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Activin A, a cytokine belonging to the transforming growth factor-β family, has been shown to play pivotal roles in tissue remodeling after renal injury and is present in elevated levels in diabetic patients. However, the association between activin A and albuminuria remains unclear. We aimed to evaluate their association by using cross-sectional data from community-dwelling middle-aged and older adults in Taiwan. We assessed 466 participants (67% male; mean age 71 ± 13 years) from the I-Lan Longitudinal Aging study for whom data pertaining to serum activin A level and urine albumin-to-creatinine ratio (UACR) were available. Of these, 323 (69%) had normal albuminuria, 123 (26%) had microalbuminuria, and 20 (4%) had overt albuminuria. Patients with overt albuminuria and microalbuminuria had significantly higher activin A concentrations than those in the normal albuminuria group (p

Cisplatin-based chemotherapy is the standard treatment for bladder urothelial carcinoma (UC). Most patients experience chemoresistance, the primary cause of treatment failure, which leads to disease relapse. The underlying mechanism of chemoresistance involves reduced apoptosis. In this study, we investigated the antitumor effect of the deubiquitylating enzyme inhibitor PR-619 in cisplatin-resistant bladder UC. Deubiquitinase (ubiquitin-specific protease 14 (USP14) and USP21) immunohistochemical staining demonstrated that deubiquitination is related to chemoresistance in patients with metastatic UC and may be a target for overcoming chemoresistance. Cytotoxicity and apoptosis were assessed using fluorescence-activated flow cytometry and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay, and PR-619 was found to enhance the cytotoxic and apoptotic effects of cisplatin in cisplatin-resistant T24/R cells. Mitigated cisplatin chemoresistance was associated with the concurrent suppression of c-Myc expression in T24/R cells. Moreover, the expression of c-Myc was upregulated in human bladder UC specimens from patients with chemoresistance. Experiments in a xenograft nude mouse model confirmed that PR-619 enhanced the antitumor effects of cisplatin. These results are promising for the development of therapeutic strategies to prevent UC chemoresistance through the combined use of chemotherapeutic agents/deubiquitination inhibitors (PR-619) by targeting the c-Myc pathway.

We studied the association of rectal dose with acute diarrhea in patients with gynecologic malignancies undergoing whole-pelvic (WP) intensity-modulated radiotherapy (IMRT). From June 2006 to April 2019, 108 patients with previous hysterectomy who underwent WP IMRT were enrolled in this cohort study. WP irradiation of 39.6&ndash, 45 Gy/22&ndash, 25 fractions was initially delivered to the patients. Common Terminology Criteria for Adverse Events (CTCAE) version 3 was used to evaluate acute diarrhea during radiotherapy. Small bowel volume at different levels of isodose curves (Vn%) and mean rectal dose (MRD) were measured for statistical analysis. The multivariate analysis showed that the MRD &ge, 32.75 Gy (p = 0.005) and small bowel volume of 100% prescribed (V100%) &ge, 60 mL (p = 0.008) were independent factors of Grade 2 or higher diarrhea. The cumulative incidence of Grade 2 or higher diarrhea at 39.6 Gy were 70.5%, 42.2%, and 15.0% (p &lt, 0.001) in patients with both high (V100% &ge, 60 mL and MRD &ge, 32.75 Gy), either high, and both low volume-dose factors, respectively. Strict constraints for the rectum/small bowel or image-guided radiotherapy to reduce these doses are suggested.

Heterogeneity of CD8 T cell play crucial roles in cancer patients and reveals the co-evolution between tumor and immunity. While CD127 expression identifies memory precursor cells during acute infections, the role of CD127 expression in defining memory T cell heterogeneity is not investigated. Here, we analyzed the Vβ-CDR3 usage of human effector memory TEM and TEMRA cells accompanied by functional and gene expression patterns based on surface CD127 expression. We found that, CD127hi subsets are associated with higher level of TCR diversity regardless of their TEM or TEMRA phenotype. CD127lo populations are presented with relatively low TCR repertoire diversity. Moreover, there is a high correlation between CD127hi and CD127lo populations which imply possible differentiation tract between CD127hi and CD127lo T cells, but not between TEM and TEMRA cells. On the other hand, both TEM and TEMRA CD127lo populations showed higher expression of effector genes including perforin, granzyme B, granzyme H, and pan-inhibitory killer immunoglobulin-like receptors, exhibited lower phenotype plasticity upon TCR activation and cytokine-driven proliferation, when compared to their CD127hi counterparts. In other words, depending on the expression of CD127, T cells from either TEM or TEMRA are similar in their gene expression and functionality patterns. These results provide the first evidence that T cell repertoire and gene expression signature can be uncoupled based on distinct CD127-dependent phenotype expression patterns but are delicately balanced in the memory T cell pool.

Background To evaluate the adverse events profile of oral prednisolone among adult asthma patients in the UK. Methods Using data from the UK-based Clinical Practice Research Datalink, we conducted a series of cohort studies to quantify incidence rates and incidence rate ratios, and a series of nested case-control analyses to estimate crude and adjusted odds ratios, of 11 different potential corticosteroid-related adverse events (bone-related conditions, hypertension, peptic ulcer, severe infections, herpes zoster, diabetes mellitus type 2, cataract, glaucoma, chronic kidney disease, affective disorders, and cardiovascular events). Results Between 165,900 and 269,368 asthma patients were included in each of the 11 cohorts, of whom between 836 and 16,192 developed an outcome of interest. Incidence rates per 1000 person-years of potential corticosteroid-related adverse events in patients with new current use of oral prednisolone ranged from 1.4 (95% confidence interval [CI], 1.0–1.8) for peptic ulcer to 78.0 (95% CI, 74.8–81.2) for severe infections. After adjusting for confounding, current oral prednisolone use was most strongly associated with an increased risk of severe infection, compared with non-use of prednisolone; OR 2.16 (95% CI, 2.05–2.27). There were smaller elevated risks of peptic ulcer, affective disorders, and cataract at higher doses, and marginally increased risks of herpes zoster, cardiovascular events, diabetes mellitus type 2, and bone related conditions, compared with non-use of prednisolone. We did not observe an association between oral prednisolone use and glaucoma, chronic kidney disease, or hypertension. Conclusion Oral prednisolone use is associated with infections, gastrointestinal, neuropsychiatric, ocular, cardiovascular, metabolic, and bone-related complications among adult asthma patients. Electronic supplementary material The online version of this article (10.1186/s12931-018-0742-y) contains supplementary material, which is available to authorized users.

Algorithm used to calculate current and past use in the cohort analysis. Schematic description of the cohort analysis. Overview on the extent of missing data to calculate current use exposure in each cohort. (PDF 327Â kb)

Flowchart of the study population. Detailed information on characteristics and co-medication of cases and controls for each outcome at the index date. (PDF 896Â kb)

MLN4924, a small molecule inhibitor of NEDD8 activating enzyme (NAE), has been reported to elicit an anti-tumor effect on various malignancies. In this study, we investigated the anti-tumor effect of MLN4924 in human urothelial carcinoma (UC) in vitro and in vivo by using three human UC cell lines of various grading (T24, NTUB1 and RT4). The impact of MLN4924 on UC cells was determined by measuring viability (MTT), proliferation (BrdU incorporation), cell cycle progression (flow cytometry with propidium iodide staining) and apoptosis (flow cytometry with annexin V-FITC labeling). The cell cycle regulatory molecules, apoptosis-related molecules, and cell stress-related proteins were examined by Western blotting. The influence of tumor cell migration and invasion was analyzed by Transwell and wound healing assays. We also evaluated the effects of MLN4924 on tumor growth by a SCID xenograft mouse model. The data show that MLN4924 induced dose-dependent cytotoxicity, anti-proliferation, anti-migration, anti-invasion and apoptosis in human UC cells, accompanied by activations of Bad, phospho-histone H2A.X, caspase-3, 7 and PARP, decreased level of phospho-Bcl2, and caused cell cycle retardation at the G2M phase. Moreover, MLN4924 activated endoplasmic reticulum stress-related molecules (caspase-4, phospho-eIF2α, ATF-4 and CHOP) and other stress responses (JNK and c-Jun activations). Finally, we confirmed MLN4924 inhibited tumor growth in a UC xenograft mouse model with minimal general toxicity. We concluded that MLN4924 induces apoptosis and cell cycle arrest, as well as activation of cell stress responses in human UC. These findings imply MLN4924 provides a novel strategy for the treatment of UC.

To evaluate the effect of different treatment plans for whole-pelvic irradiation on small-bowel volumes (SBVs) in patients with gynecologic malignancies, 40 patients were enrolled in this study. Computed tomography (CT) simulations were performed, and the small bowel of each patient was outlined manually. Treatment plans with equal-weighted (EW) and non-equal-weighted (NEW) (70% in bilateral directions) techniques of four-field and intensity-modulated radiation therapy (IMRT) were performed. The V10–V100 represented the volume (cm 3 ) at different levels of the prescribed doses (10–100%). The V10–V100 was compared among the different treatment planning techniques, and patients who were suitable for IMRT or NEW were identified. IMRT and NEW significantly reduced the V50–V100 and V40–V60 levels compared with EW, respectively. NEW caused a significant reduction in the V30–V60 levels in patients with a BMI ≥26 kg/m 2 . Patients with IMRT demonstrated lower V70–V100 levels compared with those with NEW. In patients with a BMI ≥26 kg/m 2 or an age ≥55 years, lower V20–V50 levels were noted using NEW compared with IMRT. Treatment planning with larger weighting in the bilateral directions in four-field radiotherapy reduces the low-dose SBV in patients with gynecologic malignancies, especially in those with a high BMI or the elderly. IMRT effectively reduces high-dose SBV, especially in patients with a low BMI.

Recent attention has focused on vitamin D insufficiency but few data exist on vitamin D status among pregnant minority youth.A screening study was undertaken in adolescents having prenatal blood samples drawn for other routine tests obtained during the second trimester (18+/-1.8 week gestation, n=44) or third trimester of pregnancy (28.4+/-2.1 week gestation, n=36). Serum 25- hydroxyvitamin D (25(OH)D) was measured and significant determinants of vitamin D insufficiency in this cohort were identified.Urban prenatal clinic.Eighty pregnant African American adolescents (or = 18 y of age).Vitamin D status, STDs, hemoglobin, season, birth weightSerum 25(OH)D in this group averaged 21.6+/-8 ng/mL (age 16.5+/-1.1 y, n=80), and did not significantly differ between the second (20.95+/-8.2 ng/mL, n=44) and third trimester cohorts (22.5+/-7.9 ng/mL, n=36). Vitamin D insufficiency (20 ng/mL) was evident in 46.25% and vitamin D deficiency (15 ng/mL) was evident in 21.25% of those studied. Significant predictors of suboptimal vitamin D status included sampling during the winter months (P=0.004), lower hemoglobin concentration (P=0.019), and higher second trimester leptin levels (P=0.018). Inverse associations between 25(OH)D and bacterial vaginosis were evident when controlled for season of sampling (P=0.02, n=80).Vitamin D insufficiency was prevalent among urban pregnant minority adolescents. Further studies are needed to address the impact of this finding on maternal and neonatal calcium homeostasis and bone health.

Although animal experiments have consistently shown a positive relationship between breast cancer and energy intake, evidence from human studies remains inconclusive. In the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort, 29,170 women, ages 55 to 75 years, who successfully completed a food frequency questionnaire (FFQ) at entry (1993-2001), were followed through 2007, and 1,319 incident breast cancers were ascertained (median time from FFQ completion to diagnosis, 4.4 years). Women in the highest quartile of energy intake, relative to the lowest, had modestly, but significantly, increased breast cancer risk [multivariate relative risk (RR), 1.21; 95% confidence interval (95% CI), 1.03-1.42; Ptrend = 0.03]. The inclusion of body mass index and physical activity in the model reduced risk slightly (RR, 1.18; 95% CI, 1.00-1.39; Ptrend = 0.07). However, in similar analyses using energy intake from a FFQ administered approximately five years after entry (27,428 women; 806 incident breast cancers; median time from FFQ completion to diagnosis, 2.7 years), women in the highest and lowest quartiles of energy intake had similar risk. When follow-up time after the first FFQ was divided into three 4-year periods, the multivariate RRs for high versus low energy intake increased from 1.21 to 1.37 to 1.55 with increasing time since dietary assessment. Although the divergent results for the two FFQs could be due to subtle questionnaire differences, our findings suggest a modest positive association between energy intake and postmenopausal breast cancer that strengthens with time since dietary assessment. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2842–50)

Consistent with a strong hormonal etiology, endometrial cancer is thought to be influenced by both obesity and physical activity. Although obesity has been consistently related to risk, associations with physical activity have been inconclusive. We examined relationships of activity patterns with endometrial cancer incidence in the NIH-AARP Diet and Health Study cohort, which included 109,621 women, ages 50-71, without cancer history, who in 1995-1996 completed a mailed baseline questionnaire capturing daily routine and vigorous (defined as any period of >or=20 min of activity at work or home causing increases in breathing, heart rate, or sweating) physical activity. A second questionnaire, completed by 70,351 women, in 1996-1997 collected additional physical activity information. State cancer registry linkage identified 1,052 primary incident endometrial cancers from baseline through December 31, 2003. In multivariate proportional hazards models, vigorous activity was inversely associated with endometrial cancer in a dose-response manner (p for trend = 0.02) (relative risk (RR) for >or=5 times/week vs. never/rarely = 0.77, 95% confidence interval (CI): 0.63-0.95); this association was more pronounced among overweight and obese women (body mass index >or=25; RR = 0.61, 95% CI: 0.47-0.79) than among lean women (body mass index

Ionizing radiation-associated breast cancer risk appears to be modified by timing of reproductive events such as age at radiation exposure, parity, age at first live birth, and age at menopause. However, potential breast cancer risk modification of low to moderate radiation dose by polymorphic estrogen metabolism-related gene variants has not been routinely investigated. We assessed breast cancer risk of 12 candidate variants in 12 genes involved in steroid metabolism, catabolism, binding, or receptor functions in a study of 859 cases and 1,083 controls within the US radiologic technologists (USRT) cohort. Using cumulative breast dose estimates from a detailed assessment of occupational and personal diagnostic ionizing radiation exposure, we investigated the joint effects of genotype on the risk of breast cancer. In multivariate analyses, we observed a significantly decreased risk of breast cancer associated with the CYP3A4 M445T minor allele (rs4986910, OR = 0.3; 95% CI 0.1-0.9). We found a borderline increased breast cancer risk with having both minor alleles of CYP1B1 V432L (rs1056836, CC vs. GG, OR = 1.2; 95% CI 0.9-1.6). Assuming a recessive model, the minor allele of CYP1B1 V432L significantly increased the dose-response relationship between personal diagnostic X-ray exposure and breast cancer risk, adjusted for cumulative occupational radiation dose (p (interaction) = 0.03) and had a similar joint effect for cumulative occupational radiation dose adjusted for personal diagnostic X-ray exposure (p (interaction) = 0.06). We found suggestive evidence that common variants in selected estrogen metabolizing genes may modify the association between ionizing radiation exposure and breast cancer risk.

Objective A history of diabetes has been fairly consistently related to a reduced prostate cancer risk, but previous investigations have not always addressed whether the relation with diabetes varies by prostate cancer aggressiveness or the association between diabetes and prostate cancer is modified by physical activity level and body mass, variables closely related to glucose metabolism. Methods We prospectively examined the diabetes–prostate cancer risk relationship among 33,088 men in the screening arm of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Results During 8.9 years follow-up, we ascertained 2,058 incident prostate cancer cases. Diabetes history was related to decreased risk of total prostate cancer (RR = 0.80, 95% CI = 0.68–0.95). The apparent protection afforded by diabetes was primarily due to the inverse relation with non-aggressive disease (i.e., the combination of low grade (Gleason sum

Biliary tract cancer, encompassing tumors of the gallbladder, extrahepatic bile ducts and ampulla of Vater, is a rare but highly fatal malignancy. Obesity and gallstones, both related to insulin resistance, are linked to an elevated risk of biliary cancer. The peroxisome proliferator-activated receptors (PPARs) and the retinoid X receptors (RXRs), expressed in adipose tissue, play a key role in the regulation of obesity-related insulin sensitivity, thus genetic variants of these two receptor genes may be related to biliary cancer and stones. We examined the associations of seven single-nucleotide polymorphisms in the PPAR-gamma, PPAR-delta, RXR-alpha, RXR-beta and INS genes with biliary cancer and stones in a population-based case-control study in Shanghai, China. We included 237 gallbladder, 127 extrahepatic bile duct and 47 ampulla of Vater cancer cases, 895 stone cases and 786 population controls. Relative to individuals with the RXR-beta C51T (rs2076310) CC genotype, those having the TT genotype had a 1.6-fold risk for bile duct cancer [odds ratio (OR) = 1.67; 95% confidence interval (CI) = 0.99-2.84], with a more pronounced association among men (OR = 2.30; 95% CI = 1.14-4.65; P interaction = 0.07). This marker was also associated with a higher risk of gallstones among subjects with a higher body mass index (BMI) (or=23 kg/m(2)) (OR = 1.80; 95% CI = 1.09-2.94), although the interaction with BMI was not statistically significant (P interaction = 0.28). No association was found between other variants and biliary cancers and stones. Results from this population-based study suggest that certain genetic variants involved in the regulation of obesity-related insulin sensitivity may increase susceptibility to bile duct cancer and gallstones.

BACKGROUND. Menopausal hormone therapy formulations for women without hysterectomy have included estrogen plus progestin for years, but endometrial cancer risks associated with the use of sequential and continuous estrogen-plus-progestin regimens remain unclear. METHODS. The National Institutes of Health-AARP Diet and Health Study included 73,211 women who were ages 50 years to 71 years at baseline and who completed 2 questionnaires (1995–1996 and 1996–1997). Linkage to state cancer registries and mortality indices identified 433 incident endometrial cancers through 2000. Using proportional hazards regression, the authors estimated relative risks (RRs) and 95% confidence intervals (95% CIs) relative to never-use of hormone therapy. RESULTS. In 51,312 women who never used hormones or only used estrogen-plus-progestin regimens at doses consistent with current practice, neither sequential estrogen plus progestin (daily estrogen plus progestin for 10–14 days per cycle: RR, 0.74; 95% CI, 0.39–1.40) nor continuous estrogen plus progestin (daily estrogen plus progestin for ≥20 days per cycle: RR, 0.80; 95% CI, 0.55–1.15) had any statistically significant association with endometrial cancer. Long durations (≥5 years) of sequential regimen use (RR, 0.79; 95% CI, 0.38–1.66) and of continuous regimen use (RR, 0.85; 95% CI, 0.53–1.36) were not associated with endometrial cancer. CONCLUSIONS. Confirmation that these estrogen-plus-progestin regimens neither increase nor decrease the risk of endometrial cancer could influence menopausal symptom management for women who are considering estrogen-plus-progestin therapy. Cancer 2007. Published 2007 by The American Cancer Society.

Background Although ecologic association and animal studies support a direct effect of dietary fat on the development of breast cancer, results of epidemiologic studies have been inconclusive. Methods We prospectively analyzed the association between fat consumption and the incidence of postmenopausal invasive breast cancer in the National Institutes of Health-AARP Diet and Health Study, a US cohort comprising 188,736 postmenopausal women who completed a 124-item food-frequency questionnaire in 1995-1996. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models with adjustment for energy and potential confounding factors. All statistical tests were two-sided. Results Over an average follow-up of 4.4 years, the cohort yielded 3501 cases of invasive breast cancer. The hazard ratio of breast cancer for the highest (median intake, 40.1% energy from total fat; 434 cases per 100,000 person-years) versus the lowest (median intake, 20.3% energy from total fat; 392 cases per 100,000 person-years) quintile of total fat intake was 1.11 (95% CI = 1.00 to 1.24; P(trend) = .017). The corresponding hazard ratio for a twofold increase in percent energy from total fat on the continuous scale was 1.15 (95% CI = 1.05 to 1.26). Positive associations were also found for subtypes of fat (hazard ratio for a twofold increase in percent energy from saturated fat = 1.13; 95% CI = 1.05 to 1.22; from monounsaturated fat, HR = 1.12; 95% CI = 1.03 to 1.21; from polyunsaturated fat, HR = 1.10, 95% CI = 1.01 to 1.20). Correction for measurement error in nutrient intakes, on the basis of a calibration substudy that used two 24-hour dietary recalls, strengthened the associations, yielding an estimated hazard ratio for total fat of 1.32 (95% CI = 1.11 to 1.58). Secondary analyses showed that associations between total, saturated, and monounsaturated fat intakes were confined to women who were not using menopausal hormone therapy at baseline. Conclusion In this large prospective cohort with a wide range of fat intake, dietary fat intake was directly associated with the risk of postmenopausal invasive breast cancer.

This study uses a national database to evaluate the incidence of inguinal hernia and associated risk factors of incarcerated hernia in children from birth to 15 years of age. The study selected children born from 1997 to 2005 from a randomly selected cohort of 1,000,000 from an insured population of 23 million. We regarded children that were classified with code 550 and hernia surgery in accordance to the International Classification of Diseases, 9th Revision, as having inguinal hernia. We used the 2 chi-square test and logistic regression modeling for statistical analyses. In total, 79,794 children (41,767 male and 38,027 female) were enrolled in the study. The cumulative incidence of inguinal hernia in males and females from birth to 15 years old were 6.62 and 0.74 %, respectively (p

Background Several epidemiologic studies suggest that higher folate intakes are associated with lower breast cancer risk, particularly in women with moderate alcohol consumption. Objective We investigated the association between dietary folate, alcohol consumption, and postmenopausal breast cancer in women from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort. Design Dietary data were collected at study enrollment between 1993 and 2001. Folate content was assigned on the basis of prefortification (ie, pre-1998) databases. Of the 25 400 women participants with a baseline age of 55-74 y and with complete dietary and multivitamin information, 691 developed breast cancer between September 1993 and May 2003. We used Cox proportional hazard models with age as the underlying time metric to generate hazard ratios (HRs) and 95% CIs. Results The adjusted HRs were 1.19 (95% CI: 1.01, 1.41; P for trend = 0.04) for women reporting supplemental folic acid intake >/=400 mug/d compared with subjects reporting no supplemental intake. Comparison of the highest with the lowest quintile gave adjusted HRs of 1.04 (95% CI: 0.83, 1.31; P for trend = 0.56) and 1.32 (95% CI: 1.04, 1.68; P for trend = 0.03) for food and total folate intake, respectively. Alcohol consumption was positively associated with breast cancer risk (highest compared with lowest quintile: HR = 1.37; 95% CI: 1.08, 1.76; P for trend = 0.02); the risk was greatest in women with lower total folate intake. Conclusions Our results do not support the hypothesis that high folate intake reduces breast cancer risk; instead, they suggest that a high intake, generally attributable to supplemental folic acid, may increase the risk in postmenopausal women. However, our results confirm previous studies showing positive associations between moderate alcohol consumption and breast cancer.

Energy restriction remains one of the most effective ways known to prevent breast cancer in animal models. However, energy intake has not been consistently associated with risk of breast cancer in humans. In a prospective study, we assessed whether energy intake, body size, and physical activity each independently influence breast cancer risk in postmenopausal women and estimated the joint effect of combinations of these individual factors. As part of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, 38,660 women, ages 55 to 74 years and recruited from 10 centers in the United States during 1993 to 2001, were randomized to the screening arm of the trial. At baseline, the women completed a self-administered questionnaire, including a food frequency questionnaire. During follow-up from 1993 to 2003, 764 incident breast cancer cases were ascertained. Women in the highest quartile of energy intake (≥2,084 kcal/d) compared with those in the lowest quartile (30 kg/m2 with

To describe maternal characteristics and birth outcomes in a group of pregnant minority adolescents and to characterize the impact of maternal age (15 years versus 15-17 years) on birth outcomes.A 10-year retrospective chart review was conducted in 1120 pregnant black adolescents (or =17 years of age) who had received prenatal care at an inner-city maternity clinic in Baltimore, Md.Pregnant black adolescents had a higher incidence of low birth weight infants, preterm delivery, and fetal death compared with normative data from the United States. Younger adolescents were more likely to have inadequate utilization of prenatal care (P.01). Older adolescents had a higher incidence of gonorrhea infections (P=.046), greater rates of self-reported substance abuse (P=.063), and a higher history of cigarette smoking (P.01). Low prepregnancy body mass index (BMI), inadequate weight gain, and poor prenatal care utilization were strong independent predictors of preterm birth (P.05). Low prepregnancy BMI, inadequate weight gain, female infant, and self-reported cigarette smoking history were significantly associated with decreased infant birth weight (P.05).Pregnant black adolescents had increased risks of adverse pregnancy outcomes. This population should be studied further to develop age-appropriate and population-specific interventions to improve birth outcomes.

Relationships between hemoglobin concentrations and birth outcomes have not been well characterized in African-American adolescents despite the fact that this group is at a higher risk of early childbearing. To address this issue, we characterized the prevalence of anemia and maternal factors associated with anemia in pregnant African-American adolescents. A retrospective medical chart review was undertaken of 918 adolescents who had received prenatal care at an inner-city maternity clinic between 1990 and 2000. Multiple log-linear regression analyses were used to address relationships between hemoglobin and adverse birth outcomes. The prevalence of anemia during the third trimester averaged 57-66% and was substantially higher than typically reported in adolescent and adult women. Multiparity, inadequate prenatal care, low prepregnancy BMI, history of self-reported cigarette use and infection with sexually transmitted diseases were significantly associated with lower hemoglobin during pregnancy. Adolescents with pre-eclampsia had higher hemoglobin (P0.01). Compared with the reference group (106-120 g/L), high hemoglobin (120 g/L) during the second and third trimester significantly increased the risk of low birth weight (risk ratio (RR) = 3.11; [CI] 1.35, 7.13), and in the second-trimester cohort only, high hemoglobin concentrations increased the risk of preterm delivery (RR = 2.33; [CI] 1.07, 5.05). A U-shaped distribution between hemoglobin concentration and adverse birth outcomes was found in the third-trimester cohort when the reference range was decreased to 96-105 g/L to adjust for potentially lower hemoglobin concentrations among the African-American population. Our results suggest that additional medical attention may be warranted in pregnant African-American adolescents with hemoglobin concentrations ofor=95 g/L or120 g/L.

A capacitive micropressure sensor with readout circuits on a single chip is fabricated using commercial 0.35μm complementary metal oxide semiconductor (CMOS) process and post‐processing. The main break through feature of the chip is the positioning of its readout circuits under the pressure sensor, allowing the chip to be smaller. Post‐processing included anisotropic dry etching and wet etching to remove the sacrificial layer, and the use of plasma enhanced chemical vapor deposition (PECVD) of nitride to seal the etching holes on the pressure sensor. The readout circuit is divided into analog and digital parts, with the digital part being an alternate coupled RS flip‐flop with four inverters that sharpened the output wave. The analog part employed switched capacitor methodology. The pressure sensor contained an 8×8 sensing cells array, and the total area of the pressure sensor chip is 2mm×2mm.

To investigate the influence of different dietary fats on lipids and anti-cardiolipin antibody levels, autoimmune NZB/W F1 mice were fed on diets containing 200 g dietary fat as palm oil, lard–soyabean oil (1:1, w/w), soyabean oil, rapeseed oil or fish oil/kg. In addition, each dietary fat group was divided into an early-feeding group with feeding from 2 months of age, and a late-feeding group with feeding from 5 months of age. Serum levels of triacylglycerol, phospholipid, cholesterol and anti-cardiolipin antibody were measured at regular intervals, and mice were killed at the age of 7 months for analysis of hepatic lipid and fatty acids. The results showed that hepatic triacylglycerol and cholesterol contents were lower in mice fed on fish oil than in those fed on palm oil. In contrast, hepatic phospholipid content was higher in mice of the fish oil group than in those of the other four dietary fat groups. Composition profiles for both hepatic and renal oleic acid (18:1n-9), linoleic acid (18:2n-6) and eicosapentaenoic acid (20:5n-3) were similar to those of the dietary fats in mice of both early-feeding and late-feeding groups. Fish oil intake decreased arachidonic acid (20:4n-6) concentration in kidney tissue but not in liver tissue. Serum triacylglycerol, cholesterol and phospholipid levels were lower in mice fed on fish oil than in those fed on palm oil. Immunoglobulin (Ig) M anti-cardiolipin antibody was lower for the fish oil group than for the other groups. The IgG anti-cardiolipin antibody level was significantly lower in mice fed on fish oil compared with that of the palm oil group only in the early-feeding group. There was a positive correlation between serum IgM anti-cardiolipin antibody and phospholipid levels (early-feeding group r 0·902, P < 0·05; late-feeding group r 0·894, P < 0·05). These findings suggest dietary fish oil may affect both lipid levels and anti-cardiolipin antibody, contributing to alleviation of the autoimmune process in autoimmune-prone NZB×NZW F1 mice.

Background. The cutaneous manifestations of human enterovirus (HEV) infection are usually limited, such as hand-foot-mouth disease. By comparison, Stevens-Johnson syndrome (SJS) is a life-threatening severe cutaneous adverse reaction (SCAR), mainly caused by drugs. During the HEV outbreaks in 2010–2012 in Taiwan, we identified 21 patients who developed widespread blistering mucocutaneous reactions without any suspected drug causality. Methods. We screened possible pathogen(s) for detecting human herpes virus (HHV1–HHV7), HEV, or Mycoplasma pneumoniae infections using throat swab virus cultures, real-time PCR, DNA sequencing, immunochemistry and electron microscopy analyses. Results. Coxsackievirus A6 (CVA6) DNA was identified in the blistering skin lesions in 6 of 21 patients. Cytotoxic T lymphocytes and natural killer cells expressing granulysin predominantly infiltrated into the skin lesions, sharing the histopathological features with SJS. Intact CVA6 viral particles were identified in the blister fluids and skin lesions by electron microscopy. The phylogenetic analysis of the viral genome showed the CVA6 DNA sequence sharing higher similarity (97.6%–98.1%) to CVA6 strains reported from Finland at 2008. Conclusions. This study identifies a new variant of CVA6 as the causative agent for severe mucocutaneous blistering reactions mimicking SCAR. An awareness of this unusual presentation of HEV infection is needed in the epidemic area.

Geographic gradients in breast cancer incidence and mortality suggest that vitamin D may reduce risk. The enzyme 25-hydroxyvitamin D 24-hydroxylase (CYP24A1), which degrades the active form of vitamin D, and the vitamin D receptor (VDR) are both found in breast tissue. We investigated six polymorphisms in CYP24A1 and two in the VDR gene in association with breast cancer risk.We conducted a case-control study within the nationwide U.S. Radiologic Technologists cohort, including 845 controls and 484 incident breast cancer cases. Associations of polymorphic variants and ecologic and personal measures of sun exposure with breast cancer risk were assessed using unconditional logistic regression.Two polymorphisms in CYP24A1 were associated with increased breast cancer risk (rs34043203, P(trend)=0.03; rs2762934, P(trend)=0.005) and one with reduced breast cancer risk (rs1570669, P(trend)=0.048). Risk was inversely associated with minor alleles for the VDR Bsm1 polymorphism (rs1544410, P(trend)=0.05) but not Fok1 (rs2228570). Sunlight measures were not associated with breast cancer risk, however significant interactions between time outdoors in the teen years and three unlinked genotypes were found for VDR (rs1544410, rs2228570) and CYP24A1 (rs1570669).In this nation-wide breast cancer case-control study, we found that the vitamin D pathway was involved in disease etiology and our results further suggest that reduced cancer risk, in association with sunlight, may depend on timing of exposure and genetic background. These findings merit further investigation.

Studies from the 1990s through mid-2000s report variable decreases in upper gastrointestinal (UGI) complications and differ regarding changes in lower gastrointestinal (LGI) complications. We determined incidence and case fatality of hospitalizations for GI complications in the United States over the past decade.We used a national inpatient database to calculate yearly projections from 2001-2009 for incidence and case fatality of hospitalizations with primary discharge diagnoses of UGI and LGI complications (bleeding, perforation, and obstruction) and of undefined GI bleeding.Age/sex-adjusted incidence of GI complications decreased non-significantly from 236.1 to 223.7/100,000 population from 2001-2009. Components were UGI complications (85.0 to 66.0/100,000), LGI complications (100.3 to 104.4/100,000), and undefined bleeding (50.8 to 53.3/100,000). Decreases were seen in UGI bleeding (78.4 to 60.6/100,000), peptic ulcer bleeding (48.7 to 32.1/100,000), LGI bleeding (41.8 to 35.7/100,000), and colonic diverticular bleeding (30.4 to 23.9/100,000), whereas LGI obstruction increased (55.0 to 66.0/100,000). Age/sex-adjusted case fatality decreased from 3.78 to 2.70%. 2009 case fatality rates were 2.45% for UGI bleeding, 3.00% for undefined bleeding, 1.47% for LGI bleeding, 2.30% for LGI obstruction, 10.7% for UGI perforation, and 16.0% for LGI perforation. Case fatality increased with age, but was 3.54% in patients75 years with bleeding or obstruction.Hospitalizations for UGI complications are decreasing in the United States owing to a decrease in UGI bleeding. LGI complications are relatively stable, with a decrease in LGI bleeding and a larger increase in LGI obstruction. Case fatality owing to bleeding or obstruction is low, increasing with age but remaining5% even in the elderly.

We examined the associations between 21 single nucleotide polymorphisms (SNPs) of eight lipid metabolism genes and lipid levels in a Chinese population. This study was conducted as part of a population-based study in China with 799 randomly selected healthy residents who provided fasting blood and an in-person interview. Associations between variants and mean lipid levels were examined using a test of trend and least squares mean test in a general linear model. Four SNPs were associated with lipid levels: LDLR rs1003723 was associated with total cholesterol (P-trend = 0.002) and LDL (P-trend = 0.01), LDLR rs6413503 was associated with total cholesterol (P-trend = 0.05), APOB rs1367117 was associated with apoB (P-trend = 0.02), and ABCB11 rs49550 was associated with total cholesterol (P-trend = 0.01), triglycerides (P-trend = 0.01), and apoA (P-trend = 0.01). We found statistically significant effects on lipid levels for LDLR rs6413503 among those with high dairy intake, LPL rs263 among those with high allium vegetable intake, and APOE rs440446 among those with high red meat intake. We identified new associations between SNPs and lipid levels in Chinese previously found in Caucasians. These findings provide insight into the role of lipid metabolism genes, as well as the mechanisms by which these genes may be linked with disease.

Background Multidisciplinary attempts to understand the etiology of breast cancer are expanding to increasingly include new potential markers of disease risk. Those efforts may have maximal scientific and practical influence if new findings are placed in context of the well-understood lifestyle and reproductive risk factors or existing risk prediction models for breast cancer. We therefore evaluated known risk factors for breast cancer in a cancer screening trial that does not have breast cancer as a study endpoint but is large enough to provide numerous analytic opportunities for breast cancer. Methods We evaluated risk factors for breast cancer (N = 2085) among 70,575 women who were randomized in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Using Poisson regression, we calculated adjusted relative risks [RRs, with 95% confidence intervals (CIs)] for lifestyle and reproductive factors during an average of 5 years of follow-up from date of randomization. Results As expected, increasing age, nulliparity, positive family history of breast cancer, and use of menopausal hormone therapy were positively associated with breast cancer. Later age at menarche (16 years or older vs. < 12: RR = 0.81, 95% CI, 0.65–1.02) or menopause (55 years or older vs. < 45: RR = 1.29, 95% CI, 1.03–1.62) were less strongly associated with breast cancer than was expected. There were weak positive associations between taller height and heavier weight, and only severe obesity [body mass index (BMI; kg/m2) 35 or more vs. 18.5–24.9: RR = 1.21, 95% CI, 1.02–1.43] was statistically significantly associated with breast cancer. Conclusion The ongoing PLCO trial offers continued opportunities for new breast cancer investigations, but these analyses suggest that the associations between breast cancer and age at menarche, age at menopause, and obesity might be changing as the underlying demographics of these factors change. Clinical Trials Registration http://www.clinicaltrials.gov, NCT00002540.

Experimental and epidemiologic studies suggest that vitamin D metabolites (1,25-dihydroxyvitamin D [1,25(OH)2D] and its precursor 25-hydroxyvitamin D [25(OH)D]) may reduce breast cancer risk. We examined subsequent breast cancer risk related to serum levels of these metabolites. In a cohort of women ages 55 to 74 years, who donated blood at baseline (1993-2001) in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we identified 1,005 incident breast cancer cases during follow-up through 2005 (mean time between blood draw and diagnosis, 3.9 years). Noncases (n = 1,005) were frequency matched to the cases based on age and year of entry. Sample weights that accounted for unequal probabilities of selecting cases and noncases were applied to make inferences that reflected the entire Prostate, Lung, Colorectal, and Ovarian cohort. Using Cox proportional hazards modeling, we computed breast cancer relative risks (RR) and 95% confidence intervals (95% CI) by quintile for each metabolite. The RR of breast cancer for the highest quintile of 25(OH)D concentration versus the lowest was 1.04 (95% CI, 0.75-1.45; Ptrend = 0.81). Similarly, the breast cancer RR for the highest quintile of 1,25(OH)2D compared with the lowest was 1.23 (95% CI, 0.91-1.68; Ptrend = 0.14). Excluding the first 2 years of follow-up did not materially alter these estimates. There was also no evidence of inverse risk in older women (≥60 years) versus younger women (

Biliary tract cancers, encompassing the gallbladder, extrahepatic bile ducts and ampulla of Vater, are rare but highly fatal malignancies. Gallstones, the predominant risk factor for biliary cancers, are linked with hyperlipidemia. As part of a population-based case-control study conducted in Shanghai, China, we examined the associations of serum lipid levels with biliary stones and cancers. We included 460 biliary cancer cases (264 gallbladder, 141 extrahepatic bile duct, and 55 ampulla of Vater), 981 biliary stone cases and 858 healthy individuals randomly selected from the population. Participants completed an in-person interview and gave overnight fasting blood samples. Participants in the highest quintile of triglycerides (>/=160 mg/dl) had a 1.4-fold risk of biliary stones (95% CI = 1.1-1.9), a 1.9-fold risk of gallbladder cancer (95% CI = 1.3-2.8), and a 4.8-fold risk of bile duct cancer (95% CI = 2.8-8.1), compared to the reference group (third quintile: 90-124 mg/dl). Participants in the lowest quintile of high-density lipoprotein (HDL) (

BACKGROUND Vitamin D has been hypothesized to reduce cancer mortality through its effects on incidence and/or survival. Epidemiologic studies of the association of 25-hydroxyvitamin D [25(OH)D] and the risk of cancer, however, have been largely limited to incident cancers at a few sites. METHODS A total of 16,818 participants in the Third National Health and Nutrition Examination Survey who were 17 years or older at enrollment were followed from 1988-1994 through 2000. Levels of serum 25(OH)D were measured at baseline by radioimmunoassay. Cox proportional hazards regression models were used to examine the relationship between serum 25(OH)D levels and total cancer mortality (in the entire population or according to race/ethnicity, sex, age, and retinol status) and mortality from specific cancers. Because serum was collected in the south in cooler months and the north in warmer months, we examined associations by collection season. All statistical tests were two-sided. RESULTS We identified 536 cancer deaths in 146,578 person-years. Total cancer mortality was unrelated to baseline vitamin D status in the entire population, men, women, non-Hispanic whites, non-Hispanic blacks, Mexican Americans, and in persons younger than 70 or 70 years or older. We found no interaction between vitamin D and season or vitamin D and serum retinol. Colorectal cancer mortality was inversely related to serum 25(OH)D level, with levels 80 nmol/L or higher associated with a 72% risk reduction (95% confidence interval = 32% to 89%) compared with lower than 50 nmol/L, P(trend) = .02. CONCLUSIONS Our results do not support an association between 25(OH)D and total cancer mortality, although there was an inverse relationship between 25(OH)D levels and colorectal cancer mortality.

Obesity and menopausal estrogen therapy are established risk factors for endometrial cancer. However, the joint effects of obesity and menopausal hormone therapy on endometrial cancer risk are incompletely understood. We addressed this issue in a cohort of 103,882 women ages 50 to 71 years at baseline in 1995 to 1996. During a median of 4.6 years, which contributed to a total of 455,304 person-years of follow-up through 2000, 677 cases of endometrial cancer were ascertained. Both baseline body mass index (BMI) and adult weight gain were associated with increased endometrial cancer risk. The multivariate relative risk (RR) comparing obese with normal weight women (BMI >30 versus

BACKGROUND. Adiposity has been linked inconsistently with prostate cancer, and few studies have evaluated whether such associations vary by disease aggressiveness. METHODS. The authors prospectively examined body mass index (BMI) and adult weight change in relation to prostate cancer incidence and mortality in 287,760 men ages 50 years to 71 years at enrollment (1995–1996) in the National Institutes of Health-AARP Diet and Health Study. At baseline, participants completed questionnaires regarding height, weight, and cancer screening practices, including digital rectal examinations and prostate-specific antigen tests. Cox regression analysis was used to calculate relative risks (RR) and 95% confidence intervals (95% CIs). RESULTS. In total, 9986 incident prostate cancers were identified during 5 years of follow-up, and 173 prostate cancer deaths were ascertained during 6 years of follow-up. In multivariate models, higher baseline BMI was associated with significantly reduced total prostate cancer incidence, largely because of the relationship with localized tumors (for men in the highest BMI category [≥40 kg/m2] vs men in the lowest BMI category [

A history of diabetes has been hypothesized to decrease prostate cancer risk, but studies have not always considered confounding or effect modification by dietary or lifestyle factors.We examined the association between diabetes history and subsequent prostate cancer risk in 328,316 men enrolled in the NIH-AARP Diet and Health Study. Participants were ages 50-71 years and without a prostate cancer diagnosis at baseline in 1995. A prior history of physician-diagnosed diabetes was assessed using a self-administered mailed questionnaire. Cases of prostate cancer were ascertained by matching the cohort to state cancer registries. Multivariable relative risks (RR) and 95% confidence intervals (CI) of prostate cancer were estimated using Cox regression.During 5 years and 1,432,676 person-years of follow-up, 11,193 prostate cancer cases were ascertained. The age-adjusted and multivariable RRs of prostate cancer comparing men with diabetes to those without diabetes were 0.69 (95% CI=0.64, 0.74) and 0.71 (95% CI=0.66, 0.76), respectively, indicating no important confounding. The inverse association between diabetes and prostate cancer was particularly strong among men in the highest category of routine physical activity at work or home (RR=0.41; 95% CI=0.23, 0.74; p value for test of interaction = 0.03). Findings were similar for organ-confined and advanced prostate cancer.Results from this large prospective study suggest that a history of diabetes is associated with a decreased risk of prostate cancer. The relationship strengthened with high levels of routine physical activity. Because increased physical activity is associated with lower circulating levels of insulin and testosterone, our findings support a role of hypoinsulinemia and low androgenicity linking diabetes to decreased prostate cancer risk.

Pregnant teenagers are at risk of delivering low-birth-weight infants because of the nutritional demands of their own growth and because they are often poor, members of a minority, have a low educational level, and receive suboptimal prenatal care. For this reason, they often are advised to gain weight up to the upper level of the recommended range. On the other hand, black women in particular are at increased risk of postpartum weight retention, leading to being overweight or obese and increasing the risk of chronic disease. Thus, the weight gain that would be ideal for both pregnant black teenagers and their infants is unknown. In this retrospective study, Nielson and colleagues reviewed the prenatal record of 815 blacks no more than 17 years of age who received prenatal care at an inner-city maternity clinic in the years 1990 through 2000. Participants were classified on the basis of the body mass index (BMI) as being underweight (less than 19.8 kg/m 2 ), average weight (19.8-26.0 kg/m 2 ), overweight (26.1-29.0 kg/m 2 ), or obese (more than 29 kg/m 2 ) and their pregnancy outcomes were analyzed. Of 815 subjects, 82.5% were primiparous, 41% were uninsured, and their BMIs ranged from 14.8 to 49 kg/m 2 . The mean gestational age at delivery was 38.8 weeks, and the mean birth weight was 3062 g. Thirty-seven percent of infants weighed less than 3000 g, and 16% were classified as small for gestational age. Across all BMI categories, women who gained in the lower half of the recommended weight had significantly larger infants and fewer infants weighing

Anemia is prevalent among pregnant adolescents, but few data exist on biochemical indicators of iron status in this group. We hypothesized that among an at-risk population of African-American, pregnant adolescents, the degree of iron depletion and deficiency would be marked, and that iron deficiency anemia would comprise the majority of the observed anemia. To examine this, blood samples were collected from 80 girls (or =18 y old) attending an inner city maternity clinic, 23 of whom were studied longitudinally in the 2nd and 3rd trimesters depending on contact at the clinic. Sample sizes for the biomarkers varied according to the blood volume available at the time the assays were completed. Descriptive statistics were applied to characterize iron status, and multivariate regression and logistic analyses were used to identify significant determinants of iron status. Depleted iron stores (ferritinor = 15 microg/L) were indicated for 25% (n = 44) and 61% (n = 59) of adolescents during the 2nd and 3rd trimesters, respectively. Serum folate (39.3 +/- 15.4 nmol/L, n = 60), RBC folate (2378 +/- 971 nmol/L, n = 60), and serum vitamin B-12 concentrations (313 +/- 163 pmol/L, n = 60) were within normal ranges. Adolescents with serum transferrin receptor:serum ferritin ratios (R:F ratio)300 during the 2nd trimester were 12.5 times (95% CI 2.83, 55.25) more likely to be classified with iron deficiency anemia during the 3rd trimester (P = 0.0002) than those with lower ratios. Estimates of body iron were lower in those tested after wk 26 of gestation (P0.0001), and reserves were depleted in 5.0% vs. 31.3% of the 2nd (n = 40) and 3rd (n = 48) trimester cohorts, respectively. In conclusion, iron-deficiency anemia was prevalent among these pregnant minority adolescents. Targeted screening and interventions to improve diet and compliance with prenatal iron supplementation are warranted for this at-risk group.

Background: Pregnant adolescents may compete with their developing fetuses for the nutrients required for optimal bone mineralization. Objective: The objective of this study was to determine the effect in pregnant African American adolescents of maternal dairy intake at entry into prenatal care on fetal femur development between 20 and 34 wk of gestation. Design: A 10-y retrospective chart review was carried out in 1120 pregnant African American adolescents (≤ 17 y of age) who had received care at an inner-city maternity clinic between 1990 and 2000. Generalized multiple linear regression models were used to address significant determinants of fetal femur length after control for gestational age, biparietal diameter, maternal age and height, and prepregnancy body mass index. Dairy intake was estimated at entry into prenatal care on the basis of 24-h dietary recall and a food-frequency questionnaire. Data from 350 subjects, for whom data on all variables were available, were included in the model. Results: In these pregnant adolescents with a mean (± SD) age of 15.9 ± 1.1 y (range: 12.7‐17.9 y), dairy intake had a significant positive effect on fetal femur growth after adjustment for gestational age, biparietal diameter, maternal age and height, and prepregnancy body mass index (P = 0.001, R 2 = 0.97). Fetal femur length was significantly lower in the lowest dairy-intake group ( 3 servings/d), and a dose-response relation was suggested in the intermediate dairy-intake group (2‐3 servings/d; P = 0.089). Conclusion: These data suggest that consumption of < 2 servings of dairy products/d by pregnant adolescents may negatively affect fetal bone development by limiting the amount of calcium provided to the fetus. Am J Clin Nutr 2003;77:1248‐54.

A capacitive micropressure sensor with readout circuits on a single chip is fabricated using commercial 0.35micrometers CMOS process technology and post-processing. The main break through feature of the chip is the positioning of its readout circuits under the pressure sensor, allowing the chip to be smaller. Post-processing included anisotropic dry etching and wet etching to remove the sacrificial layer, and the use of PECVD nitride to seal the etching holes of the pressure sensor. The sacrificial layer was the metal 3 layer of the standard 0.35 micrometers CMOS process. In addition, the readout circuit is divided into analog and digital parts, with the digital part being an alternate coupled RS flip- flop with four inverters that sharpened the output wave. Moreover, the analog part is employed switched capacitor methodology. The pressure sensor contained an 8 X 8 sensing cells array, and the total area of the pressure sensor chip is 2mmx2 mm. In addition to illustrating the design and fabrication of the capacitive pressure sensor, this investigation demonstrates the simulation and testing results of the readout circuit.