The CHEK2*1100delC allelic variant and risk of breast cancer: screening results from the Breast Cancer Family Registry.

CHEK2, a serine-threonine kinase, is activated in response to agents, such as ionizing radiation, which induce DNA double-strand breaks. Activation of CHEK2 can result in cell cycle checkpoint arrest or apoptosis. One specific variant, CHEK2*1100delC, has been associated with an increased risk of breast cancer. In this population-based study, we screened 2,311 female breast cancer cases and 496 general population controls enrolled in the Ontario and Northern California Breast Cancer Family Registries for this variant (all controls were Canadian). Overall, 30 cases and one control carried the 1100delC allele. In Ontario, the weighted mutation carrier frequency among cases and controls was 1.34% and 0.20%, respectively [odds ratio (OR), 6.65; 95% confidence interval (95% CI), 2.37-18.68]. In California, the weighted population mutation carrier frequency in cases was 0.40%. Across all cases, 1 of 524 non-Caucasians (0.19%) and 29 of 1,775 Caucasians (1.63%) were mutation carriers (OR, 0.12; 95% CI, 0.02-0.89). Among Caucasian cases >45 years age at diagnosis, carrier status was associated with history of benign breast disease (OR, 3.18; 95% CI, 1.30-7.80) and exposure to diagnostic ionizing radiation (excluding mammography; OR, 3.21; 95% CI, 1.13-9.14); compared with women without exposure to ionizing radiation, the association was strongest among women exposed >15 years before diagnosis (OR, 4.28; 95% CI, 1.50-12.20) and among those who received two or more chest X-rays (OR, 3.63; 95% CI, 1.25-10.52). These data supporting the biological relevance of CHEK2 in breast carcinogenesis suggest that further studies examining the joint roles of CHEK2*1100delC carrier status and radiation exposure may be warranted.

[Clinical significance of subchorionic and retroplacental hematomas detected in the first trimester of pregnancy]. / A subchorialis és retroplacentaris haematomák szülészeti következményei.

AIMS: To evaluate the long-term clinical significance of intrauterine hematomas detected in the first trimester of pregnancy in a general obstetric population. METHODS: A prospective study was designed to compare the perinatal outcome in 187 pregnant women with intrauterine hematomas to 6488 controls in which hematomas were not detected at first trimester by ultrasound examination. RESULTS: The incidence of intrauterine hematoma in the first trimester in a general obstetric population was 3.1%. A retroplacental position of the hematoma was significantly correlated with an increased risk for adverse maternal and neonatal complications. The presence or absence of symptoms of threatened abortion did not affect these outcomes. The rates of operative vaginal delivery (RR: 1.9; CI: 1.1-3.2) and cesarean section (RR: 1.4; CI: 1.1-1.8) were significantly greater in the hematoma group as compared to the control group, as well as the rates of pregnancy induced hypertension (RR: 2.1; CI: 1.5-2.9) and preeclampsia (RR: 4.0; CI: 2.4-6.7). Placental abruption (RR: 5.6; CI: 2.8-11.1), and the incidence of placental separation abnormalities was also significantly more frequent in the hematoma group (RR: 3.2; CI: 2.2-4.7). Perinatal complications, including the rate of preterm delivery (RR: 2.3; CI: 1.6-3.2), intrauterine growth restriction (RR: 2.4; CI: 1.4-4.1), fetal distress (RR: 2.6; CI: 1.9-3.5), meconium stained amniotic fluid (RR: 2.2; CI: 1.7-2.9), and NICU admission (RR: 5.6; CI: 4.1-7.6) were also significantly increased in this group. Furthermore, the frequency of intrauterine demise and perinatal mortality was increased in the hematoma group, but this difference did not reach statistical significance (p = 0.6 and p = 0.2). CONCLUSION: The authors' study suggests that the presence of an intrauterine hematoma during the first trimester may identify a population of patients at increased risk for adverse pregnancy outcome.

Yield of laboratory testing to identify secondary contributors to osteoporosis in otherwise healthy women.

Our purpose in this study was to determine the prevalence of undetected disorders of bone and mineral metabolism in women with osteoporosis and to identify the most useful and cost-efficient screening tests to detect these disorders. A cross-sectional study was conducted among 664 postmenopausal women with osteoporosis at the Osteoporosis and Metabolic Bone Disease Program at the Mount Sinai Hospital in New York between January 1992 and June 1996. Women without a history of diseases or medications known to adversely affect bone who completed extensive laboratory testing including complete blood count, chemistry profile, 24-h urinary calcium, 25(OH)vitamin D, and PTH were included. Among 173 women who met the inclusion criteria for the study, previously undiagnosed disorders of bone and mineral metabolism were identified in 55 women (32%). Disorders of calcium metabolism and hyperparathyroidism were the most frequent diagnoses. A testing strategy involving measurement of 24-h urine calcium, serum calcium, and serum PTH for all women and serum TSH among women on thyroid replacement therapy would have been sufficient to diagnose 47 of these 55 women (85%) at an estimated cost of $75 per patient screened. Previously undiagnosed disorders affecting the skeleton are common in otherwise healthy women with low bone density. A simple testing strategy is likely to identify most such disorders.

Characteristics of pubertal development in a multi-ethnic population of nine-year-old girls.

PURPOSE: Early age at menarche increases future disease risk. Secular decline in age at menarche has been attributed to body size characteristics, diet, and energy expenditure. Risk factors for puberty have been less frequently explored. METHODS: A cross-sectional study of 186 New York Metropolitan Area, 9-year-old girls (54 African-American, 70 Hispanic, 62 Caucasians) used interviewer-administered questionnaires to assess exposures. Height and weight were measured. Pediatricians assessed pubertal development according to Tanner stages. RESULTS: African-Americans were more likely than Caucasians to have achieved puberty as determined by breast or hair development (stage 2 or higher) [age-adjusted odds ratios and 95% confidence intervals = 4.91 (2.15-11.19) and 4.25 (1.85-9.77), respectively]. Pubertal development was similar among Hispanics and Caucasians. Adiposity and height were significantly positively associated with breast or hair development. More sedentary activity hours non-significantly increased the likelihood of hair development. Lower energy, but higher polyunsaturated fat, consumption were suggestive of an association with breast development. Vitamin C and hair development were inversely related. No other nutrients or physical activity measures were related to pubertal development. CONCLUSIONS: Results are consistent with height and adiposity being associated with pubertal development. Sedentary activity or diet might possibly influence maturation.

Prospective study of blood and tibia lead in women undergoing surgical menopause.

Despite the dramatic decline in environmental lead exposure in the United States during the past couple of decades, concern has been expressed regarding mobilization during menopause of existing lead stored in bone. To investigate whether bone lead concentrations decrease and blood lead levels increase, we conducted a prospective study of 91 women who were scheduled to undergo a bilateral oophorectomy for a benign condition at Mount Sinai Hospital in New York City during October 1994 through April 1999. We excluded women who were younger than 30 years of age or who were postmenopausal at the time of the surgery. We observed a small but significant increase in median blood lead levels between the baseline visit and the 6-month visit (0.4 microg/dL, p<0.0001), particularly for women who were not on estrogen replacement therapy (0.7 microg/dL, p=0.008). No significant change was observed in blood lead values between 6 and 18 months postsurgery, nor was there evidence of significant changes in tibia lead concentrations during the follow-up period. These findings do not point to substantial mobilization of lead from cortical bone during menopause.

Exposure to indoor pesticides during pregnancy in a multiethnic, urban cohort.

Evidence is growing that indoor pesticide exposure is of considerable magnitude in the United States and that pesticide concentrations may be especially high in urban areas. Of particular concern is exposure of pregnant women because animal data suggest that exposure to pesticides during pregnancy and early life may impair neurodevelopment in the offspring. To investigate the relationship between prenatal exposure to indoor pesticides and infant growth and development, we are conducting a prospective, multiethnic cohort study of mothers and infants delivered at Mount Sinai Hospital in New York City. This article provides data on pesticide exposure based on questionnaire items and analysis of maternal urinary metabolite levels among 386 women. Both the questionnaire and laboratory data revealed that exposure to indoor pesticides was considerable. The proportion of women estimated from questionnaire data as having been exposed during pregnancy to indoor pesticides (approximately 70%) was somewhat lower than the 80-90% of American households who reportedly used pesticides in previous surveys, but some of the latter surveys included both indoor and outdoor pesticide use. Urinary metabolite levels of 3,5,6-trichloro-2-pyridinol (TCPy; median = 11.3 micro g/g creatinine), phenoxybenzoic acid (PBA; median =19.3 micro g/g creatinine), and pentachlorophenol (PCP; median =7.3 micro g/g creatinine) were higher than those reported in other studies of adults in the United States. Furthermore, no associations were evident between the pesticide questionnaire data and the urinary metabolites. Assessments of sociodemographic and building characteristics with questionnaire data and the metabolite levels revealed no consistent trends. Significant temporal variations were observed for urinary PBA but not TCPy or PCP. The temporal variations for PBA were consistent with seasonal spraying of pyrethroid pesticides. These data underscore the need to assess the potentially adverse effects of pesticide exposure on fetuses and infants and the importance of finding alternative methods for pest management to reduce pesticide exposures.

In utero pesticide exposure, maternal paraoxonase activity, and head circumference.

Although the use of pesticides in inner-city homes of the United States is of considerable magnitude, little is known about the potentially adverse health effects of such exposure. Recent animal data suggest that exposure to pesticides during pregnancy and early life may impair growth and neurodevelopment in the offspring. To investigate the relationship among prenatal pesticide exposure, paraoxonase (PON1) polymorphisms and enzyme activity, and infant growth and neurodevelopment, we are conducting a prospective, multiethnic cohort study of mothers and infants delivered at Mount Sinai Hospital in New York City. In this report we evaluate the effects of pesticide exposure on birth weight, length, head circumference, and gestational age among 404 births between May 1998 and May 2002. Pesticide exposure was assessed by a prenatal questionnaire administered to the mothers during the early third trimester as well as by analysis of maternal urinary pentachlorophenol levels and maternal metabolites of chlorpyrifos and pyrethroids. Neither the questionnaire data nor the pesticide metabolite levels were associated with any of the fetal growth indices or gestational age. However, when the level of maternal PON1 activity was taken into account, maternal levels of chlorpyrifos above the limit of detection coupled with low maternal PON1 activity were associated with a significant but small reduction in head circumference. In addition, maternal PON1 levels alone, but not PON1 genetic polymorphisms, were associated with reduced head size. Because small head size has been found to be predictive of subsequent cognitive ability, these data suggest that chlorpyrifos may have a detrimental effect on fetal neurodevelopment among mothers who exhibit low PON1 activity.

Clinical significance of subchorionic and retroplacental hematomas detected in the first trimester of pregnancy.

OBJECTIVE: To evaluate the long-term clinical significance of intrauterine hematomas detected in the first trimester of pregnancy in a general obstetric population. METHODS: A prospective study was designed to compare perinatal outcomes in 187 pregnant women with intrauterine hematomas and 6488 controls in whom hematomas were not detected at first-trimester ultrasonographic examination. RESULTS: The incidence of intrauterine hematoma in the first trimester in a general obstetric population was 3.1%. A retroplacental position of the hematoma was significantly correlated with an increased risk for adverse maternal and neonatal complications. The presence or absence of symptoms of threatened abortion did not affect these outcomes. The rates of operative vaginal delivery (relative risk [RR] 1.9; confidence interval [CI] 1.1, 3.2) and cesarean delivery (RR 1.4; CI 1.1, 1.8), as well as the rates of pregnancy-induced hypertension (RR 2.1; CI 1.5, 2.9) and preeclampsia (RR 4.0; CI 2.4, 6.7), were significantly greater in the hematoma group. Placental abruption (RR 5.6; CI 2.8, 11.1) and placental separation abnormalities (RR 3.2; CI 2.2, 4.7) were also significantly more frequent in the hematoma group. Perinatal complications, including the rate of preterm delivery (RR 2.3; CI 1.6, 3.2), fetal growth restriction (RR 2.4; CI 1.4, 4.1), fetal distress (RR 2.6; CI 1.9, 3.5), meconium-stained amniotic fluid (RR 2.2; CI 1.7, 2.9), and neonatal intensive care unit admission (RR 5.6; CI 4.1, 7.6), were also significantly increased in this group. Furthermore, the frequency of intrauterine demise and perinatal mortality was increased in the hematoma group, but this difference did not reach statistical significance (Ps =.6 and.2). CONCLUSION: Our study suggests that the presence of an intrauterine hematoma during the first trimester may identify a population of patients at increased risk for adverse pregnancy outcome.

Is discordant growth in twins an independent risk factor for adverse neonatal outcome?

OBJECTIVE: To estimate whether discordant growth is associated with adverse perinatal outcomes in twins after adjusting for growth restriction. METHODS: This was a retrospective, hospital-based cohort study of twin gestations with 2 live births delivered at 24 weeks or later from 1992 to 2001. Twin gestations were classified as small for gestational age (SGA) if one or both infants was less than the 10th percentile at birth by singleton Brenner norms and discordant if there was a 20% or more weight discordance. RESULTS: Of 1318 twin pairs, 856 were appropriate for gestational age (AGA) and concordant, 70 pairs were AGA and discordant, 254 pairs were SGA and concordant, and 138 pairs were SGA and discordant. The 4 groups had similar maternal demographics and medical comorbidity. When adjusting for chorionicity, antenatal steroid use, oligohydramnios, preeclampsia, and gestational age at delivery, discordant twins were more likely to have a cesarean delivery (odds ratio 1.87; 95% confidence interval 1.22, 2.87) and to be associated with some adverse neonatal outcomes (low and very low birthweight, neonatal intensive care unit admission, neonatal oxygen requirement and hyperbilirubinemia) independent of SGA status. A statistically nonsignificant trend (odds ratio 2.4; 95% confidence interval 0.99, 6.01) toward higher rates of intraventricular hemorrhage was noted in discordant twins, and no difference was seen for ventilator requirement, respiratory distress syndrome, or necrotizing enterocolitis. CONCLUSION: Discordance places twins at increased risk for some adverse perinatal outcomes, whether they are AGA or SGA. Discordance was not an independent risk factor for serious neonatal morbidity or mortality; however, this study was underpowered to detect those differences.

Race, cardiovascular reactivity, and preterm delivery among active-duty military women.

BACKGROUND: Rates of preterm delivery in the United States are higher in black women compared with whites. In this study, we examined cardiovascular reactivity and risk of preterm delivery among black and white military women. METHODS: We recruited a total of 500 black and white active-duty military women from the prenatal clinic at a large military installation, interviewing them early in pregnancy and again at 28 weeks of gestation. A subgroup of women underwent a computerized stress test to determine cardiovascular reactivity assessed as increases in heart rate and blood pressure compared with measurements taken before the stress test. RESULTS: Despite a relatively low overall risk of preterm delivery (8.2%), we found the same 2-fold racial disparity reported in other populations (hazard ratio for preterm delivery in black women vs whites = 2.30; 95% confidence interval = 1.24-4.27). The disparity is present in all military ranks and is largest for medically indicated preterm deliveries. Among the 313 subjects who participated in the computerized stress testing, blacks exhibited more cardiac reactivity than whites. In black subjects only, a 1-mm increase in diastolic blood pressure reactivity was associated with 1.1 a day earlier delivery (-0.17 weeks). A similar trend was seen with heart rate. CONCLUSIONS: Autonomic dysfunction after exposure to stressors may play a role in the timing of delivery among black women.

Factors influencing mortality among young women with second primary breast carcinoma.

BACKGROUND: Tumor characteristics are strong predictors of survival among women with breast carcinoma, yet the variability in prognosis among women presenting with similar stages suggests other factors may also play an important role. We examine the prognostic significance of etiologic risk factors for breast carcinoma to determine whether factors that influence the development of breast carcinoma also affect the course of the disease among a prospective cohort of young women with bilateral breast carcinoma. METHODS: The 369 U.S. women included in this study were from the Cancer and Steroid Hormone Study who were diagnosed with an invasive first primary breast carcinoma between 1980 and 1982 and a second primary breast carcinoma before 1999. Cox proportional hazards models were used to evaluate factors known and suspected to be associated with breast carcinoma and with survival, based on reporting at the time of the first primary. RESULTS: One hundred sixty women died during the 16-18-year follow-up period. The adjusted 1, 5, 10, and 15-year survival rates following diagnosis of second primary breast carcinoma were 94%, 70%, 55%, and 49%, respectively. Survival rates werepoorest among the youngest women, those diagnosed with a second primary within 5 years of their first, poor African American women, women with either primary diagnosed at a later stage, those with less than 12 years of school, single women, and those with major weight gain between age 18 and adulthood. CONCLUSIONS: This study provided little evidence that important etiologic factors for breast carcinoma predict mortality following diagnosis of a second primary breast carcinoma.

The descriptive epidemiology of second primary breast cancer.

BACKGROUND: It is well established that the incidence rates of first primary breast cancer have been increasing over time. In contrast, the incidence rates of second primary breast cancer are largely undocumented. This study describes the epidemiology of second primary breast cancer among a population-based cohort of 305,533 U.S. women diagnosed with breast cancer between 1973 and 1998. METHODS: We compared age-specific incidence rates for overall and second primary breast cancer according to year of diagnosis and demographic and tumor characteristics. RESULTS: Overall, age-specific rates of breast cancer increased with increasing age and year of diagnosis, whereas incidence of second primary breast cancer peaked among young women and declined after 1988. Consistent with what is known about genetic susceptibility to breast cancer, at every age the rate of second primaries was greater than the overall rate; among women age 20 to 29 years the rate of second primary was more than 100 times greater. Although overall age-specific rates of breast cancer for African-American women were lower than for whites, rates of second primaries were higher. Women with a first primary that was either lobular or medullary had a greater likelihood of developing a second primary, although, there were relatively few with these histologic types. CONCLUSIONS: The pattern of incidence rates for first and second primary breast cancer differ markedly over time and by age.

Detection of antibody-mediated reduction of annexin A5 anticoagulant activity in plasmas of patients with the antiphospholipid syndrome.

Annexin A5 (A5) forms 2-dimensional crystals over phospholipid bilayers, blocking their availability for coagulation reactions. Recently, human antiphospholipid (aPL) monoclonal antibodies (mAbs) have been demonstrated by atomic force microscopy (AFM) to disrupt this crystallization and accelerate coagulation. We therefore performed a study with small, well-defined groups of patients to investigate whether these effects on A5 binding and activity are also detectable in plasmas from patients with the aPL syndrome. A5 binding to phospholipid was significantly reduced by plasmas of patients with the aPL syndrome and thromboembolism compared with healthy controls (mean +/- SD, 26.7 +/- 4.3 ng/well [n = 25] vs 30.5 +/- 3.1 ng/well [n = 20], P < .01) and the non-aPL thromboembolism group (29.9 +/- 3.2 ng/well [n = 15], P < .05). A5 anticoagulant activity was reduced by plasmas of patients with aPL syndrome and thromboembolism compared with aPL antibodies without thrombosis (182 +/- 31% [n = 25] vs 210 +/- 35% [n = 26], P < .01), non-aPL thromboembolism (229 +/- 16% [n = 15], P < .001), and healthy controls (231 +/- 14% [n = 30], P < .001). In conclusion, in accordance with recent AFM data with monoclonal human aPL antibodies, plasmas from patients with aPL antibodies with thromboembolism reduce both A5 binding to phospholipid and A5 anticoagulant activity. This "annexin A5 resistance" identifies a novel mechanism for thrombosis in the aPL syndrome.