SNPs and cardiovascular deaths or events. In contrast, statistically significant age-adjusted associations were observed for PPARG rs4684847 with both baseline body mass and blood pressure, and for PPARG rs709158, PPARG rs1175543, and PPARD rs2016520 with baseline cholesterol levels. Future studies should be conducted to confirm these findings and to explore the associations in populations with greater racial and ethnic diversity.

Measurement of cyclin E genomic copy number and strand length in cell-free DNA distinguish malignant versus benign effusions.

PURPOSE: Previous studies have shown that the concentration of cell-free DNA was higher and its strand length longer in body fluids obtained from patients with cancer as compared to patients with benign diseases. We hypothesized that analysis of both DNA copy number and strand length of cell-free DNA from an amplified chromosomal region could improve the diagnosis of malignant diseases in body fluids. EXPERIMENTAL DESIGN: To test this hypothesis, we used ovarian cancer effusion as an example and applied a quantitative real-time PCR to measure the relative copy number and strand length of DNA fragments from one of the most frequently amplified genes, cyclin E, in ovarian serous carcinomas. RESULTS: As compared with nonamplified chromosomal loci, including beta-actin, p53, 2p24.1, and 4p15.31, measurement of cyclin E DNA copy number (100 bp) had the best performance in distinguishing malignant (n = 88) from benign (n = 70) effusions after normalization to effusion volume or Line-1 DNA with areas under the receiver operating characteristics curve (AUC) of 0.832 and 0.847, respectively. Different DNA lengths of the cyclin E locus were further analyzed and we found that the AUC was highest by measuring the 400-bp cyclin E locus (AUC = 0.896). The AUC was improved to 0.936 when it was combined with the length integrity index as defined by the relative abundance of 400 bp cyclin E to 100 bp p53 loci. Cyclin E real-time PCR assay had a higher sensitivity (95.6%) than routine cytology examination (73.9%) and was able to diagnose false-negative cytology cases in this study. CONCLUSIONS: The above findings indicate that measurement of the DNA copy number and strand length of the cyclin E locus is a useful cancer diagnostic tool.

Body mass, polymorphisms in obesity-related genes, and the risk of developing breast cancer among women with benign breast disease.

BACKGROUND: A cohort study was conducted among post-menopausal women to determine whether genetic polymorphisms in selected obesity-related genes (PPARG, LPL, LEPR, PON1, PON2, TNF-alpha) were associated with the progression of benign breast disease (BBD) to breast cancer and whether the selected polymorphisms modified the association between body mass and breast cancer among women with BBD. METHODS: Among participants in an ongoing cohort study, 994 Caucasian post-menopausal women had a breast biopsy for BBD. Of these women, 61 subsequently developed breast cancer. A short questionnaire was administered at baseline in 1989. Genotypes were determined using DNA extracted from blood collected in 1989. RESULTS: In this cohort, body mass index (BMI) was positively associated with the risk of developing breast cancer. In contrast, polymorphisms in PON1 (Gln192Arg) and LEPR (IVS2+6920) were associated with a decreased risk of developing invasive breast cancer. No statistically significant associations were observed for polymorphisms in PPARG, PON2, LPL, or TNF and breast cancer risk or for interactions between the polymorphisms and BMI and breast cancer risk. CONCLUSIONS: The findings suggest that specific polymorphisms in the PON1 and LEPR genes may play a role in progression of BBD to breast cancer among post-menopausal Caucasian women.

Frequencies of single nucleotide polymorphisms in genes regulating inflammatory responses in a community-based population.

BACKGROUND: Allele frequencies reported from public databases or articles are mostly based on small sample sizes. Differences in genotype frequencies by age, race and sex have implications for studies designed to examine genetic susceptibility to disease. In a community-based cohort of 9,960 individuals, we compared the allele frequencies of 49 single nucleotide polymorphisms (SNPs) of genes involved in inflammatory pathways to the frequencies reported on public databases, and examined the genotypes frequencies by age and sex. The genes in which SNPs were analyzed include CCR2, CCR5, COX1, COX2, CRP, CSF1, CSF2, IFNG, IL1A, IL1B, IL2, IL4, IL6, IL8, IL10, IL13, IL18, LTA, MPO, NOS2A, NOS3, PPARD, PPARG, PPARGC1 and TNF. RESULTS: Mean(SD) age was 53.2(15.5); 98% were Caucasians and 62% were women. Only 1 out of 33 SNPs differed from the SNP500Cancer database in allele frequency by >10% in Caucasians (n = 9,831), whereas 12 SNPs differed by >10% (up to 50%) in African Americans (n = 105). Two out of 15 SNPs differed from the dbSNP database in allele frequencies by >10% in Caucasians, and 5 out of 15 SNPs differed by >10% in African Americans. Age was similar across most genotype groups. Genotype frequencies did not differ by sex except for TNF(rs1799724), IL2(rs2069762), IL10(rs1800890), PPARG(rs1801282), and CRP(rs1800947) with differences of less than 4%. CONCLUSION: When estimating the size of samples needed for a study, particularly if a reference sample is used, one should take into consideration the size and ethnicity of the reference sample. Larger sample size is needed for public databases that report allele frequencies in non-Caucasian populations.

The efficacy and safety of multivitamin and mineral supplement use to prevent cancer and chronic disease in adults: a systematic review for a National Institutes of Health state-of-the-science conference.

BACKGROUND: Multivitamin and mineral supplements are the most commonly used dietary supplements in the United States. PURPOSE: To synthesize studies on the efficacy and safety of multivitamin/mineral supplement use in primary prevention of cancer and chronic disease in the general population. DATA SOURCES: English-language literature search of the MEDLINE, EMBASE, and Cochrane databases through February 2006 and hand-searching of pertinent journals and articles. STUDY SELECTION: Randomized, controlled trials in adults were reviewed to assess efficacy, and randomized, controlled trials and observational studies in adults or children were reviewed to assess safety. DATA EXTRACTION: Paired reviewers extracted data and independently assessed study quality. DATA SYNTHESIS: 12 articles from 5 randomized, controlled trials that assessed efficacy and 8 articles from 4 randomized, controlled trials and 3 case reports on adverse effects were identified. Study quality was rated fair for the studies on cancer, cardiovascular disease, cataracts, or age-related macular degeneration and poor for the studies on hypertension. In a poorly nourished Chinese population, combined supplementation with beta-carotene, alpha-tocopherol, and selenium reduced the incidence of and mortality rate from gastric cancer and the overall mortality rate from cancer by 13% to 21%. In a French trial, combined supplementation with vitamin C, vitamin E, beta-carotene, selenium, and zinc reduced the rate of cancer by 31% in men but not in women. Multivitamin and mineral supplements had no significant effect on cardiovascular disease or cataracts, except that combined beta-carotene, selenium, alpha-tocopherol, retinol, and zinc supplementation reduced the mortality rate from stroke by 29% in the Linxian study and that a combination of 7 vitamins and minerals stabilized visual acuity loss in a small trial. Combined zinc and antioxidants slowed the progression of advanced age-related macular degeneration in high-risk persons. No consistent adverse effects of multivitamin and mineral supplements were evident. LIMITATIONS: Only randomized, controlled trials were considered for efficacy assessment. Special nutritional needs, such as use of folic acid by pregnant women to prevent birth defects, were not addressed. Findings may not apply to use of commercial multivitamin supplements by the general U.S. population. CONCLUSIONS: Evidence is insufficient to prove the presence or absence of benefits from use of multivitamin and mineral supplements to prevent cancer and chronic disease.

Nonsteroidal antiinflammatory drugs, cyclooxygenase polymorphisms, and the risk of developing breast carcinoma among women with benign breast disease.

BACKGROUND: Biopsy-proven benign breast disease (BBD) is a risk factor for developing breast carcinoma; however, to the authors' knowledge, little is known regarding factors related to progression to carcinoma. A cohort study was conducted to examine the role of cyclooxygenase (COX) polymorphisms and nonsteroidal anti-inflammatory drugs (NSAIDs) in the progression of BBD to breast carcinoma. METHODS: Among participants in an ongoing cohort study, 1467 women underwent a breast biopsy for BBD. Of these women, 91 subsequently developed breast carcinoma. Medication data were collected in 1989 and in 1996. COX genotypes were determined using DNA extracted from blood specimens collected in 1989. RESULTS: A decrease in breast carcinoma risk was observed among women who reported using aspirin in 1989 (odds ratio [OR] of .46; 95% confidence interval [95% CI], .22-.98) and in 1996 (OR of .47, 95% CI, .18-1.21). Furthermore, a higher frequency, dose, and longer duration of aspirin use were associated with a decrease in the odds of developing breast carcinoma. Overall, no association was observed between COX genotypes and the subsequent development of breast carcinoma. However, among women not using NSAIDs, one COX-2 polymorphism (rs2143416) was found to be significantly associated with the development of breast carcinoma. CONCLUSIONS: Findings from the current study suggest that inflammation through COX-2 pathways may play a role in the progression of BBD to breast carcinoma and that aspirin may help to lower the risk of progression to breast carcinoma among women with BBD.

C47T polymorphism in manganese superoxide dismutase (MnSOD), antioxidant intake and survival.

INTRODUCTION AND OBJECTIVE: Manganese superoxide dismutase (MnSOD), an enzyme that catalyzes superoxide radical quenching, is hypothesized to protect against premature aging. A C47T transition in the MnSOD gene may affect the enzyme's distribution to the mitochondrion, a site of high oxidative stress. We examined the association between this polymorphism and survival. METHODS: Individuals who donated a blood sample to the CLUE I and II campaigns in 1974 and 1989, respectively, and completed a food frequency questionnaire in 1989 (N=6151) were included in the analysis. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated by Cox proportional hazards models. Mortality follow-up extended from 1989 to 2002. RESULTS: MnSOD genotype distributions were 27% CC (wildtype homozygotes), 50% CT (heterozygotes) and 23% TT (variant homozygotes). TT and CT genotypes compared to the CC genotype were not associated with all-cause or cardiovascular disease mortality. A slight, but non-statistically significant higher risk of cancer mortality was observed for the CT (HR=1.13, 95% CI: 0.86-1.49) and TT (HR=1.24, 95% CI: 0.90-1.70) genotypes compared to CC genotype (p-trend=0.19). CONCLUSION: We did not observe an association between the C47T polymorphism in the MnSOD gene and survival. These null associations were not modified by fruit and vegetable intake, cigarette smoking status, or body mass index.